ALBERT — All Library Books, journals and Electronic Records Telegrafenberg

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Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases (2021)

Kapoor, Manav ; Chao, Michael J. ; Johnson, Emma C. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5071. Published 2021 Aug 20. doi: 10.1038/s41467-021-25392-y.

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Publication Date: 2021-08-20

Description: Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Ultrahigh-speed graphene-based optical coherent receiver (2021)

Wang, Yilun ; Li, Xiang ; Jiang, Zhibin ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5076. Published 2021 Aug 20. doi: 10.1038/s41467-021-25374-0.

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Publication Date: 2021-08-20

Description: Graphene-based photodetectors have attracted significant attention for high-speed optical communication due to their large bandwidth, compact footprint, and compatibility with silicon-based photonics platform. Large-bandwidth silicon-based optical coherent receivers are crucial elements for large-capacity optical communication networks with advanced modulation formats. Here, we propose and experimentally demonstrate an integrated optical coherent receiver based on a 90-degree optical hybrid and graphene-on-plasmonic slot waveguide photodetectors, featuring a compact footprint and a large bandwidth far exceeding 67 GHz. Combined with the balanced detection, 90 Gbit/s binary phase-shift keying signal is received with a promoted signal-to-noise ratio. Moreover, receptions of 200 Gbit/s quadrature phase-shift keying and 240 Gbit/s 16 quadrature amplitude modulation signals on a single-polarization carrier are realized with a low additional power consumption below 14 fJ/bit. This graphene-based optical coherent receiver will promise potential applications in 400-Gigabit Ethernet and 800-Gigabit Ethernet technology, paving another route for future high-speed coherent optical communication networks.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Gold-like activity copper-like selectivity of heteroatomic transition metal carbides for electrocatalytic carbon dioxide reduction reaction (2021)

Esmaeilirad, Mohammadreza ; Baskin, Artem ; Kondori, Alireza ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5067. Published 2021 Aug 20. doi: 10.1038/s41467-021-25295-y.

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Publication Date: 2021-08-20

Description: An overarching challenge of the electrochemical carbon dioxide reduction reaction (eCO2RR) is finding an earth-abundant, highly active catalyst that selectively produces hydrocarbons at relatively low overpotentials. Here, we report the eCO2RR performance of two-dimensional transition metal carbide class of materials. Our results indicate a maximum methane (CH4) current density of −421.63 mA/cm2 and a CH4 faradic efficiency of 82.7% ± 2% for di-tungsten carbide (W2C) nanoflakes in a hybrid electrolyte of 3 M potassium hydroxide and 2 M choline-chloride. Powered by a triple junction photovoltaic cell, we demonstrate a flow electrolyzer that uses humidified CO2 to produce CH4 in a 700-h process under one sun illumination with a CO2RR energy efficiency of about 62.3% and a solar-to-fuel efficiency of 20.7%. Density functional theory calculations reveal that dissociation of water, chemisorption of CO2 and cleavage of the C-O bond—the most energy consuming elementary steps in other catalysts such as copper—become nearly spontaneous at the W2C surface. This results in instantaneous formation of adsorbed CO—an important reaction intermediate—and an unlimited source of protons near the tungsten surface sites that are the main reasons for the observed superior activity, selectivity, and small potential.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans (2021)

Wang, Feng ; Dai, Yuxi ; Zhu, Xufeng ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5073. Published 2021 Aug 20. doi: 10.1038/s41467-021-25398-6.

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Publication Date: 2021-08-20

Description: The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair (2021)

Jamsen, Joonas A. ; Sassa, Akira ; Perera, Lalith ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5055. Published 2021 Aug 20. doi: 10.1038/s41467-021-24486-x.

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Publication Date: 2021-08-20

Description: Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers (2021)

Mao, Ninghui ; Zhang, Zeda ; Lee, Young Sun ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5053. Published 2021 Aug 20. doi: 10.1038/s41467-021-25341-9.

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Publication Date: 2021-08-20

Description: Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Detection and characterization of lung cancer using cell-free DNA fragmentomes (2021)

Mathios, Dimitrios ; Johansen, Jakob Sidenius ; Cristiano, Stephen ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5060. Published 2021 Aug 20. doi: 10.1038/s41467-021-24994-w.

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Publication Date: 2021-08-20

Description: Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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WS2 moiré superlattices derived from mechanical flexibility for hydrogen evolution reaction (2021)

Xie, Lingbin ; Wang, Longlu ; Zhao, Weiwei ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5070. Published 2021 Aug 20. doi: 10.1038/s41467-021-25381-1.

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Publication Date: 2021-08-20

Description: The discovery of moiré superlattices (MSLs) opened an era in the research of ‘twistronics’. Engineering MSLs and realizing unique emergent properties are key challenges. Herein, we demonstrate an effective synthetic strategy to fabricate MSLs based on mechanical flexibility of WS2 nanobelts by a facile one-step hydrothermal method. Unlike previous MSLs typically created through stacking monolayers together with complicated method, WS2 MSLs reported here could be obtained directly during synthesis of nanobelts driven by the mechanical instability. Emergent properties are found including superior conductivity, special superaerophobicity and superhydrophilicity, and strongly enhanced electro-catalytic activity when we apply ‘twistronics’ to the field of catalytic hydrogen production. Theoretical calculations show that such excellent catalytic performance could be attributed to a closer to thermoneutral hydrogen adsorption free energy value of twisted bilayers active sites. Our findings provide an exciting opportunity to design advanced WS2 catalysts through moiré superlattice engineering based on mechanical flexibility.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Achieving high strength and ductility in ODS-W alloy by employing oxide@W core-shell nanopowder as precursor (2021)

Dong, Zhi ; Ma, Zongqing ; Yu, Liming ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5052. Published 2021 Aug 20. doi: 10.1038/s41467-021-25283-2.

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Publication Date: 2021-08-20

Description: With excellent creep resistance, good high-temperature microstructural stability and good irradiation resistance, oxide dispersion strengthened (ODS) alloys are a class of important alloys that are promising for high-temperature applications. However, plagued by a nerve-wracking fact that the oxide particles tend to aggregate at grain boundary of metal matrix, their improvement effect on the mechanical properties of metal matrix tends to be limited. In this work, we employ a unique in-house synthesized oxide@W core-shell nanopowder as precursor to prepare W-based ODS alloy. After low-temperature sintering and high-energy-rate forging, high-density oxide nanoparticles are dispersed homogeneously within W grains in the prepared alloy, accompanying with the intergranular oxide particles completely disappearing. As a result, our prepared alloy achieves a great enhancement of strength and ductility at room temperature. Our strategy using core-shell powder as precursor to prepare high-performance ODS alloy has potential to be applied to other dispersion-strengthened alloy systems.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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UbiD domain dynamics underpins aromatic decarboxylation (2021)

Marshall, Stephen A. ; Payne, Karl A. P. ; Fisher, Karl ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5065. Published 2021 Aug 20. doi: 10.1038/s41467-021-25278-z.

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Publication Date: 2021-08-20

Description: The widespread UbiD enzyme family utilises the prFMN cofactor to achieve reversible decarboxylation of acrylic and (hetero)aromatic compounds. The reaction with acrylic compounds based on reversible 1,3-dipolar cycloaddition between substrate and prFMN occurs within the confines of the active site. In contrast, during aromatic acid decarboxylation, substantial rearrangement of the substrate aromatic moiety associated with covalent catalysis presents a molecular dynamic challenge. Here we determine the crystal structures of the multi-subunit vanillic acid decarboxylase VdcCD. We demonstrate that the small VdcD subunit acts as an allosteric activator of the UbiD-like VdcC. Comparison of distinct VdcCD structures reveals domain motion of the prFMN-binding domain directly affects active site architecture. Docking of substrate and prFMN-adduct species reveals active site reorganisation coupled to domain motion supports rearrangement of the substrate aromatic moiety. Together with kinetic solvent viscosity effects, this establishes prFMN covalent catalysis of aromatic (de)carboxylation is afforded by UbiD dynamics.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4 (2021)

Diener, Johanna ; Baggiolini, Arianna ; Pernebrink, Mattias ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5056. Published 2021 Aug 20. doi: 10.1038/s41467-021-25326-8.

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Publication Date: 2021-08-20

Description: Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a−/− melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes (2021)

Rui, Jinxiu ; Deng, Songyan ; Perdigoto, Ana Luisa ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5074. Published 2021 Aug 20. doi: 10.1038/s41467-021-25367-z.

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Publication Date: 2021-08-20

Description: β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor (2021)

Wang, Yue ; Guo, Shimeng ; Zhuang, Youwen ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5064. Published 2021 Aug 20. doi: 10.1038/s41467-021-25364-2.

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Publication Date: 2021-08-20

Description: Ghrelin, also called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Ferromagnetic soft catheter robots for minimally invasive bioprinting (2021)

Zhou, Cheng ; Yang, Youzhou ; Wang, Jiaxin ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5072. Published 2021 Aug 20. doi: 10.1038/s41467-021-25386-w.

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Publication Date: 2021-08-20

Description: In vivo bioprinting has recently emerged as a direct fabrication technique to create artificial tissues and medical devices on target sites within the body, enabling advanced clinical strategies. However, existing in vivo bioprinting methods are often limited to applications near the skin or require open surgery for printing on internal organs. Here, we report a ferromagnetic soft catheter robot (FSCR) system capable of in situ computer-controlled bioprinting in a minimally invasive manner based on magnetic actuation. The FSCR is designed by dispersing ferromagnetic particles in a fiber-reinforced polymer matrix. This design results in stable ink extrusion and allows for printing various materials with different rheological properties and functionalities. A superimposed magnetic field drives the FSCR to achieve digitally controlled printing with high accuracy. We demonstrate printing multiple patterns on planar surfaces, and considering the non-planar surface of natural organs, we then develop an in situ printing strategy for curved surfaces and demonstrate minimally invasive in vivo bioprinting of hydrogels in a rat model. Our catheter robot will permit intelligent and minimally invasive bio-fabrication.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter (2021)

Plenge, Per ; Yang, Dongxue ; Salomon, Kristine ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5063. Published 2021 Aug 20. doi: 10.1038/s41467-021-25363-3.

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Publication Date: 2021-08-20

Description: Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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O-GlcNAcylated p53 in the liver modulates hepatic glucose production (2021)

Gonzalez-Rellan, Maria J. ; Fondevila, Marcos F. ; Fernandez, Uxia ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5068. Published 2021 Aug 20. doi: 10.1038/s41467-021-25390-0.

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Publication Date: 2021-08-20

Description: p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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The regulatory impact of RNA-binding proteins on microRNA targeting (2021)

Kim, Sukjun ; Kim, Soyoung ; Chang, Hee Ryung ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5057. Published 2021 Aug 20. doi: 10.1038/s41467-021-25078-5.

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Publication Date: 2021-08-20

Description: Argonaute is the primary mediator of metazoan miRNA targeting (MT). Among the currently identified 〉1,500 human RNA-binding proteins (RBPs), there are only a handful of RBPs known to enhance MT and several others reported to suppress MT, leaving the global impact of RBPs on MT elusive. In this study, we have systematically analyzed transcriptome-wide binding sites for 150 human RBPs and evaluated the quantitative effect of individual RBPs on MT efficacy. In contrast to previous studies, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers rather than suppressors, by making the local secondary structure of the target site accessible to Argonaute. Our findings illuminate the unappreciated regulatory impact of human RBPs on MT, and as these RBPs may play key roles in the gene regulatory network governed by metazoan miRNAs, MT should be understood in the context of co-regulating RBPs.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Bowls, vases and goblets—the microcrockery of polymer and nanocomposite morphology revealed by two-photon optical tomography (2021)

Yang, Shu-Gui ; Wei, Zhen-Zhen ; Cseh, Liliana ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5054. Published 2021 Aug 20. doi: 10.1038/s41467-021-25297-w.

