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The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation (2021)

Vorstandlechner, Vera ; Laggner, Maria ; Copic, Dragan ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6242. Published 2021 Oct 29. doi: 10.1038/s41467-021-26495-2.

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Publikationsdatum: 2021-10-29

Beschreibung: Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we investigate mature human hypertrophic scars and developing scars in mice at single cell resolution. Compared to normal skin, we find significant differences in gene expression in most cell types present in scar tissue. Fibroblasts show the most prominent alterations in gene expression, displaying a distinct fibrotic signature. By comparing genes upregulated in murine fibroblasts during scar development with genes highly expressed in mature human hypertrophic scars, we identify a group of serine proteases, tentatively involved in scar formation. Two of them, dipeptidyl-peptidase 4 (DPP4) and urokinase (PLAU), are further analyzed in functional assays, revealing a role in TGFβ1-mediated myofibroblast differentiation and over-production of components of the extracellular matrix in vitro. Topical treatment with inhibitors of DPP4 and PLAU during scar formation in vivo shows anti-fibrotic activity and improvement of scar quality, most prominently after application of the PLAU inhibitor BC-11. In this study, we delineate the genetic landscape of hypertrophic scars and present insights into mechanisms involved in hypertrophic scar formation. Our data suggest the use of serine protease inhibitors for the treatment of skin fibrosis.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Genome-wide association study identifies susceptibility loci for acute myeloid leukemia (2021)

Lin, Wei-Yu ; Fordham, Sarah E. ; Hungate, Eric ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6233. Published 2021 Oct 29. doi: 10.1038/s41467-021-26551-x.

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Publikationsdatum: 2021-10-29

Beschreibung: Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Author Correction: Berberine is an insulin secretagogue targeting the KCNH6 potassium channel (2021)

Zhao, Miao-Miao ; Lu, Jing ; Li, Sen ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6342. Published 2021 Oct 29. doi: 10.1038/s41467-021-26635-8.

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Publikationsdatum: 2021-10-29

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Magnetic memory driven by topological insulators (2021)

Wu, Hao ; Chen, Aitian ; Zhang, Peng ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6251. Published 2021 Oct 29. doi: 10.1038/s41467-021-26478-3.

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Publikationsdatum: 2021-10-29

Beschreibung: Giant spin-orbit torque (SOT) from topological insulators (TIs) provides an energy efficient writing method for magnetic memory, which, however, is still premature for practical applications due to the challenge of the integration with magnetic tunnel junctions (MTJs). Here, we demonstrate a functional TI-MTJ device that could become the core element of the future energy-efficient spintronic devices, such as SOT-based magnetic random-access memory (SOT-MRAM). The state-of-the-art tunneling magnetoresistance (TMR) ratio of 102% and the ultralow switching current density of 1.2 × 105 A cm−2 have been simultaneously achieved in the TI-MTJ device at room temperature, laying down the foundation for TI-driven SOT-MRAM. The charge-spin conversion efficiency θSH in TIs is quantified by both the SOT-induced shift of the magnetic switching field (θSH = 1.59) and the SOT-induced ferromagnetic resonance (ST-FMR) (θSH = 1.02), which is one order of magnitude larger than that in conventional heavy metals. These results inspire a revolution of SOT-MRAM from classical to quantum materials, with great potential to further reduce the energy consumption.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Giant charge-to-spin conversion in ferromagnet via spin-orbit coupling (2021)

Hibino, Yuki ; Taniguchi, Tomohiro ; Yakushiji, Kay ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6254. Published 2021 Oct 29. doi: 10.1038/s41467-021-26445-y.

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Publikationsdatum: 2021-10-29

Beschreibung: Converting charge current into spin current via the spin Hall effect enables efficient manipulation of magnetization by electrical current. However, its geometrical restriction is a serious obstacle to device applications because it prevents switching of perpendicular magnetization in the absence of an external field. To resolve this issue, ferromagnetic materials have attracted attentions because their time reversal asymmetry induces magnetic-dependent charge-to-spin conversion that removes this restriction. Here, we achieved a large enhancement of magnetic-dependent charge-to-spin conversion by clarifying its mechanism. Through layer thickness dependence of the conversion efficiency, we revealed a coexistence of interfacial and bulk contributions to the magnetic-dependent charge-to-spin conversion. Moreover, the interfacial contribution to charge-to-spin conversion is found to be dominant and can be controlled via interfacial band engineering. The efficiency of charge-to-spin conversion in ferromagnet was found to be an order larger than that of other materials with reduced symmetry.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Structural basis for high selectivity of a rice silicon channel Lsi1 (2021)

Saitoh, Yasunori ; Mitani-Ueno, Namiki ; Saito, Keisuke ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6236. Published 2021 Oct 29. doi: 10.1038/s41467-021-26535-x.

