ALBERT

Description: by Stefanie Hoehl, Gabriela Markova Infants’ cognitive development and learning rely profoundly on their interactions with other people. In the first year, infants become increasingly sensitive to others’ gaze and use it to focus their own attention on relevant visual input. However, infants are not passive observers in early social interactions, and these exchanges are characterized by high levels of contingency and reciprocity. Wass and colleagues offer first insights into the neurobehavioral dynamics of caregiver–infant interactions, demonstrating that caregivers’ scalp-recorded theta band activity responds to their infant’s changes in attention, and parental brain activation is associated with infants’ sustenance of attention. This research opens up entirely new ways of exploring caregiver–infant interactions and to understand early social attention as a reciprocal and dynamic process.

Description: by Anne Keitel, Joachim Gross, Christoph Kayser During online speech processing, our brain tracks the acoustic fluctuations in speech at different timescales. Previous research has focused on generic timescales (for example, delta or theta bands) that are assumed to map onto linguistic features such as prosody or syllables. However, given the high intersubject variability in speaking patterns, such a generic association between the timescales of brain activity and speech properties can be ambiguous. Here, we analyse speech tracking in source-localised magnetoencephalographic data by directly focusing on timescales extracted from statistical regularities in our speech material. This revealed widespread significant tracking at the timescales of phrases (0.6–1.3 Hz), words (1.8–3 Hz), syllables (2.8–4.8 Hz), and phonemes (8–12.4 Hz). Importantly, when examining its perceptual relevance, we found stronger tracking for correctly comprehended trials in the left premotor (PM) cortex at the phrasal scale as well as in left middle temporal cortex at the word scale. Control analyses using generic bands confirmed that these effects were specific to the speech regularities in our stimuli. Furthermore, we found that the phase at the phrasal timescale coupled to power at beta frequency (13–30 Hz) in motor areas. This cross-frequency coupling presumably reflects top-down temporal prediction in ongoing speech perception. Together, our results reveal specific functional and perceptually relevant roles of distinct tracking and cross-frequency processes along the auditory–motor pathway.

Description: by Gerry Q. Tonkin-Hill, Leily Trianty, Rintis Noviyanti, Hanh H. T. Nguyen, Boni F. Sebayang, Daniel A. Lampah, Jutta Marfurt, Simon A. Cobbold, Janavi S. Rambhatla, Malcolm J. McConville, Stephen J. Rogerson, Graham V. Brown, Karen P. Day, Ric N. Price, Nicholas M. Anstey, Anthony T. Papenfuss, Michael F. Duffy Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria.

Description: by Hugo Cruces-Solís, Zhizi Jing, Olga Babaev, Jonathan Rubin, Burak Gür, Dilja Krueger-Burg, Nicola Strenzke, Livia de Hoz Detecting regular patterns in the environment, a process known as statistical learning, is essential for survival. Neuronal adaptation is a key mechanism in the detection of patterns that are continuously repeated across short (seconds to minutes) temporal windows. Here, we found in mice that a subcortical structure in the auditory midbrain was sensitive to patterns that were repeated discontinuously, in a temporally sparse manner, across windows of minutes to hours. Using a combination of behavioral, electrophysiological, and molecular approaches, we found changes in neuronal response gain that varied in mechanism with the degree of sound predictability and resulted in changes in frequency coding. Analysis of population activity (structural tuning) revealed an increase in frequency classification accuracy in the context of increased overlap in responses across frequencies. The increase in accuracy and overlap was paralleled at the behavioral level in an increase in generalization in the absence of diminished discrimination. Gain modulation was accompanied by changes in gene and protein expression, indicative of long-term plasticity. Physiological changes were largely independent of corticofugal feedback, and no changes were seen in upstream cochlear nucleus responses, suggesting a key role of the auditory midbrain in sensory gating. Subsequent behavior demonstrated learning of predictable and random patterns and their importance in auditory conditioning. Using longer timescales than previously explored, the combined data show that the auditory midbrain codes statistical learning of temporally sparse patterns, a process that is critical for the detection of relevant stimuli in the constant soundscape that the animal navigates through.