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Publication Date: 2021-08-20

Description: On the 〉1 µm scale the morphology of semicrystalline plastics like polyethylene or Nylon features spherulites, “shish-kebabs”, cylinddrites and other crystalline aggregates which strongly affect mechanical and other material properties. Current imaging techniques give only a 2D picture of these objects. Here we show how they can be visualized in 3D using fluorescent labels and confocal microscopy. As a result, we see spherulites in 3D, both in neat polymers and their nanocomposites, and observe how unevenly nanoparticles and other additives are distributed in the material. Images of i-polypropylene and biodegradable poly(lactic acid) reveal previously unsuspected morphologies such as “vases” and “goblets”, nonspherical “spherulites” and, unexpectedly, “shish-kebabs” grown from quiescent melt. Also surprisingly, in nanocomposite sheets spherulite nucleation is seen to be copied from one surface to another, mediated by crystallization-induced pressure drop and local melt-flow. These first results reveal unfamiliar modes of self-assembly in familiar plastics and open fresh perspectives on polymer microstructure.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer (2021)

Kalogirou, C. ; Linxweiler, J. ; Schmucker, P. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5066. Published 2021 Aug 20. doi: 10.1038/s41467-021-25325-9.

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Publication Date: 2021-08-20

Description: Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Posterior subthalamic nucleus (PSTh) mediates innate fear-associated hypothermia in mice (2021)

Liu, Can ; Lee, Chia-Ying ; Asher, Greg ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2648. Published 2021 May 11. doi: 10.1038/s41467-021-22914-6.

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Publication Date: 2021-05-11

Description: The neural mechanisms of fear-associated thermoregulation remain unclear. Innate fear odor 2-methyl-2-thiazoline (2MT) elicits rapid hypothermia and elevated tail temperature, indicative of vasodilation-induced heat dissipation, in wild-type mice, but not in mice lacking Trpa1–the chemosensor for 2MT. Here we report that Trpa1−/− mice show diminished 2MT-evoked c-fos expression in the posterior subthalamic nucleus (PSTh), external lateral parabrachial subnucleus (PBel) and nucleus of the solitary tract (NTS). Whereas tetanus toxin light chain-mediated inactivation of NTS-projecting PSTh neurons suppress, optogenetic activation of direct PSTh-rostral NTS pathway induces hypothermia and tail vasodilation. Furthermore, selective opto-stimulation of 2MT-activated, PSTh-projecting PBel neurons by capturing activated neuronal ensembles (CANE) causes hypothermia. Conversely, chemogenetic suppression of vGlut2+ neurons in PBel or PSTh, or PSTh-projecting PBel neurons attenuates 2MT-evoked hypothermia and tail vasodilation. These studies identify PSTh as a major thermoregulatory hub that connects PBel to NTS to mediate 2MT-evoked innate fear-associated hypothermia and tail vasodilation.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Superconductivity up to 243 K in the yttrium-hydrogen system under high pressure (2021)

Kong, Panpan ; Minkov, Vasily S. ; Kuzovnikov, Mikhail A. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5075. Published 2021 Aug 20. doi: 10.1038/s41467-021-25372-2.

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Publication Date: 2021-08-20

Description: The discovery of superconducting H3S with a critical temperature Tc∼200 K opened a door to room temperature superconductivity and stimulated further extensive studies of hydrogen-rich compounds stabilized by high pressure. Here, we report a comprehensive study of the yttrium-hydrogen system with the highest predicted Tcs among binary compounds and discuss the contradictions between different theoretical calculations and experimental data. We synthesized yttrium hydrides with the compositions of YH3, YH4, YH6 and YH9 in a diamond anvil cell and studied their crystal structures, electrical and magnetic transport properties, and isotopic effects. We found superconductivity in the Im-3m YH6 and P63/mmc YH9 phases with maximal Tcs of ∼220 K at 183 GPa and ∼243 K at 201 GPa, respectively. Fm-3m YH10 with the highest predicted Tc 〉 300 K was not observed in our experiments, and instead, YH9 was found to be the hydrogen-richest yttrium hydride in the studied pressure and temperature range up to record 410 GPa and 2250 K.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes (2021)

Shoaib, Muhammad ; Chen, Qinming ; Shi, Xiangyan ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 4800. Published 2021 Aug 20. doi: 10.1038/s41467-021-25051-2.

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Publication Date: 2021-08-20

Description: Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Gut microbiome-mediated metabolism effects on immunity in rural and urban African populations (2021)

Stražar, Martin ; Temba, Godfrey S. ; Vlamakis, Hera ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 4845. Published 2021 Aug 11. doi: 10.1038/s41467-021-25213-2.

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Publication Date: 2021-08-11

Description: The human gut microbiota is increasingly recognized as an important factor in modulating innate and adaptive immunity through release of ligands and metabolites that translocate into circulation. Urbanizing African populations harbor large intestinal diversity due to a range of lifestyles, providing the necessary variation to gauge immunomodulatory factors. Here, we uncover a gradient of intestinal microbial compositions from rural through urban Tanzanian, towards European samples, manifested both in relative abundance and genomic variation observed in stool metagenomics. The rural population shows increased Bacteroidetes, led by Prevotella copri, but also presence of fungi. Measured ex vivo cytokine responses were significantly associated with 34 immunomodulatory microbes, which have a larger impact on circulating metabolites than non-significant microbes. Pathway effects on cytokines, notably TNF-α and IFN-γ, differential metabolome analysis and enzyme copy number enrichment converge on histidine and arginine metabolism as potential immunomodulatory pathways mediated by Bifidobacterium longum and Akkermansia muciniphila.

Electronic ISSN: 2041-1723

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Elastocapillary cleaning of twisted bilayer graphene interfaces (2021)

Hou, Yuan ; Dai, Zhaohe ; Zhang, Shuai ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 5069. Published 2021 Aug 20. doi: 10.1038/s41467-021-25302-2.

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Publication Date: 2021-08-20

Description: Although layered van der Waals (vdW) materials involve vast interface areas that are often subject to contamination, vdW interactions between layers may squeeze interfacial contaminants into nanopockets. More intriguingly, those nanopockets could spontaneously coalesce into larger ones, which are easier to be squeezed out the atomic channels. Such unusual phenomena have been thought of as an Ostwald ripening process that is driven by the capillarity of the confined liquid. The underlying mechanism, however, is unclear as the crucial role played by the sheet’s elasticity has not been previously appreciated. Here, we demonstrate the coalescence of separated nanopockets and propose a cleaning mechanism in which both elastic and capillary forces are at play. We elucidate this mechanism in terms of control of the nanopocket morphology and the coalescence of nanopockets via a mechanical stretch. Besides, we demonstrate that bilayer graphene interfaces excel in self-renewal phenomena.

Electronic ISSN: 2041-1723

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Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors (2021)

Valero, Cristina ; Lee, Mark ; Hoen, Douglas ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 729. Published 2021 Feb 01. doi: 10.1038/s41467-021-20935-9.

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Publication Date: 2021-02-01

Description: Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P

Electronic ISSN: 2041-1723

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Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging (2021)

Ziegler, Dorian V. ; Vindrieux, David ; Goehrig, Delphine ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 720. Published 2021 Feb 01. doi: 10.1038/s41467-021-20993-z.

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Publication Date: 2021-02-01

Description: Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

Electronic ISSN: 2041-1723

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Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism (2021)

Horne, Christopher R. ; Venugopal, Hariprasad ; Panjikar, Santosh ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1988. Published 2021 Mar 31. doi: 10.1038/s41467-021-22253-6.

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Publication Date: 2021-03-31

Description: Bacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. The Escherichia coli GntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Single-particle cryo-electron microscopy structures reveal the DNA-binding domain is reorganized to engage DNA, while three dimers assemble in close proximity across the (GGTATA)3-repeat operator. Such an interaction allows cooperative protein-protein interactions between NanR dimers via their N-terminal extensions. The effector, N-acetylneuraminate, binds NanR and attenuates the NanR-DNA interaction. The crystal structure of NanR in complex with N-acetylneuraminate reveals a domain rearrangement upon N-acetylneuraminate binding to lock NanR in a conformation that weakens DNA binding. Our data provide a molecular basis for the regulation of bacterial sialic acid metabolism.

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Multicentric tracking of multiple agents by anterior cingulate cortex during pursuit and evasion (2021)

Yoo, Seng Bum Michael ; Tu, Jiaxin Cindy ; Hayden, Benjamin Yost

Springer Nature

In: Nature Communications. 2021; 12(1): 1985. Published 2021 Mar 31. doi: 10.1038/s41467-021-22195-z.

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Publication Date: 2021-03-31

Description: Successful pursuit and evasion require rapid and precise coordination of navigation with adaptive motor control. We hypothesize that the dorsal anterior cingulate cortex (dACC), which communicates bidirectionally with both the hippocampal complex and premotor/motor areas, would serve a mapping role in this process. We recorded responses of dACC ensembles in two macaques performing a joystick-controlled continuous pursuit/evasion task. We find that dACC carries two sets of signals, (1) world-centric variables that together form a representation of the position and velocity of all relevant agents (self, prey, and predator) in the virtual world, and (2) avatar-centric variables, i.e. self-prey distance and angle. Both sets of variables are multiplexed within an overlapping set of neurons. Our results suggest that dACC may contribute to pursuit and evasion by computing and continuously updating a multicentric representation of the unfolding task state, and support the hypothesis that it plays a high-level abstract role in the control of behavior.

Electronic ISSN: 2041-1723

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Identification and analysis of splicing quantitative trait loci across multiple tissues in the human genome (2021)

Garrido-Martín, Diego ; Borsari, Beatrice ; Calvo, Miquel ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 727. Published 2021 Feb 01. doi: 10.1038/s41467-020-20578-2.

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Publication Date: 2021-02-01

Description: Alternative splicing (AS) is a fundamental step in eukaryotic mRNA biogenesis. Here, we develop an efficient and reproducible pipeline for the discovery of genetic variants that affect AS (splicing QTLs, sQTLs). We use it to analyze the GTEx dataset, generating a comprehensive catalog of sQTLs in the human genome. Downstream analysis of this catalog provides insight into the mechanisms underlying splicing regulation. We report that a core set of sQTLs is shared across multiple tissues. sQTLs often target the global splicing pattern of genes, rather than individual splicing events. Many also affect the expression of the same or other genes, uncovering regulatory loci that act through different mechanisms. sQTLs tend to be located in post-transcriptionally spliced introns, which would function as hotspots for splicing regulation. While many variants affect splicing patterns by altering the sequence of splice sites, many more modify the binding sites of RNA-binding proteins. Genetic variants affecting splicing can have a stronger phenotypic impact than those affecting gene expression.

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A glucose meter interface for point-of-care gene circuit-based diagnostics (2021)

Amalfitano, Evan ; Karlikow, Margot ; Norouzi, Masoud ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 724. Published 2021 Feb 01. doi: 10.1038/s41467-020-20639-6.