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Publikationsdatum: 2021-10-29

Beschreibung: Silicon (Si), the most abundant mineral element in the earth’s crust, is taken up by plant roots in the form of silicic acid through Low silicon rice 1 (Lsi1). Lsi1 belongs to the Nodulin 26-like intrinsic protein subfamily in aquaporin and shows high selectivity for silicic acid. To uncover the structural basis for this high selectivity, here we show the crystal structure of the rice Lsi1 at a resolution of 1.8 Å. The structure reveals transmembrane helical orientations different from other aquaporins, characterized by a unique, widely opened, and hydrophilic selectivity filter (SF) composed of five residues. Our structural, functional, and theoretical investigations provide a solid structural basis for the Si uptake mechanism in plants, which will contribute to secure and sustainable rice production by manipulating Lsi1 selectivity for different metalloids.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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7

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Coordination of fungal biofilm development by extracellular vesicle cargo (2021)

Zarnowski, Robert ; Noll, Andrea ; Chevrette, Marc G. ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6235. Published 2021 Oct 29. doi: 10.1038/s41467-021-26525-z.

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Publikationsdatum: 2021-10-29

Beschreibung: The fungal pathogen Candida albicans can form biofilms that protect it from drugs and the immune system. The biofilm cells release extracellular vesicles (EVs) that promote extracellular matrix formation and resistance to antifungal drugs. Here, we define functions for numerous EV cargo proteins in biofilm matrix assembly and drug resistance, as well as in fungal cell adhesion and dissemination. We use a machine-learning analysis of cargo proteomic data from mutants with EV production defects to identify 63 candidate gene products for which we construct mutant and complemented strains for study. Among these, 17 mutants display reduced biofilm matrix accumulation and antifungal drug resistance. An additional subset of 8 cargo mutants exhibit defects in adhesion and/or dispersion. Representative cargo proteins are shown to function as EV cargo through the ability of exogenous wild-type EVs to complement mutant phenotypic defects. Most functionally assigned cargo proteins have roles in two or more of the biofilm phases. Our results support that EVs provide community coordination throughout biofilm development in C. albicans.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Subnanometer high-entropy alloy nanowires enable remarkable hydrogen oxidation catalysis (2021)

Zhan, Changhong ; Xu, Yong ; Bu, Lingzheng ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6261. Published 2021 Oct 29. doi: 10.1038/s41467-021-26425-2.

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Publikationsdatum: 2021-10-29

Beschreibung: High-entropy alloys (HEAs) with unique physicochemical properties have attracted tremendous attention in many fields, yet the precise control on dimension and morphology at atomic level remains formidable challenges. Herein, we synthesize unique PtRuNiCoFeMo HEA subnanometer nanowires (SNWs) for alkaline hydrogen oxidation reaction (HOR). The mass and specific activities of HEA SNWs/C reach 6.75 A mgPt+Ru−1 and 8.96 mA cm−2, respectively, which are 2.8/2.6, 4.1/2.4, and 19.8/18.7 times higher than those of HEA NPs/C, commercial PtRu/C and Pt/C, respectively. It can even display enhanced resistance to CO poisoning during HOR in the presence of 1000 ppm CO. Density functional theory calculations reveal that the strong interactions between different metal sites in HEA SNWs can greatly regulate the binding strength of proton and hydroxyl, and therefore enhances the HOR activity. This work not only provides a viable synthetic route for the fabrication of Pt-based HEA subnano/nano materials, but also promotes the fundamental researches on catalysis and beyond.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Clinical outcomes and cost-effectiveness of COVID-19 vaccination in South Africa (2021)

Reddy, Krishna P. ; Fitzmaurice, Kieran P. ; Scott, Justine A. ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6238. Published 2021 Oct 29. doi: 10.1038/s41467-021-26557-5.

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Publikationsdatum: 2021-10-29

Beschreibung: Low- and middle-income countries are implementing COVID-19 vaccination strategies in light of varying vaccine efficacies and costs, supply shortages, and resource constraints. Here, we use a microsimulation model to evaluate clinical outcomes and cost-effectiveness of a COVID-19 vaccination program in South Africa. We varied vaccination coverage, pace, acceptance, effectiveness, and cost as well as epidemic dynamics. Providing vaccines to at least 40% of the population and prioritizing vaccine rollout prevented 〉9 million infections and 〉73,000 deaths and reduced costs due to fewer hospitalizations. Model results were most sensitive to assumptions about epidemic growth and prevalence of prior immunity to SARS-CoV-2, though the vaccination program still provided high value and decreased both deaths and health care costs across a wide range of assumptions. Vaccination program implementation factors, including prompt procurement, distribution, and rollout, are likely more influential than characteristics of the vaccine itself in maximizing public health benefits and economic efficiency.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity (2021)

Bido, Simone ; Muggeo, Sharon ; Massimino, Luca ; [weitere]

Springer Nature

In: Nature Communications. 2021; 12(1): 6237. Published 2021 Oct 29. doi: 10.1038/s41467-021-26519-x.

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Publikationsdatum: 2021-10-29

Beschreibung: Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.

Digitale ISSN: 2041-1723

Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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