Description: by Keira Sztukowski, Kaila Nip, Paige N. Ostwald, Matheus F. Sathler, Julianna L. Sun, Jiayi Shou, Emily T. Jorgensen, Travis E. Brown, John H. Elder, Craig Miller, Franz Hofmann, Sue VandeWoude, Seonil Kim Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca 2+ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca 2+ activity using intracellular Ca 2+ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca 2+ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca 2+ by the activation of the endoplasmic reticulum (ER)-associated Ca 2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95’s stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca 2+ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca 2+ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca 2+ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.

Description: by Weilong Chen, Yuanyuan Qin, Dong Wang, Lei Zhou, Yin Liu, Sheng Chen, Liang Yin, Yaoxing Xiao, Xiao-Hong Yao, Xiaoli Yang, Wei Ma, Weifeng Chen, Xueyan He, Lixing Zhang, Qifeng Yang, Xiuwu Bian, Zhi-ming Shao, Suling Liu Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.

Description: by Heather Hall, Dalia Perelman, Alessandra Breschi, Patricia Limcaoco, Ryan Kellogg, Tracey McLaughlin, Michael Snyder Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called “glucotypes” that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.

Description: by Dushyant Mishra, Natasha Thorne, Chika Miyamoto, Christopher Jagge, Hubert Amrein Animals employ various types of taste receptors to identify and discriminate between different nutritious food chemicals. These macronutrients are thought to fall into 3 major groups: carbohydrates/sugars, proteins/amino acids, and fats. Here, we report that Drosophila larvae exhibit a novel appetitive feeding behavior towards ribose, ribonucleosides, and RNA. We identified members of the gustatory receptor (Gr) subfamily 28 (Gr28), expressed in both external and internal chemosensory neurons as molecular receptors necessary for cellular and appetitive behavioral responses to ribonucleosides and RNA. Specifically, behavioral preference assays show that larvae are strongly attracted to ribose- or RNA-containing agarose in a Gr28 -dependent manner. Moreover, Ca 2+ imaging experiments reveal that Gr28a -expressing taste neurons are activated by ribose, RNA and some ribonucleosides and that these responses can be conveyed to Gr43a GAL4 fructose-sensing neurons by expressing single members of the Gr28 gene family. Lastly, we establish a critical role in behavioral fitness for the Gr28 genes by showing that Gr28 mutant larvae exhibit low survival rates when challenged to find ribonucleosides in food. Together, our work identifies a novel taste modality dedicated to the detection of RNA and ribonucleosides, nutrients that are essential for survival during the accelerated growth phase of Drosophila larvae.

Description: by Jing Zhao, Lei Zhang, Xiaodong Mu, Christelle Doebelin, William Nguyen, Callen Wallace, Daniel P. Reay, Sara J. McGowan, Lana Corbo, Paula R. Clemens, Gabriela Mustata Wilson, Simon C. Watkins, Laura A. Solt, Michael D. Cameron, Johnny Huard, Laura J. Niedernhofer, Theodore M. Kamenecka, Paul D. Robbins Nuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11–amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of β subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKβ and the IKKγ subunit NEMO. A structure-based pharmacophore model was developed to identify NBD mimetics by in silico screening. Two optimized lead NBD mimetics, SR12343 and SR12460, inhibited tumor necrosis factor α (TNF-α)- and lipopolysaccharide (LPS)-induced NF-κB activation by blocking the interaction between IKKβ and NEMO and suppressed LPS-induced acute pulmonary inflammation in mice. Chronic treatment of a mouse model of Duchenne muscular dystrophy (DMD) with SR12343 and SR12460 attenuated inflammatory infiltration, necrosis and muscle degeneration, demonstrating that these small-molecule NBD mimetics are potential therapeutics for inflammatory and degenerative diseases.