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Publication Date: 2021-02-01

Description: Recent advances in cell-free synthetic biology have given rise to gene circuit-based sensors with the potential to provide decentralized and low-cost molecular diagnostics. However, it remains a challenge to deliver this sensing capacity into the hands of users in a practical manner. Here, we leverage the glucose meter, one of the most widely available point-of-care sensing devices, to serve as a universal reader for these decentralized diagnostics. We describe a molecular translator that can convert the activation of conventional gene circuit-based sensors into a glucose output that can be read by off-the-shelf glucose meters. We show the development of new glucogenic reporter systems, multiplexed reporter outputs and detection of nucleic acid targets down to the low attomolar range. Using this glucose-meter interface, we demonstrate the detection of a small-molecule analyte; sample-to-result diagnostics for typhoid, paratyphoid A/B; and show the potential for pandemic response with nucleic acid sensors for SARS-CoV-2.

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Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer (2021)

McGuire, Jeremy J. ; Frieling, Jeremy S. ; Lo, Chen Hao ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 723. Published 2021 Feb 01. doi: 10.1038/s41467-021-20962-6.

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Publication Date: 2021-02-01

Description: Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.

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PopDel identifies medium-size deletions simultaneously in tens of thousands of genomes (2021)

Niehus, Sebastian ; Jónsson, Hákon ; Schönberger, Janina ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 730. Published 2021 Feb 01. doi: 10.1038/s41467-020-20850-5.

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Publication Date: 2021-02-01

Description: Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel’s running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.

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Palladium-catalyzed allene synthesis enabled by β-hydrogen elimination from sp2-carbon (2021)

Zhang, Ge ; Song, Yi-Kang ; Zhang, Fang ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 728. Published 2021 Feb 01. doi: 10.1038/s41467-020-20740-w.

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Publication Date: 2021-02-01

Description: The rational design based on a deep understanding of the present reaction mechanism is an important, viable approach to discover new organic transformations. β-Hydrogen elimination from palladium complexes is a fundamental reaction in palladium catalysis. Normally, the eliminated β-hydrogen has to be attached to a sp3-carbon. We envision that the hydrogen elimination from sp2-carbon is possible by using thoroughly designed reaction systems, which may offer a new strategy for the preparation of allenes. Here, we describe a palladium-catalyzed cross-coupling of 2,2-diarylvinyl bromides and diazo compounds, where a β-vinylic hydrogen elimination from allylic palladium intermediate is proposed to be the key step. Both aryl diazo carbonyl compounds and N-tosylhydrazones are competent carbene precursors in this reaction. The reaction mechanism is explored by control experiments, KIE studies and DFT calculations.

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Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism (2021)

Yu, Ruofan ; Cao, Xiaohua ; Sun, Luyang ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1981. Published 2021 Mar 31. doi: 10.1038/s41467-021-22257-2.

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Publication Date: 2021-03-31

Description: Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses. Using the high-throughput SEquencing-Based Yeast replicative Lifespan screen method and the yeast knockout collection, we demonstrate that the HDA complex, a class-II histone deacetylase (HDAC), regulates aging through its target of acetylated H3K18 at storage carbohydrate genes. We find that, in addition to longer lifespan, disruption of HDA results in resistance to DNA damage and osmotic stresses. We show that these effects are due to increased promoter H3K18 acetylation and transcriptional activation in the trehalose metabolic pathway in the absence of HDA. Furthermore, we determine that the longevity effect of HDA is independent of the Cyc8-Tup1 repressor complex known to interact with HDA and coordinate transcriptional repression. Silencing the HDA homologs in C. elegans and Drosophila increases their lifespan and delays aging-associated physical declines in adult flies. Hence, we demonstrate that this HDAC controls an evolutionarily conserved longevity pathway.

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Statistics of pathogenic bacteria in the search of host cells (2021)

Otte, Stefan ; Ipiña, Emiliano Perez ; Pontier-Bres, Rodolphe ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1990. Published 2021 Mar 31. doi: 10.1038/s41467-021-22156-6.

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Publication Date: 2021-03-31

Description: A crucial phase in the infection process, which remains poorly understood, is the localization of suitable host cells by bacteria. It is often assumed that chemotaxis plays a key role during this phase. Here, we report a quantitative study on how Salmonella Typhimurium search for T84 human colonic epithelial cells. Combining time-lapse microscopy and mathematical modeling, we show that bacteria can be described as chiral active particles with strong active speed fluctuations, which are of biological, as opposed to thermal, origin. We observe that there exists a giant range of inter-individual variability of the bacterial exploring capacity. Furthermore, we find Salmonella Typhimurium does not exhibit biased motion towards the cells and show that the search time statistics is consistent with a random search strategy. Our results indicate that in vitro localization of host cells, and also cell infection, are random processes, not involving chemotaxis, that strongly depend on bacterial motility parameters.

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Single trial neuronal activity dynamics of attentional intensity in monkey visual area V4 (2021)

Ghosh, Supriya ; Maunsell, John H. R.

Springer Nature

In: Nature Communications. 2021; 12(1): 2003. Published 2021 Mar 31. doi: 10.1038/s41467-021-22281-2.

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Publication Date: 2021-03-31

Description: Understanding how activity of visual neurons represents distinct components of attention and their dynamics that account for improved visual performance remains elusive because single-unit experiments have not isolated the intensive aspect of attention from attentional selectivity. We isolated attentional intensity and its single trial dynamics as determined by spatially non-selective attentional performance in an orientation discrimination task while recording from neurons in monkey visual area V4. We found that attentional intensity is a distinct cognitive signal that can be distinguished from spatial selectivity, reward expectations and motor actions. V4 spiking on single trials encodes a combination of sensory and cognitive signals on different time scales. Attentional intensity and the detection of behaviorally relevant sensory signals are well represented, but immediate reward expectation and behavioral choices are poorly represented in V4 spiking. These results provide a detailed representation of perceptual and cognitive signals in V4 that are crucial for attentional performance.

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In vivo activation of pH-responsive oxidase-like graphitic nanozymes for selective killing of Helicobacter pylori (2021)

Zhang, Lufeng ; Zhang, Liang ; Deng, Hui ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2002. Published 2021 Mar 31. doi: 10.1038/s41467-021-22286-x.

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Publication Date: 2021-03-31

Description: Helicobacter pylori infection is a major etiological factor in gastric diseases. However, clinical antibiotic therapy for H. pylori is limited by continuously decreased therapeutic efficacy and side effects to symbiotic bacteria. Herein, we develop an in vivo activatable pH-responsive graphitic nanozyme, PtCo@Graphene (PtCo@G), for selective treatment of H. pylori. Such nanozymes can resist gastric acid corrosion, exhibit oxidase-like activity to stably generate reactive oxygen species only in acidic gastric milieu and demonstrate superior selective bactericidal property. C18-PEGn-Benzeneboronic acid molecules are modified on PtCo@G, improving its targeting capability. Under acidic gastric pH, graphitic nanozymes show notable bactericidal activity toward H. pylori, while no bacterial killing is observed under intestinal conditions. In mouse model, high antibacterial capability toward H. pylori and negligible side effects toward normal tissues and symbiotic bacteria are achieved. Graphitic nanozyme displays the desired enzyme-like activities at corresponding physiological sites and may address critical issues in clinical treatment of H. pylori infections.

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Simultaneous readout of multiple FRET pairs using photochromism (2021)

Roebroek, Thijs ; Vandenberg, Wim ; Sipieter, François ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2005. Published 2021 Mar 31. doi: 10.1038/s41467-021-22043-0.

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Publication Date: 2021-03-31

Description: Förster resonant energy transfer (FRET) is a powerful mechanism to probe associations in situ. Simultaneously performing more than one FRET measurement can be challenging due to the spectral bandwidth required for the donor and acceptor fluorophores. We present an approach to distinguish overlapping FRET pairs based on the photochromism of the donor fluorophores, even if the involved fluorophores display essentially identical absorption and emission spectra. We develop the theory underlying this method and validate our approach using numerical simulations. To apply our system, we develop rsAKARev, a photochromic biosensor for cAMP-dependent protein kinase (PKA), and combine it with the spectrally-identical biosensor EKARev, a reporter for extracellular signal-regulated kinase (ERK) activity, to deliver simultaneous readout of both activities in the same cell. We further perform multiplexed PKA, ERK, and calcium measurements by including a third, spectrally-shifted biosensor. Our work demonstrates that exploiting donor photochromism in FRET can be a powerful approach to simultaneously read out multiple associations within living cells.

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Long-range optofluidic control with plasmon heating (2021)

Ciraulo, B. ; Garcia-Guirado, J. ; de Miguel, I. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2001. Published 2021 Mar 31. doi: 10.1038/s41467-021-22280-3.

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Publication Date: 2021-03-31

Description: Using light to manipulate fluids has been a long-sought-after goal for lab-on-a-chip applications to address the size mismatch between bulky external fluid controllers and microfluidic devices. Yet, this goal has remained elusive due to the complexity of thermally driven fluid dynamic phenomena, and the lack of approaches that allow comprehensive multiscale and multiparameter studies. Here, we report an innovative optofluidic platform that fulfills this need by combining digital holographic microscopy with state-of-the-art thermoplasmonics, allowing us to identify the different contributions from thermophoresis, thermo-osmosis, convection, and radiation pressure. In our experiments, we demonstrate that a local thermal perturbation at the microscale can lead to mm-scale changes in both the particle and fluid dynamics, thus achieving long-range transport. Furthermore, thanks to a comprehensive parameter study involving sample geometry, temperature increase, light fluence, and size of the heat source, we showcase an integrated and reconfigurable all-optical control strategy for microfluidic devices, thereby opening new frontiers in fluid actuation technology.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Emitting long-distance spiral airborne sound using low-profile planar acoustic antenna (2021)

Gao, Shuxiang ; Li, Yunbo ; Ma, Chengrong ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2006. Published 2021 Mar 31. doi: 10.1038/s41467-021-22325-7.

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Publication Date: 2021-03-31

Description: Recent years have witnessed a rapidly growing interest in exploring the use of spiral sound carrying artificial orbital angular momentum (OAM), toward establishing a spiral-wave-based technology that is significantly more efficient in energy or information delivering than the ordinary plane wave technology. A major bottleneck of advancing this technology is the efficient excitation of far-field spiral waves in free space, which is a must in exploring the use of spiral waves for long-distance information transmission and particle manipulation. Here, we report a low-profile planar acoustic antenna to modulate wavefronts emitted from a near-field point source and achieve far-field spiral airborne sound carrying OAM. Using the holographic interferogram as a 2D modulated artificial acoustic impedance metasurface, we show the efficient conversion from the surface wave into the propagating spiral shape beam both numerically and experimentally. The vortex fields with spiral phases originate from the complex inter-modal interactions between cylindrical surface waves and a spatially-modulated impedance boundary condition. This antenna can open new routes to highly integrated spiral sound emitters that are critical for practical acoustic functional devices.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response (2021)

Georgopoulou, Dimitra ; , ; Callari, Maurizio ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1998. Published 2021 Mar 31. doi: 10.1038/s41467-021-22303-z.

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Publication Date: 2021-03-31

Description: The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Author Correction: Determinants of genome-wide distribution and evolution of uORFs in eukaryotes (2021)

Zhang, Hong ; Wang, Yirong ; Wu, Xinkai ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2101. Published 2021 Mar 31. doi: 10.1038/s41467-021-22435-2.

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Publication Date: 2021-03-31

Description: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22435-2

Electronic ISSN: 2041-1723

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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus (2021)

Buang, Norzawani ; Tapeng, Lunnathaya ; Gray, Victor ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1980. Published 2021 Mar 31. doi: 10.1038/s41467-021-22312-y.