Description: by Leandro Fórnias Machado de Rezende, Juan Pablo Rey-López, Thiago Hérick de Sá, Nicholas Chartres, Alice Fabbri, Lauren Powell, Emmanuel Stamatakis, Lisa Bero Reporting bias in the literature occurs when there is selective revealing or suppression of results, influenced by the direction of findings. We assessed the risk of reporting bias in the epidemiological literature on health-related behavior (tobacco, alcohol, diet, physical activity, and sedentary behavior) and cardiovascular disease mortality and all-cause mortality and provided a comparative assessment of reporting bias between health-related behavior and statin (in primary prevention) meta-analyses. We searched Medline, Embase, Cochrane Methodology Register Database, and Web of Science for systematic reviews synthesizing the associations of health-related behavior and statins with cardiovascular disease mortality and all-cause mortality published between 2010 and 2016. Risk of bias in systematic reviews was assessed using the ROBIS tool. Reporting bias in the literature was evaluated via small-study effect and excess significance tests. We included 49 systematic reviews in our study. The majority of these reviews exhibited a high overall risk of bias, with a higher extent in health-related behavior reviews, relative to statins. We reperformed 111 meta-analyses conducted across these reviews, of which 65% had statistically significant results ( P 〈 0.05). Around 22% of health-related behavior meta-analyses showed small-study effect, as compared to none of statin meta-analyses. Physical activity and the smoking research areas had more than 40% of meta-analyses with small-study effect. We found evidence of excess significance in 26% of health-related behavior meta-analyses, as compared to none of statin meta-analyses. Half of the meta-analyses from physical activity, 26% from diet, 18% from sedentary behavior, 14% for smoking, and 12% from alcohol showed evidence of excess significance bias. These biases may be distorting the body of evidence available by providing inaccurate estimates of preventive effects on cardiovascular and all-cause mortality.

Description: by Marion McElwee, Swetha Vijayakrishnan, Frazer Rixon, David Bhella Herpesviruses include many important human pathogens such as herpes simplex virus, cytomegalovirus, varicella-zoster virus, and the oncogenic Epstein–Barr virus and Kaposi sarcoma–associated herpesvirus. Herpes virions contain a large icosahedral capsid that has a portal at a unique 5-fold vertex, similar to that seen in the tailed bacteriophages. The portal is a molecular motor through which the viral genome enters the capsid during virion morphogenesis. The genome also exits the capsid through the portal-vertex when it is injected through the nuclear pore into the nucleus of a new host cell to initiate infection. Structural investigations of the herpesvirus portal-vertex have proven challenging, owing to the small size of the tail-like portal-vertex–associated tegument (PVAT) and the presence of the tegument layer that lays between the nucleocapsid and the viral envelope, obscuring the view of the portal-vertex. Here, we show the structure of the herpes simplex virus portal-vertex at subnanometer resolution, solved by electron cryomicroscopy (cryoEM) and single-particle 3D reconstruction. This led to a number of new discoveries, including the presence of two previously unknown portal-associated structures that occupy the sites normally taken by the penton and the Ta triplex. Our data revealed that the PVAT is composed of 10 copies of the C-terminal domain of pUL25, which are uniquely arranged as two tiers of star-shaped density. Our 3D reconstruction of the portal-vertex also shows that one end of the viral genome extends outside the portal in the manner described for some bacteriophages but not previously seen in any eukaryote viruses. Finally, we show that the viral genome is consistently packed in a highly ordered left-handed spool to form concentric shells of DNA. Our data provide new insights into the structure of a molecular machine critical to the biology of an important class of human pathogens.

Description: by Roger Palou, Thillaivillalan Dhanaraman, Rim Marrakchi, Mirela Pascariu, Mike Tyers, Damien D’Amours Effective transfer of genetic information during cell division requires a major reorganization of chromosome structure. This process is triggered by condensin, a conserved pentameric ATPase essential for chromosome condensation. How condensin harnesses the energy of ATP hydrolysis to promote chromatin reorganization is unknown. To address this issue, we performed a genetic screen specifically focused on the ATPase domain of Smc4, a core subunit of condensin. Our screen identified mutational hotspots that impair condensin’s ability to condense chromosomes to various degrees. These mutations have distinct effects on viability, genome stability, and chromosome morphology, revealing unique thresholds for condensin enzymatic activity in the execution of its cellular functions. Biochemical analyses indicate that inactivation of Smc4 ATPase activity results in cell lethality because it favors a specific configuration of condensin that locks ATP in the enzyme. Together, our results provide critical insights into the mechanism used by condensin to harness the energy of ATP hydrolysis for the compaction of chromatin.