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Publication Date: 2021-03-31

Description: The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Connecting structure to function with the recovery of over 1000 high-quality metagenome-assembled genomes from activated sludge using long-read sequencing (2021)

Singleton, Caitlin M. ; Petriglieri, Francesca ; Kristensen, Jannie M. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2009. Published 2021 Mar 31. doi: 10.1038/s41467-021-22203-2.

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Publication Date: 2021-03-31

Description: Microorganisms play crucial roles in water recycling, pollution removal and resource recovery in the wastewater industry. The structure of these microbial communities is increasingly understood based on 16S rRNA amplicon sequencing data. However, such data cannot be linked to functional potential in the absence of high-quality metagenome-assembled genomes (MAGs) for nearly all species. Here, we use long-read and short-read sequencing to recover 1083 high-quality MAGs, including 57 closed circular genomes, from 23 Danish full-scale wastewater treatment plants. The MAGs account for ~30% of the community based on relative abundance, and meet the stringent MIMAG high-quality draft requirements including full-length rRNA genes. We use the information provided by these MAGs in combination with 〉13 years of 16S rRNA amplicon sequencing data, as well as Raman microspectroscopy and fluorescence in situ hybridisation, to uncover abundant undescribed lineages belonging to important functional groups.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Sulfate formation is dominated by manganese-catalyzed oxidation of SO2 on aerosol surfaces during haze events (2021)

Wang, Weigang ; Liu, Mingyuan ; Wang, Tiantian ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1993. Published 2021 Mar 31. doi: 10.1038/s41467-021-22091-6.

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Publication Date: 2021-03-31

Description: The formation mechanism of aerosol sulfate during wintertime haze events in China is still largely unknown. As companions, SO2 and transition metals are mainly emitted from coal combustion. Here, we argue that the transition metal-catalyzed oxidation of SO2 on aerosol surfaces could be the dominant sulfate formation pathway and investigate this hypothesis by integrating chamber experiments, numerical simulations and in-field observations. Our analysis shows that the contribution of the manganese-catalyzed oxidation of SO2 on aerosol surfaces is approximately one to two orders of magnitude larger than previously known routes, and contributes 69.2% ± 5.0% of the particulate sulfur production during haze events. This formation pathway could explain the missing source of sulfate and improve the understanding of atmospheric chemistry and climate change.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Magnetic domains and domain wall pinning in atomically thin CrBr3 revealed by nanoscale imaging (2021)

Sun, Qi-Chao ; Song, Tiancheng ; Anderson, Eric ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1989. Published 2021 Mar 31. doi: 10.1038/s41467-021-22239-4.

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Publication Date: 2021-03-31

Description: The emergence of atomically thin van der Waals magnets provides a new platform for the studies of two-dimensional magnetism and its applications. However, the widely used measurement methods in recent studies cannot provide quantitative information of the magnetization nor achieve nanoscale spatial resolution. These capabilities are essential to explore the rich properties of magnetic domains and spin textures. Here, we employ cryogenic scanning magnetometry using a single-electron spin of a nitrogen-vacancy center in a diamond probe to unambiguously prove the existence of magnetic domains and study their dynamics in atomically thin CrBr3. By controlling the magnetic domain evolution as a function of magnetic field, we find that the pinning effect is a dominant coercivity mechanism and determine the magnetization of a CrBr3 bilayer to be about 26 Bohr magnetons per square nanometer. The high spatial resolution of this technique enables imaging of magnetic domains and allows to locate the sites of defects that pin the domain walls and nucleate the reverse domains. Our work highlights scanning nitrogen-vacancy center magnetometry as a quantitative probe to explore nanoscale features in two-dimensional magnets.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Two-timescale response of a large Antarctic ice shelf to climate change (2021)

Naughten, Kaitlin A. ; De Rydt, Jan ; Rosier, Sebastian H. R. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1991. Published 2021 Mar 31. doi: 10.1038/s41467-021-22259-0.

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Publication Date: 2021-03-31

Description: A potentially irreversible threshold in Antarctic ice shelf melting would be crossed if the ocean cavity beneath the large Filchner–Ronne Ice Shelf were to become flooded with warm water from the deep ocean. Previous studies have identified this possibility, but there is great uncertainty as to how easily it could occur. Here, we show, using a coupled ice sheet-ocean model forced by climate change scenarios, that any increase in ice shelf melting is likely to be preceded by an extended period of reduced melting. Climate change weakens the circulation beneath the ice shelf, leading to colder water and reduced melting. Warm water begins to intrude into the cavity when global mean surface temperatures rise by approximately 7 °C above pre-industrial, which is unlikely to occur this century. However, this result should not be considered evidence that the region is unconditionally stable. Unless global temperatures plateau, increased melting will eventually prevail.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Harnessing machine learning to guide phylogenetic-tree search algorithms (2021)

Azouri, Dana ; Abadi, Shiran ; Mansour, Yishay ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1983. Published 2021 Mar 31. doi: 10.1038/s41467-021-22073-8.

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Publication Date: 2021-03-31

Description: Inferring a phylogenetic tree is a fundamental challenge in evolutionary studies. Current paradigms for phylogenetic tree reconstruction rely on performing costly likelihood optimizations. With the aim of making tree inference feasible for problems involving more than a handful of sequences, inference under the maximum-likelihood paradigm integrates heuristic approaches to evaluate only a subset of all potential trees. Consequently, existing methods suffer from the known tradeoff between accuracy and running time. In this proof-of-concept study, we train a machine-learning algorithm over an extensive cohort of empirical data to predict the neighboring trees that increase the likelihood, without actually computing their likelihood. This provides means to safely discard a large set of the search space, thus potentially accelerating heuristic tree searches without losing accuracy. Our analyses suggest that machine learning can guide tree-search methodologies towards the most promising candidate trees.

Electronic ISSN: 2041-1723

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Bacterial cyclic diguanylate signaling networks sense temperature (2021)

Almblad, Henrik ; Randall, Trevor E. ; Liu, Fanny ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1986. Published 2021 Mar 31. doi: 10.1038/s41467-021-22176-2.

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Publication Date: 2021-03-31

Description: Many bacteria use the second messenger cyclic diguanylate (c-di-GMP) to control motility, biofilm production and virulence. Here, we identify a thermosensory diguanylate cyclase (TdcA) that modulates temperature-dependent motility, biofilm development and virulence in the opportunistic pathogen Pseudomonas aeruginosa. TdcA synthesizes c-di-GMP with catalytic rates that increase more than a hundred-fold over a ten-degree Celsius change. Analyses using protein chimeras indicate that heat-sensing is mediated by a thermosensitive Per-Arnt-SIM (PAS) domain. TdcA homologs are widespread in sequence databases, and a distantly related, heterologously expressed homolog from the Betaproteobacteria order Gallionellales also displayed thermosensitive diguanylate cyclase activity. We propose, therefore, that thermotransduction is a conserved function of c-di-GMP signaling networks, and that thermosensitive catalysis of a second messenger constitutes a mechanism for thermal sensing in bacteria.

Electronic ISSN: 2041-1723

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Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms (2021)

Johnson, Thomas A. ; Paakinaho, Ville ; Kim, Sohyoung ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1987. Published 2021 Mar 31. doi: 10.1038/s41467-021-22234-9.

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Publication Date: 2021-03-31

Description: A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Unusual solute segregation phenomenon in coherent twin boundaries (2021)

He, Cong ; Li, Zhiqiao ; Chen, Houwen ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 722. Published 2021 Feb 01. doi: 10.1038/s41467-021-21104-8.

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Publication Date: 2021-02-01

Description: Interface segregation of solute atoms has a profound effect on properties of engineering alloys. The occurrence of solute segregation in coherent twin boundaries (CTBs) in Mg alloys is commonly considered to be induced by atomic size effect where solute atoms larger than Mg take extension sites and those smaller ones take compression sites in CTBs. Here we report an unusual solute segregation phenomenon in a group of Mg alloys—solute atoms larger than Mg unexpectedly segregate to compression sites of {10$$overline 1$$ 1 ¯ 1} fully coherent twin boundary and do not segregate to the extension or compression site of {10$$overline 1$$ 1 ¯ 2} fully coherent twin boundary. We propose that such segregation is dominated by chemical bonding (coordination and solute electronic configuration) rather than elastic strain minimization. We further demonstrate that the chemical bonding factor can also predict the solute segregation phenomena reported previously. Our findings advance the atomic-level understanding of the role of electronic structure in solute segregation in fully coherent twin boundaries, and more broadly grain boundaries, in Mg alloys. They are likely to provide insights into interface boundaries in other metals and alloys of different structures.

Electronic ISSN: 2041-1723

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Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease (2021)

Roe, James M. ; , ; Vidal-Piñeiro, Didac ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 721. Published 2021 Feb 01. doi: 10.1038/s41467-021-21057-y.

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Publication Date: 2021-02-01

Description: Aging and Alzheimer’s disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it is unknown whether continuous age- and AD-related cortical degradation alters cortical asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order cortical regions exhibiting pronounced asymmetry at age ~20 also show progressive asymmetry-loss across the adult lifespan. Hence, accelerated thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This organizational principle showed high consistency across cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Asymmetry-change was further accelerated in AD. Results suggest a system-wide dedifferentiation of the adaptive asymmetric organization of heteromodal cortex in aging and AD.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Market-oriented job skill valuation with cooperative composition neural network (2021)

Sun, Ying ; Zhuang, Fuzhen ; Zhu, Hengshu ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1992. Published 2021 Mar 31. doi: 10.1038/s41467-021-22215-y.

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Publication Date: 2021-03-31

Description: The value assessment of job skills is important for companies to select and retain the right talent. However, there are few quantitative ways available for this assessment. Therefore, we propose a data-driven solution to assess skill value from a market-oriented perspective. Specifically, we formulate the task of job skill value assessment as a Salary-Skill Value Composition Problem, where each job position is regarded as the composition of a set of required skills attached with the contextual information of jobs, and the job salary is assumed to be jointly influenced by the context-aware value of these skills. Then, we propose an enhanced neural network with cooperative structure, namely Salary-Skill Composition Network (SSCN), to separate the job skills and measure their value based on the massive job postings. Experiments show that SSCN can not only assign meaningful value to job skills, but also outperforms benchmark models for job salary prediction.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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90% yield production of polymer nano-memristor for in-memory computing (2021)

Zhang, Bin ; Chen, Weilin ; Zeng, Jianmin ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1984. Published 2021 Mar 31. doi: 10.1038/s41467-021-22243-8.

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Publication Date: 2021-03-31

Description: Polymer memristors with light weight and mechanical flexibility are preeminent candidates for low-power edge computing paradigms. However, the structural inhomogeneity of most polymers usually leads to random resistive switching characteristics, which lowers the production yield and reliability of nanoscale devices. In this contribution, we report that by adopting the two-dimensional conjugation strategy, a record high 90% production yield of polymer memristors has been achieved with miniaturization and low power potentials. By constructing coplanar macromolecules with 2D conjugated thiophene derivatives to enhance the π–π stacking and crystallinity of the thin film, homogeneous switching takes place across the entire polymer layer, with fast responses in 32 ns, D2D variation down to 3.16% ~ 8.29%, production yield approaching 90%, and scalability into 100 nm scale with tiny power consumption of ~ 10−15 J/bit. The polymer memristor array is capable of acting as both the arithmetic-logic element and multiply-accumulate accelerator for neuromorphic computing tasks.

Electronic ISSN: 2041-1723

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Intratumoral immunotherapy using platelet-cloaked nanoparticles enhances antitumor immunity in solid tumors (2021)

Bahmani, Baharak ; Gong, Hua ; Luk, Brian T. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1999. Published 2021 Mar 31. doi: 10.1038/s41467-021-22311-z.

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Publication Date: 2021-03-31

Description: Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities.

Electronic ISSN: 2041-1723

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Sub-diffractional cavity modes of terahertz hyperbolic phonon polaritons in tin oxide (2021)

Feres, Flávio H. ; Mayer, Rafael A. ; Wehmeier, Lukas ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1995. Published 2021 Mar 31. doi: 10.1038/s41467-021-22209-w.

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Publication Date: 2021-03-31

Description: Hyperbolic phonon polaritons have recently attracted considerable attention in nanophotonics mostly due to their intrinsic strong electromagnetic field confinement, ultraslow polariton group velocities, and long lifetimes. Here we introduce tin oxide (SnO2) nanobelts as a photonic platform for the transport of surface and volume phonon polaritons in the mid- to far-infrared frequency range. This report brings a comprehensive description of the polaritonic properties of SnO2 as a nanometer-sized dielectric and also as an engineered material in the form of a waveguide. By combining accelerator-based IR-THz sources (synchrotron and free-electron laser) with s-SNOM, we employed nanoscale far-infrared hyper-spectral-imaging to uncover a Fabry–Perot cavity mechanism in SnO2 nanobelts via direct detection of phonon-polariton standing waves. Our experimental findings are accurately supported by notable convergence between theory and numerical simulations. Thus, the SnO2 is confirmed as a natural hyperbolic material with unique photonic properties essential for future applications involving subdiffractional light traffic and detection in the far-infrared range.

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Green synthesis of olefin-linked covalent organic frameworks for hydrogen fuel cell applications (2021)

Wang, Zhifang ; Yang, Yi ; Zhao, Zhengfeng ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1982. Published 2021 Mar 31. doi: 10.1038/s41467-021-22288-9.

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Publication Date: 2021-03-31

Description: Green synthesis of crystalline porous materials for energy-related applications is of great significance but very challenging. Here, we create a green strategy to fabricate a highly crystalline olefin-linked pyrazine-based covalent organic framework (COF) with high robustness and porosity under solvent-free conditions. The abundant nitrogen sites, high hydrophilicity, and well-defined one-dimensional nanochannels make the resulting COF an ideal platform to confine and stabilize the H3PO4 network in the pores through hydrogen-bonding interactions. The resulting material exhibits low activation energy (Ea) of 0.06 eV, and ultrahigh proton conductivity across a wide relative humidity (10–90 %) and temperature range (25–80 °C). A realistic proton exchange membrane fuel cell using the olefin-linked COF as the solid electrolyte achieve a maximum power of 135 mW cm−2 and a current density of 676 mA cm−2, which exceeds all reported COF materials.

Electronic ISSN: 2041-1723

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A continuum of invariant sensory and behavioral-context perceptual coding in secondary somatosensory cortex (2021)

Rossi-Pool, Román ; Zainos, Antonio ; Alvarez, Manuel ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 2000. Published 2021 Mar 31. doi: 10.1038/s41467-021-22321-x.

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Publication Date: 2021-03-31

Description: A crucial role of cortical networks is the conversion of sensory inputs into perception. In the cortical somatosensory network, neurons of the primary somatosensory cortex (S1) show invariant sensory responses, while frontal lobe neuronal activity correlates with the animal’s perceptual behavior. Here, we report that in the secondary somatosensory cortex (S2), neurons with invariant sensory responses coexist with neurons whose responses correlate with perceptual behavior. Importantly, the vast majority of the neurons fall along a continuum of combined sensory and categorical dynamics. Furthermore, during a non-demanding control task, the sensory responses remain unaltered while the sensory information exhibits an increase. However, perceptual responses and the associated categorical information decrease, implicating a task context-dependent processing mechanism. Conclusively, S2 neurons exhibit intriguing dynamics that are intermediate between those of S1 and frontal lobe. Our results contribute relevant evidence about the role that S2 plays in the conversion of touch into perception.

Electronic ISSN: 2041-1723

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Bi-directional regulation of cognitive control by distinct prefrontal cortical output neurons to thalamus and striatum (2021)

de Kloet, Sybren F. ; Bruinsma, Bastiaan ; Terra, Huub ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1994. Published 2021 Mar 31. doi: 10.1038/s41467-021-22260-7.

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Publication Date: 2021-03-31

Description: The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Author Correction: A data-driven simulation platform to predict cultivars’ performances under uncertain weather conditions (2021)

de los Campos, Gustavo ; Pérez-Rodríguez, Paulino ; Bogard, Matthieu ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1966. Published 2021 Mar 24. doi: 10.1038/s41467-021-22384-w.

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Publication Date: 2021-03-24

Description: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22384-w

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Author Correction: Genome evolution and the emergence of pathogenicity in avian Escherichia coli (2021)

Mageiros, Leonardos ; Méric, Guillaume ; Bayliss, Sion C. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1934. Published 2021 Mar 22. doi: 10.1038/s41467-021-22238-5.

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Publication Date: 2021-03-22

Description: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22238-5

Electronic ISSN: 2041-1723

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Increased autumn and winter precipitation during the Last Glacial Maximum in the European Alps (2021)

Spötl, C. ; Koltai, G. ; Jarosch, A. H. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1839. Published 2021 Mar 23. doi: 10.1038/s41467-021-22090-7.

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Description: The culmination of the glaciers in the European Alps during the Last Glacial Maximum (LGM) is one of the most intensively studied paleoglaciological events, but its trigger and forcing remain incompletely understood. Here, we provide evidence that the timing of this glacier maximum coincided within age uncertainties with a 3100 yr-long interval of subsurface warming (26.6 to 23.5 ka BP) as recorded by an archive preserved in caves, cryogenic carbonates. This interval of sustained permafrost degradation during one of the coldest intervals of the last glacial period calls for a fundamental change in the dry Arctic-style precipitation regime. Instead, heavy snowfall during autumn and early winter led to the accumulation of a seasonal snowpack insulating the ground from the winter chill. Combined with thermal modelling, the data provide compelling evidence that the LGM glacier advance in the Alps was fueled by intensive snowfall late in the year, likely sourced from the Mediterranean Sea.

Electronic ISSN: 2041-1723

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Axonal chemokine-like Orion induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling (2021)

Boulanger, Ana ; Thinat, Camille ; Züchner, Stephan ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1849. Published 2021 Mar 23. doi: 10.1038/s41467-021-22054-x.

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Publication Date: 2021-03-23

Description: The remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Astrocytes can clear neuronal debris and they have an active role in neuronal remodeling. Developmental axon pruning of Drosophila memory center neurons occurs via a degenerative process mediated by infiltrating astrocytes. However, how astrocytes are recruited to the axons during brain development is unclear. Using an unbiased screen, we identify the gene requirement of orion, encoding for a chemokine-like protein, in the developing mushroom bodies. Functional analysis shows that Orion is necessary for both axonal pruning and removal of axonal debris. Orion performs its functions extracellularly and bears some features common to chemokines, a family of chemoattractant cytokines. We propose that Orion is a neuronal signal that elicits astrocyte infiltration and astrocyte-driven axonal engulfment required during neuronal remodeling in the Drosophila developing brain.

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Robust and flexible platform for directed evolution of yeast genetic switches (2021)

Tominaga, Masahiro ; Nozaki, Kenta ; Umeno, Daisuke ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1846. Published 2021 Mar 23. doi: 10.1038/s41467-021-22134-y.

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Publication Date: 2021-03-23

Description: A wide repertoire of genetic switches has accelerated prokaryotic synthetic biology, while eukaryotic synthetic biology has lagged in the model organism Saccharomyces cerevisiae. Eukaryotic genetic switches are larger and more complex than prokaryotic ones, complicating the rational design and evolution of them. Here, we present a robust workflow for the creation and evolution of yeast genetic switches. The selector system was designed so that both ON- and OFF-state selection of genetic switches is completed solely by liquid handling, and it enabled parallel screen/selection of different motifs with different selection conditions. Because selection threshold of both ON- and OFF-state selection can be flexibly tuned, the desired selection conditions can be rapidly pinned down for individual directed evolution experiments without a prior knowledge either on the library population. The system’s utility was demonstrated using 20 independent directed evolution experiments, yielding genetic switches with elevated inducer sensitivities, inverted switching behaviours, sensory functions, and improved signal-to-noise ratio (〉100-fold induction). The resulting yeast genetic switches were readily integrated, in a plug-and-play manner, into an AND-gated carotenoid biosynthesis pathway.

Electronic ISSN: 2041-1723

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A wearable patch for continuous analysis of thermoregulatory sweat at rest (2021)

Nyein, Hnin Yin Yin ; Bariya, Mallika ; Tran, Brandon ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1823. Published 2021 Mar 23. doi: 10.1038/s41467-021-22109-z.

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Publication Date: 2021-03-23

Description: The body naturally and continuously secretes sweat for thermoregulation during sedentary and routine activities at rates that can reflect underlying health conditions, including nerve damage, autonomic and metabolic disorders, and chronic stress. However, low secretion rates and evaporation pose challenges for collecting resting thermoregulatory sweat for non-invasive analysis of body physiology. Here we present wearable patches for continuous sweat monitoring at rest, using microfluidics to combat evaporation and enable selective monitoring of secretion rate. We integrate hydrophilic fillers for rapid sweat uptake into the sensing channel, reducing required sweat accumulation time towards real-time measurement. Along with sweat rate sensors, we integrate electrochemical sensors for pH, Cl−, and levodopa monitoring. We demonstrate patch functionality for dynamic sweat analysis related to routine activities, stress events, hypoglycemia-induced sweating, and Parkinson’s disease. By enabling sweat analysis compatible with sedentary, routine, and daily activities, these patches enable continuous, autonomous monitoring of body physiology at rest.

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Functional annotations of three domestic animal genomes provide vital resources for comparative and agricultural research (2021)

Kern, Colin ; Wang, Ying ; Xu, Xiaoqin ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1821. Published 2021 Mar 23. doi: 10.1038/s41467-021-22100-8.

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Publication Date: 2021-03-23

Description: Gene regulatory elements are central drivers of phenotypic variation and thus of critical importance towards understanding the genetics of complex traits. The Functional Annotation of Animal Genomes consortium was formed to collaboratively annotate the functional elements in animal genomes, starting with domesticated animals. Here we present an expansive collection of datasets from eight diverse tissues in three important agricultural species: chicken (Gallus gallus), pig (Sus scrofa), and cattle (Bos taurus). Comparative analysis of these datasets and those from the human and mouse Encyclopedia of DNA Elements projects reveal that a core set of regulatory elements are functionally conserved independent of divergence between species, and that tissue-specific transcription factor occupancy at regulatory elements and their predicted target genes are also conserved. These datasets represent a unique opportunity for the emerging field of comparative epigenomics, as well as the agricultural research community, including species that are globally important food resources.

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Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis (2021)

Liu, Xiaonan ; Chai, Yu ; Liu, Guanqiao ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1832. Published 2021 Mar 23. doi: 10.1038/s41467-021-22131-1.