Description: by William J. Fitzsimmons, Robert J. Woods, John T. McCrone, Andrew Woodman, Jamie J. Arnold, Madhumita Yennawar, Richard Evans, Craig E. Cameron, Adam S. Lauring Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3D G64S , has a significant replication defect and that wild-type (WT) and 3D G64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3D G64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3D G64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3D G64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.

Description: by Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9–mediated genome-wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N -linked protein glycosylation and fucosylation. The screens also identified lysosomal-associated protein transmembrane 4 alpha (LAPTM4A), a poorly characterized four-pass membrane protein, as a factor specifically required for Stxs. Mass spectrometry analysis of glycolipids and their precursors demonstrates that LAPTM4A knockout (KO) cells lack Gb3 biosynthesis. This requirement of LAPTM4A for Gb3 synthesis is not shared by its homolog lysosomal-associated protein transmembrane 4 beta (LAPTM4B), and switching the domains between them determined that the second luminal domain of LAPTM4A is required, potentially acting as a specific “activator” for the GT that synthesizes Gb3. These screens also revealed two Golgi proteins, Transmembrane protein 165 (TMEM165) and Transmembrane 9 superfamily member 2 (TM9SF2), as shared factors required for both Stxs and ricin. TMEM165 KO and TM9SF2 KO cells both showed a reduction in not only Gb3 but also other glycosphingolipids, suggesting that they are required for maintaining proper levels of glycosylation in general in the Golgi. In addition, TM9SF2 KO cells also showed defective endosomal trafficking. These studies reveal key Golgi proteins critical for regulating glycosylation and glycolipid synthesis and provide novel therapeutic targets for blocking Stxs and ricin toxicity.

Description: by Adityarup Chakravorty, Bill Sugden High-risk human papillomaviruses (HPVs) are a major cause of cancers. HPVs infect epithelial cells, and viral oncogenes disrupt several cellular processes, including cell division, differentiation, and apoptosis. Expression of these oncogenes is relatively low in undifferentiated epithelial cells but increases in differentiating cells by unknown mechanisms. In a new study, Parish and colleagues unveil how two cellular proteins, CCCTC-binding factor (CTCF) and Yin Yang 1 (YY1), mediate looping of the HPV18 genome, which regulates expression of viral oncogenes in both dividing and differentiating epithelial cells.

Description: by Sam V. Norman-Haignere, Josh H. McDermott A central goal of sensory neuroscience is to construct models that can explain neural responses to natural stimuli. As a consequence, sensory models are often tested by comparing neural responses to natural stimuli with model responses to those stimuli. One challenge is that distinct model features are often correlated across natural stimuli, and thus model features can predict neural responses even if they do not in fact drive them. Here, we propose a simple alternative for testing a sensory model: we synthesize a stimulus that yields the same model response as each of a set of natural stimuli, and test whether the natural and “model-matched” stimuli elicit the same neural responses. We used this approach to test whether a common model of auditory cortex—in which spectrogram-like peripheral input is processed by linear spectrotemporal filters—can explain fMRI responses in humans to natural sounds. Prior studies have that shown that this model has good predictive power throughout auditory cortex, but this finding could reflect feature correlations in natural stimuli. We observed that fMRI responses to natural and model-matched stimuli were nearly equivalent in primary auditory cortex (PAC) but that nonprimary regions, including those selective for music or speech, showed highly divergent responses to the two sound sets. This dissociation between primary and nonprimary regions was less clear from model predictions due to the influence of feature correlations across natural stimuli. Our results provide a signature of hierarchical organization in human auditory cortex, and suggest that nonprimary regions compute higher-order stimulus properties that are not well captured by traditional models. Our methodology enables stronger tests of sensory models and could be broadly applied in other domains.

Description: by Andrew W. Brooks, Sambhawa Priya, Ran Blekhman, Seth R. Bordenstein Composed of hundreds of microbial species, the composition of the human gut microbiota can vary with chronic diseases underlying health disparities that disproportionally affect ethnic minorities. However, the influence of ethnicity on the gut microbiota remains largely unexplored and lacks reproducible generalizations across studies. By distilling associations between ethnicity and differences in two US-based 16S gut microbiota data sets including 1,673 individuals, we report 12 microbial genera and families that reproducibly vary by ethnicity. Interestingly, a majority of these microbial taxa, including the most heritable bacterial family, Christensenellaceae, overlap with genetically associated taxa and form co-occurring clusters linked by similar fermentative and methanogenic metabolic processes. These results demonstrate recurrent associations between specific taxa in the gut microbiota and ethnicity, providing hypotheses for examining specific members of the gut microbiota as mediators of health disparities.