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Publication Date: 2021-03-23

Description: Synthetic glucocorticoids (GCs), one of the most effective treatments for chronic inflammatory and autoimmune conditions in children, have adverse effects on the growing skeleton. GCs inhibit angiogenesis in growing bone, but the underlying mechanisms remain unclear. Here, we show that GC treatment in young mice induces vascular endothelial cell senescence in metaphysis of long bone, and that inhibition of endothelial cell senescence improves GC-impaired bone angiogenesis with coupled osteogenesis. We identify angiogenin (ANG), a ribonuclease with pro-angiogenic activity, secreted by osteoclasts as a key factor for protecting the neighboring vascular cells against senescence. ANG maintains the proliferative activity of endothelial cells through plexin-B2 (PLXNB2)-mediated transcription of ribosomal RNA (rRNA). GC treatment inhibits ANG production by suppressing osteoclast formation in metaphysis, resulting in impaired endothelial cell rRNA transcription and subsequent cellular senescence. These findings reveal the role of metaphyseal blood vessel senescence in mediating the action of GCs on growing skeleton and establish the ANG/PLXNB2 axis as a molecular basis for the osteoclast-vascular interplay in skeletal angiogenesis.

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NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients (2021)

March, Michael E. ; Gutierrez-Uzquiza, Alvaro ; Snorradottir, Asbjorg Osk ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1827. Published 2021 Mar 23. doi: 10.1038/s41467-021-22120-4.

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Publication Date: 2021-03-23

Description: Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50–90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver (2021)

Kim, KyeongJin ; Kang, Jin Ku ; Jung, Young Hoon ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1822. Published 2021 Mar 23. doi: 10.1038/s41467-021-22106-2.

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Publication Date: 2021-03-23

Description: Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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Translation error clusters induced by aminoglycoside antibiotics (2021)

Wohlgemuth, Ingo ; Garofalo, Raffaella ; Samatova, Ekaterina ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1830. Published 2021 Mar 23. doi: 10.1038/s41467-021-21942-6.

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Publication Date: 2021-03-23

Description: Aminoglycoside antibiotics target the ribosome and induce mistranslation, yet which translation errors induce bacterial cell death is unclear. The analysis of cellular proteins by quantitative mass spectrometry shows that bactericidal aminoglycosides induce not only single translation errors, but also clusters of errors in full-length proteins in vivo with as many as four amino acid substitutions in a row. The downstream errors in a cluster are up to 10,000-fold more frequent than the first error and independent of the intracellular aminoglycoside concentration. The prevalence, length, and composition of error clusters depends not only on the misreading propensity of a given aminoglycoside, but also on its ability to inhibit ribosome translocation along the mRNA. Error clusters constitute a distinct class of misreading events in vivo that may provide the predominant source of proteotoxic stress at low aminoglycoside concentration, which is particularly important for the autocatalytic uptake of the drugs.

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The M-phase regulatory phosphatase PP2A-B55δ opposes protein kinase A on Arpp19 to initiate meiotic division (2021)

Lemonnier, Tom ; Daldello, Enrico Maria ; Poulhe, Robert ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1837. Published 2021 Mar 23. doi: 10.1038/s41467-021-22124-0.

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Publication Date: 2021-03-23

Description: Oocytes are held in meiotic prophase for prolonged periods until hormonal signals trigger meiotic divisions. Key players of M-phase entry are the opposing Cdk1 kinase and PP2A-B55δ phosphatase. In Xenopus, the protein Arpp19, phosphorylated at serine 67 by Greatwall, plays an essential role in inhibiting PP2A-B55δ, promoting Cdk1 activation. Furthermore, Arpp19 has an earlier role in maintaining the prophase arrest through a second serine (S109) phosphorylated by PKA. Prophase release, induced by progesterone, relies on Arpp19 dephosphorylation at S109, owing to an unknown phosphatase. Here, we identified this phosphatase as PP2A-B55δ. In prophase, PKA and PP2A-B55δ are simultaneously active, suggesting the presence of other important targets for both enzymes. The drop in PKA activity induced by progesterone enables PP2A-B55δ to dephosphorylate S109, unlocking the prophase block. Hence, PP2A-B55δ acts critically on Arpp19 on two distinct sites, opposing PKA and Greatwall to orchestrate the prophase release and M-phase entry.

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Organic multicomponent microparticle libraries (2021)

Zhang, Dandan ; De, Jianbo ; Lei, Yilong ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1838. Published 2021 Mar 23. doi: 10.1038/s41467-021-22060-z.

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Publication Date: 2021-03-23

Description: Multimetallic nanostructures can be synthesized by integrating up to seven or eight metallic elements into a single nanoparticle, which represent a great advance in developing complex multicomponent nanoparticle libraries. Contrary, organic micro- and nanoparticles beyond three π-conjugated components have not been explored because of the diversity and structural complexity of molecular assemblies. Here, we report a library of microparticles composed of an arbitrary combination of four luminescent organic semiconductors. We demonstrate that the composition and emission color of each domain as well as its spatial distribution can be rationally modulated. Unary, binary, ternary, and quaternary microparticles are thus realized in a predictable manner based on the miscibility of the components, resulting in mixed-composition phases or alloyed or phase separated heterostructures. This work reports a simple yet available synthetic methodology for rational modulation of organic multicomponent microparticles with complex architectures, which can be used to direct the design of functional microparticles.

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Single-atom alloy catalysts designed by first-principles calculations and artificial intelligence (2021)

Han, Zhong-Kang ; Sarker, Debalaya ; Ouyang, Runhai ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1833. Published 2021 Mar 23. doi: 10.1038/s41467-021-22048-9.

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Publication Date: 2021-03-23

Description: Single-atom-alloy catalysts (SAACs) have recently become a frontier in catalysis research. Simultaneous optimization of reactants’ facile dissociation and a balanced strength of intermediates’ binding make them highly efficient catalysts for several industrially important reactions. However, discovery of new SAACs is hindered by lack of fast yet reliable prediction of catalytic properties of the large number of candidates. We address this problem by applying a compressed-sensing data-analytics approach parameterized with density-functional inputs. Besides consistently predicting efficiency of the experimentally studied SAACs, we identify more than 200 yet unreported promising candidates. Some of these candidates are more stable and efficient than the reported ones. We have also introduced a novel approach to a qualitative analysis of complex symbolic regression models based on the data-mining method subgroup discovery. Our study demonstrates the importance of data analytics for avoiding bias in catalysis design, and provides a recipe for finding best SAACs for various applications.

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Common Era sea-level budgets along the U.S. Atlantic coast (2021)

Walker, Jennifer S. ; Kopp, Robert E. ; Shaw, Timothy A. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1841. Published 2021 Mar 23. doi: 10.1038/s41467-021-22079-2.

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Publication Date: 2021-03-23

Description: Sea-level budgets account for the contributions of processes driving sea-level change, but are predominantly focused on global-mean sea level and limited to the 20th and 21st centuries. Here we estimate site-specific sea-level budgets along the U.S. Atlantic coast during the Common Era (0–2000 CE) by separating relative sea-level (RSL) records into process-related signals on different spatial scales. Regional-scale, temporally linear processes driven by glacial isostatic adjustment dominate RSL change and exhibit a spatial gradient, with fastest rates of rise in southern New Jersey (1.6 ± 0.02 mm yr−1). Regional and local, temporally non-linear processes, such as ocean/atmosphere dynamics and groundwater withdrawal, contributed between −0.3 and 0.4 mm yr−1 over centennial timescales. The most significant change in the budgets is the increasing influence of the common global signal due to ice melt and thermal expansion since 1800 CE, which became a dominant contributor to RSL with a 20th century rate of 1.3 ± 0.1 mm yr−1.

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Vegetation feedback causes delayed ecosystem response to East Asian Summer Monsoon Rainfall during the Holocene (2021)

Cheng, Jun ; Wu, Haibin ; Liu, Zhengyu ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1843. Published 2021 Mar 23. doi: 10.1038/s41467-021-22087-2.

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Publication Date: 2021-03-23

Description: One long-standing issue in the paleoclimate records is whether East Asian Summer Monsoon peaked in the early Holocene or mid-Holocene. Here, combining a set of transient earth system model simulations with proxy records, we propose that, over northern China, monsoon rainfall peaked in the early Holocene, while soil moisture and tree cover peaked in the mid-Holocene. The delayed ecosystem (soil moisture and tree cover) response to rainfall is caused by the vegetation response to winter warming and the subsequent feedback with soil moisture. Our study provides a mechanism for reconciling different evolution behaviors of monsoon proxy records; it sheds light on the driving mechanism of the monsoon evolution and monsoon-ecosystem feedback over northern China, with implications to climate changes in other high climate sensitivity regions over the globe.

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Network community structure of substorms using SuperMAG magnetometers (2021)

Orr, L. ; Chapman, S. C. ; Gjerloev, J. W. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1842. Published 2021 Mar 23. doi: 10.1038/s41467-021-22112-4.

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Publication Date: 2021-03-23

Description: Geomagnetic substorms are a global magnetospheric reconfiguration, during which energy is abruptly transported to the ionosphere. Central to this are the auroral electrojets, large-scale ionospheric currents that are part of a larger three-dimensional system, the substorm current wedge. Many, often conflicting, magnetospheric reconfiguration scenarios have been proposed to describe the substorm current wedge evolution and structure. SuperMAG is a worldwide collaboration providing easy access to ground based magnetometer data. Here we show application of techniques from network science to analyze data from 137 SuperMAG ground-based magnetometers. We calculate a time-varying directed network and perform community detection on the network, identifying locally dense groups of connections. Analysis of 41 substorms exhibit robust structural change from many small, uncorrelated current systems before substorm onset, to a large spatially-extended coherent system, approximately 10 minutes after onset. We interpret this as strong indication that the auroral electrojet system during substorm expansions is inherently a large-scale phenomenon and is not solely due to many meso-scale wedgelets.

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Covalent organic framework nanofluidic membrane as a platform for highly sensitive bionic thermosensation (2021)

Zhang, Pengcheng ; Chen, Sifan ; Zhu, Changjia ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1844. Published 2021 Mar 23. doi: 10.1038/s41467-021-22141-z.

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Publication Date: 2021-03-23

Description: Thermal sensation, which is the conversion of a temperature stimulus into a biological response, is the basis of the fundamental physiological processes that occur ubiquitously in all organisms from bacteria to mammals. Significant efforts have been devoted to fabricating artificial membranes that can mimic the delicate functions of nature; however, the design of a bionic thermometer remains in its infancy. Herein, we report a nanofluidic membrane based on an ionic covalent organic framework (COF) that is capable of intelligently monitoring temperature variations and expressing it in the form of continuous potential differences. The high density of the charged sites present in the sub-nanochannels renders superior permselectivity to the resulting nanofluidic system, leading to a high thermosensation sensitivity of 1.27 mV K−1, thereby outperforming any known natural system. The potential applicability of the developed system is illustrated by its excellent tolerance toward a broad range of salt concentrations, wide working temperatures, synchronous response to temperature stimulation, and long-term ultrastability. Therefore, our study pioneers a way to explore COFs for mimicking the sophisticated signaling system observed in the nature.

Electronic ISSN: 2041-1723

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Strain rate dependency of dislocation plasticity (2021)

Fan, Haidong ; Wang, Qingyuan ; El-Awady, Jaafar A. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1845. Published 2021 Mar 23. doi: 10.1038/s41467-021-21939-1.

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Publication Date: 2021-03-23

Description: Dislocation glide is a general deformation mode, governing the strength of metals. Via discrete dislocation dynamics and molecular dynamics simulations, we investigate the strain rate and dislocation density dependence of the strength of bulk copper and aluminum single crystals. An analytical relationship between material strength, dislocation density, strain rate and dislocation mobility is proposed, which agrees well with current simulations and published experiments. Results show that material strength displays a decreasing regime (strain rate hardening) and then increasing regime (classical forest hardening) as the dislocation density increases. Accordingly, the strength displays universally, as the strain rate increases, a strain rate-independent regime followed by a strain rate hardening regime. All results are captured by a single scaling function, which relates the scaled strength to a coupling parameter between dislocation density and strain rate. Such coupling parameter also controls the localization of plasticity, fluctuations of dislocation flow and distribution of dislocation velocity.

Electronic ISSN: 2041-1723

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Quantum measurement arrow of time and fluctuation relations for measuring spin of ultracold atoms (2021)

Jayaseelan, Maitreyi ; K. Manikandan, Sreenath ; Jordan, Andrew N. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1847. Published 2021 Mar 23. doi: 10.1038/s41467-021-22094-3.

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Publication Date: 2021-03-23

Description: The origin of macroscopic irreversibility from microscopically time-reversible dynamical laws—often called the arrow-of-time problem—is of fundamental interest in both science and philosophy. Experimentally probing such questions in quantum theory requires systems with near-perfect isolation from the environment and long coherence times. Ultracold atoms are uniquely suited to this task. We experimentally demonstrate a striking parallel between the statistical irreversibility of wavefunction collapse and the arrow of time problem in the weak measurement of the quantum spin of an atomic cloud. Our experiments include statistically rare events where the arrow of time is inferred backward; nevertheless we provide evidence for absolute irreversibility and a strictly positive average arrow of time for the measurement process, captured by a fluctuation theorem. We further demonstrate absolute irreversibility for measurements performed on a quantum many-body entangled wavefunction—a unique opportunity afforded by our platform—with implications for studying quantum many-body dynamics and quantum thermodynamics.

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Herbaceous perennial plants with short generation time have stronger responses to climate anomalies than those with longer generation time (2021)

Compagnoni, Aldo ; Levin, Sam ; Childs, Dylan Z. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1824. Published 2021 Mar 23. doi: 10.1038/s41467-021-21977-9.

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Publication Date: 2021-03-23

Description: There is an urgent need to synthesize the state of our knowledge on plant responses to climate. The availability of open-access data provide opportunities to examine quantitative generalizations regarding which biomes and species are most responsive to climate drivers. Here, we synthesize time series of structured population models from 162 populations of 62 plants, mostly herbaceous species from temperate biomes, to link plant population growth rates (λ) to precipitation and temperature drivers. We expect: (1) more pronounced demographic responses to precipitation than temperature, especially in arid biomes; and (2) a higher climate sensitivity in short-lived rather than long-lived species. We find that precipitation anomalies have a nearly three-fold larger effect on λ than temperature. Species with shorter generation time have much stronger absolute responses to climate anomalies. We conclude that key species-level traits can predict plant population responses to climate, and discuss the relevance of this generalization for conservation planning.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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G-quadruplexes originating from evolutionary conserved L1 elements interfere with neuronal gene expression in Alzheimer’s disease (2021)

Hanna, Roy ; Flamier, Anthony ; Barabino, Andrea ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1828. Published 2021 Mar 23. doi: 10.1038/s41467-021-22129-9.

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Publication Date: 2021-03-23

Description: DNA sequences containing consecutive guanines organized in 4-interspaced tandem repeats can form stable single-stranded secondary structures, called G-quadruplexes (G4). Herein, we report that the Polycomb group protein BMI1 is enriched at heterochromatin regions containing putative G4 DNA sequences, and that G4 structures accumulate in cells with reduced BMI1 expression and/or relaxed chromatin, including sporadic Alzheimer’s disease (AD) neurons. In AD neurons, G4 structures preferentially accumulate in lamina-associated domains, and this is rescued by re-establishing chromatin compaction. ChIP-seq analyses reveal that G4 peaks correspond to evolutionary conserved Long Interspersed Element-1 (L1) sequences predicted to be transcriptionally active. Hence, G4 structures co-localize with RNAPII, and inhibition of transcription can reverse the G4 phenotype without affecting chromatin’s state, thus uncoupling both components. Intragenic G4 structures affecting splicing events are furthermore associated with reduced neuronal gene expression in AD. Active L1 sequences are thus at the origin of most G4 structures observed in human neurons.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level (2021)

Clark, Helen R. ; McKenney, Connor ; Livingston, Nathan M. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1836. Published 2021 Mar 23. doi: 10.1038/s41467-021-22070-x.

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Publication Date: 2021-03-23

Description: To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Integrated avalanche photodetectors for visible light (2021)

Yanikgonul, Salih ; Leong, Victor ; Ong, Jun Rong ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1834. Published 2021 Mar 23. doi: 10.1038/s41467-021-22046-x.

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Publication Date: 2021-03-23

Description: Integrated photodetectors are essential components of scalable photonics platforms for quantum and classical applications. However, most efforts in the development of such devices to date have been focused on infrared telecommunications wavelengths. Here, we report the first monolithically integrated avalanche photodetector (APD) for visible light. Our devices are based on a doped silicon rib waveguide with a novel end-fire input coupling to a silicon nitride waveguide. We demonstrate a high gain-bandwidth product of 234 ± 25 GHz at 20 V reverse bias measured for 685 nm input light, with a low dark current of 0.12 μA. We also observe open eye diagrams at up to 56 Gbps. This performance is very competitive when benchmarked against other integrated APDs operating in the infrared range. With CMOS-compatible fabrication and integrability with silicon photonic platforms, our devices are attractive for sensing, imaging, communications, and quantum applications at visible wavelengths.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice (2021)

Yoshida, Tomoyuki ; Yamagata, Atsushi ; Imai, Ayako ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1848. Published 2021 Mar 23. doi: 10.1038/s41467-021-22059-6.

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Publication Date: 2021-03-23

Description: Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway (2021)

Fujino, Takeshi ; Goyama, Susumu ; Sugiura, Yuki ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1826. Published 2021 Mar 23. doi: 10.1038/s41467-021-22053-y.

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Publication Date: 2021-03-23

Description: Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Reconfigurable electronics by disassembling and reassembling van der Waals heterostructures (2021)

Tao, Quanyang ; Wu, Ruixia ; Li, Qianyuan ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1825. Published 2021 Mar 23. doi: 10.1038/s41467-021-22118-y.

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Publication Date: 2021-03-23

Description: Van der Waals heterostructures (vdWHs) have attracted tremendous interest owing to the ability to assemble diverse building blocks without the constraints of lattice matching and processing compatibility. However, once assembled, the fabricated vdWHs can hardly be separated into individual building blocks for further manipulation, mainly due to technical difficulties in the disassembling process. Here, we show a method to disassemble the as-fabricated vdWHs into individual building blocks, which can be further reassembled into new vdWHs with different device functionalities. With this technique, we demonstrate reconfigurable transistors from n-type to p-type and back-gate to dual-gate structures through re-stacking. Furthermore, reconfigurable device behaviors from floating gate memory to Schottky diode and reconfigurable anisotropic Raman behaviors have been obtained through layer re-sequencing and re-twisting, respectively. Our results could lead to a reverse engineering concept of disassembled vdWHs electronics in parallel with state-of-the-art vdWHs electronics, offering a general method for multi-functional pluggable electronics and optoelectronics with limited material building blocks.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Promoting photocatalytic CO2 reduction with a molecular copper purpurin chromophore (2021)

Yuan, Huiqing ; Cheng, Banggui ; Lei, Jingxiang ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 1835. Published 2021 Mar 23. doi: 10.1038/s41467-021-21923-9.

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Publication Date: 2021-03-23

Description: CO2 reduction through artificial photosynthesis represents a prominent strategy toward the conversion of solar energy into fuels or useful chemical feedstocks. In such configuration, designing highly efficient chromophores comprising earth-abundant elements is essential for both light harvesting and electron transfer. Herein, we report that a copper purpurin complex bearing an additional redox-active center in natural organic chromophores is capable to shift the reduction potential 540 mV more negative than its organic dye component. When this copper photosensitizer is employed with an iron porphyrin as the catalyst and 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole as the sacrificial reductant, the system achieves over 16100 turnover number of CO from CO2 with a 95% selectivity (CO vs H2) under visible-light irradiation, which is among the highest reported for a homogeneous noble metal-free system. This work may open up an effective approach for the rational design of highly efficient chromophores in artificial photosynthesis.

Electronic ISSN: 2041-1723

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Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification (2021)

Yu, Corey H. ; Bhattacharya, Akash ; Persaud, Mirjana ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 731. Published 2021 Feb 02. doi: 10.1038/s41467-021-21023-8.

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Publication Date: 2021-02-02

Description: SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, and the enzymatic activity of the protein—dephosphorylation of deoxynucleotide triphosphates (dNTPs)—implicates enzymatic dNTP depletion in innate antiviral immunity. Here we show that the allosteric binding sites of the enzyme are plastic and can accommodate oligonucleotides in place of the allosteric activators, GTP and dNTP. SAMHD1 displays a preference for oligonucleotides containing phosphorothioate bonds in the Rp configuration located 3’ to G nucleotides (GpsN), the modification pattern that occurs in a mechanism of antiviral defense in prokaryotes. In the presence of GTP and dNTPs, binding of GpsN-containing oligonucleotides promotes formation of a distinct tetramer with mixed occupancy of the allosteric sites. Mutations that impair formation of the mixed-occupancy complex abolish the antiretroviral activity of SAMHD1, but not its ability to deplete dNTPs. The findings link nucleic acid binding to the antiretroviral activity of SAMHD1, shed light on the immunomodulatory effects of synthetic phosphorothioated oligonucleotides and raise questions about the role of nucleic acid phosphorothioation in human innate immunity.

Electronic ISSN: 2041-1723

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Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution (2021)

Liu, Yang ; He, Shuai ; Wang, Xi-Liang ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 741. Published 2021 Feb 02. doi: 10.1038/s41467-021-21043-4.

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Publication Date: 2021-02-02

Description: The heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8+ T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8+ T and immune-suppressive TNFRSF4+ Treg cells in tumours might derive from peripheral CX3CR1+CD8+ T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3+ DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3+ DCs, Treg, exhausted CD8+ T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Activatable polymer nanoagonist for second near-infrared photothermal immunotherapy of cancer (2021)

Jiang, Yuyan ; Huang, Jiaguo ; Xu, Cheng ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 742. Published 2021 Feb 02. doi: 10.1038/s41467-021-21047-0.

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Publication Date: 2021-02-02

Description: Nanomedicine in combination with immunotherapy offers opportunities to treat cancer in a safe and effective manner; however, remote control of immune response with spatiotemporal precision remains challenging. We herein report a photothermally activatable polymeric pro-nanoagonist (APNA) that is specifically regulated by deep-tissue-penetrating second near-infrared (NIR-II) light for combinational photothermal immunotherapy. APNA is constructed from covalent conjugation of an immunostimulant onto a NIR-II semiconducting transducer through a labile thermo-responsive linker. Upon NIR-II photoirradiation, APNA mediates photothermal effect, which not only triggers tumor ablation and immunogenic cell death but also initiates the cleavage of thermolabile linker to liberate caged agonist for in-situ immune activation in deep solid tumor (8 mm). Such controlled immune regulation potentiates systemic antitumor immunity, leading to promoted cytotoxic T lymphocytes and helper T cell infiltration in distal tumor, lung and liver to inhibit cancer metastasis. Thereby, the present work illustrates a generic strategy to prepare pro-immunostimulants for spatiotemporal regulation of cancer nano-immunotherapy.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Surface-bound reactive oxygen species generating nanozymes for selective antibacterial action (2021)

Gao, Feng ; Shao, Tianyi ; Yu, Yunpeng ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 745. Published 2021 Feb 02. doi: 10.1038/s41467-021-20965-3.

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Publication Date: 2021-02-02

Description: Acting by producing reactive oxygen species (ROS) in situ, nanozymes are promising as antimicrobials. ROS’ intrinsic inability to distinguish bacteria from mammalian cells, however, deprives nanozymes of the selectivity necessary for an ideal antimicrobial. Here we report that nanozymes that generate surface-bound ROS selectively kill bacteria over mammalian cells. This result is robust across three distinct nanozymes that universally generate surface-bound ROS, with an oxidase-like silver-palladium bimetallic alloy nanocage, AgPd0.38, being the lead model. The selectivity is attributable to both the surface-bound nature of ROS these nanozymes generate and an unexpected antidote role of endocytosis. Though surface-bound, the ROS on AgPd0.38 efficiently eliminated antibiotic-resistant bacteria and effectively delayed the onset of bacterial resistance emergence. When used as coating additives, AgPd0.38 enabled an inert substrate to inhibit biofilm formation and suppress infection-related immune responses in mouse models. This work opens an avenue toward biocompatible nanozymes and may have implication in our fight against antimicrobial resistance.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Cryo-EM of mammalian PA28αβ-iCP immunoproteasome reveals a distinct mechanism of proteasome activation by PA28αβ (2021)

Chen, Jinhuan ; Wang, Yifan ; Xu, Cong ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 739. Published 2021 Feb 02. doi: 10.1038/s41467-021-21028-3.

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Publication Date: 2021-02-02

Description: The proteasome activator PA28αβ affects MHC class I antigen presentation by associating with immunoproteasome core particles (iCPs). However, due to the lack of a mammalian PA28αβ-iCP structure, how PA28αβ regulates proteasome remains elusive. Here we present the complete architectures of the mammalian PA28αβ-iCP immunoproteasome and free iCP at near atomic-resolution by cryo-EM, and determine the spatial arrangement between PA28αβ and iCP through XL-MS. Our structures reveal a slight leaning of PA28αβ towards the α3-α4 side of iCP, disturbing the allosteric network of the gatekeeper α2/3/4 subunits, resulting in a partial open iCP gate. We find that the binding and activation mechanism of iCP by PA28αβ is distinct from those of constitutive CP by the homoheptameric TbPA26 or PfPA28. Our study sheds lights on the mechanism of enzymatic activity stimulation of immunoproteasome and suggests that PA28αβ-iCP has experienced profound remodeling during evolution to achieve its current level of function in immune response.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Photoactivatable CaMKII induces synaptic plasticity in single synapses (2021)

Shibata, Akihiro C. E. ; Ueda, Hiromi H. ; Eto, Kei ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 751. Published 2021 Feb 02. doi: 10.1038/s41467-021-21025-6.

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Publication Date: 2021-02-02

Description: Optogenetic approaches for studying neuronal functions have proven their utility in the neurosciences. However, optogenetic tools capable of inducing synaptic plasticity at the level of single synapses have been lacking. Here, we engineered a photoactivatable (pa)CaMKII by fusing a light-sensitive domain, LOV2, to CaMKIIα. Blue light or two-photon excitation reversibly activated paCaMKII. Activation in single spines was sufficient to induce structural long-term potentiation (sLTP) in vitro and in vivo. paCaMKII activation was also sufficient for the recruitment of AMPA receptors and functional LTP in single spines. By combining paCaMKII with protein activity imaging by 2-photon FLIM-FRET, we demonstrate that paCaMKII activation in clustered spines induces robust sLTP via a mechanism that involves the actin-regulatory small GTPase, Cdc42. This optogenetic tool for dissecting the function of CaMKII activation (i.e., the sufficiency of CaMKII rather than necessity) and for manipulating synaptic plasticity will find many applications in neuroscience and other fields.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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TGFβ signalling acts as a molecular brake of myoblast fusion (2021)

Melendez, Julie ; Sieiro, Daniel ; Salgado, David ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 749. Published 2021 Feb 02. doi: 10.1038/s41467-020-20290-1.

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Publication Date: 2021-02-02

Description: Fusion of nascent myoblasts to pre-existing myofibres is critical for skeletal muscle growth and repair. The vast majority of molecules known to regulate myoblast fusion are necessary in this process. Here, we uncover, through high-throughput in vitro assays and in vivo studies in the chicken embryo, that TGFβ (SMAD2/3-dependent) signalling acts specifically and uniquely as a molecular brake on muscle fusion. While constitutive activation of the pathway arrests fusion, its inhibition leads to a striking over-fusion phenotype. This dynamic control of TGFβ signalling in the embryonic muscle relies on a receptor complementation mechanism, prompted by the merging of myoblasts with myofibres, each carrying one component of the heterodimer receptor complex. The competence of myofibres to fuse is likely restored through endocytic degradation of activated receptors. Altogether, this study shows that muscle fusion relies on TGFβ signalling to regulate its pace.

Electronic ISSN: 2041-1723

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Molecular mechanism for vitamin C-derived C5-glyceryl-methylcytosine DNA modification catalyzed by algal TET homologue CMD1 (2021)

Li, Wenjing ; Zhang, Tianlong ; Sun, Mingliang ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 744. Published 2021 Feb 02. doi: 10.1038/s41467-021-21061-2.

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Publication Date: 2021-02-02

Description: C5-glyceryl-methylcytosine (5gmC) is a novel DNA modification catalyzed by algal TET homologue CMD1 using vitamin C (VC) as co-substrate. Here, we report the structures of CMD1 in apo form and in complexes with VC or/and dsDNA. CMD1 exhibits comparable binding affinities for DNAs of different lengths, structures, and 5mC levels, and displays a moderate substrate preference for 5mCpG-containing DNA. CMD1 adopts the typical DSBH fold of Fe2+/2-OG-dependent dioxygenases. The lactone form of VC binds to the active site and mono-coordinates the Fe2+ in a manner different from 2-OG. The dsDNA binds to a positively charged cleft of CMD1 and the 5mC/C is inserted into the active site and recognized by CMD1 in a similar manner as the TET proteins. The functions of key residues are validated by mutagenesis and activity assay. Our structural and biochemical data together reveal the molecular mechanism for the VC-derived 5gmC DNA modification by CMD1.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Author Correction: Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals (2021)

Whiffin, Nicola ; , ; Karczewski, Konrad J. ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 839. Published 2021 Feb 02. doi: 10.1038/s41467-021-21052-3.

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Publication Date: 2021-02-02

Description: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21052-3

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Extreme temperatures compromise male and female fertility in a large desert bird (2021)

Schou, Mads F. ; Bonato, Maud ; Engelbrecht, Anel ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 666. Published 2021 Feb 02. doi: 10.1038/s41467-021-20937-7.

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Publication Date: 2021-02-02

Description: Temperature has a crucial influence on the places where species can survive and reproduce. Past research has primarily focused on survival, making it unclear if temperature fluctuations constrain reproductive success, and if so whether populations harbour the potential to respond to climatic shifts. Here, using two decades of data from a large experimental breeding programme of the iconic ostrich (Struthio camelus) in South Africa, we show that the number of eggs females laid and the number of sperm males produced were highly sensitive to natural temperature extremes (ranging from −5 °C to 45 °C). This resulted in reductions in reproductive success of up to 44% with 5 °C deviations from their thermal optimum. In contrast, gamete quality was largely unaffected by temperature. Extreme temperatures also did not expose trade-offs between gametic traits. Instead, some females appeared to invest more in reproducing at high temperatures, which may facilitate responses to climate change. These results show that the robustness of fertility to temperature fluctuations, and not just temperature increases, is a critical aspect of species persistence in regions predicted to undergo the greatest change in climate volatility.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

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Under-reporting of greenhouse gas emissions in U.S. cities (2021)

Gurney, Kevin Robert ; Liang, Jianming ; Roest, Geoffrey ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 553. Published 2021 Feb 02. doi: 10.1038/s41467-020-20871-0.

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Publication Date: 2021-02-02

Description: Cities dominate greenhouse gas emissions. Many have generated self-reported emission inventories, but their value to emissions mitigation depends on their accuracy, which remains untested. Here, we compare self-reported inventories from 48 US cities to independent estimates from the Vulcan carbon dioxide emissions data product, which is consistent with atmospheric measurements. We found that cities under-report their own greenhouse gas emissions, on average, by 18.3% (range: −145.5% to +63.5%) – a difference which if extrapolated to all U.S. cities, exceeds California’s total emissions by 23.5%. Differences arise because city inventories omit particular fuels and source types and estimate transportation emissions differently. These results raise concerns about self-reported inventories in planning or assessing emissions, and warrant consideration of the new urban greenhouse gas information system recently developed by the scientific community.

Electronic ISSN: 2041-1723

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Histone Parylation factor 1 contributes to the inhibition of PARP1 by cancer drugs (2021)

Rudolph, Johannes ; Roberts, Genevieve ; Luger, Karolin

Springer Nature

In: Nature Communications. 2021; 12(1): 736. Published 2021 Feb 02. doi: 10.1038/s41467-021-20998-8.

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Publication Date: 2021-02-02

Description: Poly-(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) are key enzymes in the DNA damage response. Four different inhibitors (PARPi) are currently in the clinic for treatment of ovarian and breast cancer. Recently, histone PARylation Factor 1 (HPF1) has been shown to play an essential role in the PARP1- and PARP2-dependent poly-(ADP-ribosylation) (PARylation) of histones, by forming a complex with both enzymes and altering their catalytic properties. Given the proximity of HPF1 to the inhibitor binding site both PARPs, we hypothesized that HPF1 may modulate the affinity of inhibitors toward PARP1 and/or PARP2. Here we demonstrate that HPF1 significantly increases the affinity for a PARP1 – DNA complex of some PARPi (i.e., olaparib), but not others (i.e., veliparib). This effect of HPF1 on the binding affinity of Olaparib also holds true for the more physiologically relevant PARP1 – nucleosome complex but does not extend to PARP2. Our results have important implications for the interpretation of PARP inhibition by current PARPi as well as for the design and analysis of the next generation of clinically relevant PARP inhibitors.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

Published by Springer Nature

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TGFβ signaling curbs cell fusion and muscle regeneration (2021)

Girardi, Francesco ; Taleb, Anissa ; Ebrahimi, Majid ; [et al.]

Springer Nature

In: Nature Communications. 2021; 12(1): 750. Published 2021 Feb 02. doi: 10.1038/s41467-020-20289-8.

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Publication Date: 2021-02-02

Description: Muscle cell fusion is a multistep process involving cell migration, adhesion, membrane remodeling and actin-nucleation pathways to generate multinucleated myotubes. However, molecular brakes restraining cell–cell fusion events have remained elusive. Here we show that transforming growth factor beta (TGFβ) pathway is active in adult muscle cells throughout fusion. We find TGFβ signaling reduces cell fusion, regardless of the cells’ ability to move and establish cell-cell contacts. In contrast, inhibition of TGFβ signaling enhances cell fusion and promotes branching between myotubes in mouse and human. Exogenous addition of TGFβ protein in vivo during muscle regeneration results in a loss of muscle function while inhibition of TGFβR2 induces the formation of giant myofibers. Transcriptome analyses and functional assays reveal that TGFβ controls the expression of actin-related genes to reduce cell spreading. TGFβ signaling is therefore requisite to limit mammalian myoblast fusion, determining myonuclei numbers and myofiber size.

Electronic ISSN: 2041-1723

Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics

Published by Springer Nature

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