Description: by Adrija Kalvisa, Majken S. Siersbæk, Stine M. Præstholm, Line J. L. Christensen, Ronni Nielsen, Oliver Stohr, Sabine Vettorazzi, Jan Tuckermann, Morris White, Susanne Mandrup, Lars Grøntved Hepatic circadian gene transcription is tightly coupled to feeding behavior, which has a profound impact on metabolic disorders associated with diet-induced obesity. Here, we describe a genomics approach to uncover mechanisms controlling hepatic postprandial gene expression. Combined transcriptomic and cistromic analysis identified hundreds of circadian-regulated genes and enhancers controlled by feeding. Postprandial suppression of enhancer activity was associated with reduced glucocorticoid receptor (GR) and Forkhead box O1 (FOXO1) occupancy of chromatin correlating with reduced serum corticosterone levels and increased serum insulin levels. Despite substantial co-occupancy of feeding-regulated enhancers by GR and FOXO1, selective disruption of corticosteroid and/or insulin signaling resulted in dysregulation of specific postprandial regulated gene programs. In combination, these signaling pathways operate a major part of the genes suppressed by feeding. Importantly, the feeding response was disrupted in diet-induced obese animals, which was associated with dysregulation of several corticosteroid- and insulin-regulated genes, providing mechanistic insights to dysregulated circadian gene transcription associated with obesity.

Description: by Shima Shahbaz, Najmeh Bozorgmehr, Petya Koleva, Afshin Namdar, Juan Jovel, Roy A. Fava, Shokrollah Elahi Cell-surface transferrin receptor (CD71 + ) erythroid cells are abundant in newborns with immunomodulatory properties. Here, we show that neonatal CD71 + erythroid cells express significant levels of V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) and, via constitutive production of transforming growth factor (TGF)- β, play a pivotal role in promotion of naïve CD4 + T cells into regulatory T cells (Tregs). Interestingly, we discovered that CD71 + VISTA + erythroid cells produce significantly higher levels of TGF-β compared to CD71 + VISTA − erythroid cells and CD71 + erythroid cells from the VISTA knock-out (KO) mice. As a result, CD71 + VISTA + erythroid cells—compared to CD71 + VISTA − and CD71 + erythroid cells from the VISTA KO mice—significantly exceed promotion of naïve CD4 + T cells into induced Tregs (iTreg) via TGF-β in vitro. However, depletion of CD71 + erythroid cells had no significant effects on the frequency of Tregs in vivo. Surprisingly, we observed that the remaining and/or newly generated CD71 + erythroid cells following anti-CD71 antibody administration exhibit a different gene expression profile, evidenced by the up-regulation of VISTA, TGF-β1, TGF-β2, and program death ligand-1 (PDL-1), which may account as a compensatory mechanism for the maintenance of Treg population. We also observed that iTreg development by CD71 + erythroid cells is mediated through the inhibition of key signaling molecules phosphorylated protein kinase B (phospho-Akt) and phosphorylated mechanistic target of rapamycin (phospho-mTOR). Finally, we found that elimination of Tregs using forkhead box P3 (FOXP3)-diptheria toxin receptor (DTR) mice resulted in a significant expansion in the frequency of CD71 + erythroid cells in vivo. Collectively, these studies provide a novel, to our knowledge, insight into the cross-talk between CD71 + erythroid cells and Tregs in newborns. Our results highlight the biological role of CD71 + erythroid cells in the neonatal period and possibly beyond.

Description: by Jia Pei Chan, Bernice H. Wong, Cheen Fei Chin, Dwight L. A. Galam, Juat Chin Foo, Loo Chin Wong, Sujoy Ghosh, Markus R. Wenk, Amaury Cazenave-Gassiot, David L. Silver Brain development requires a massive increase in brain lipogenesis and accretion of the essential omega-3 fatty acid docosahexaenoic acid (DHA). Brain acquisition of DHA is primarily mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) expressed in the endothelium of the blood-brain barrier (BBB) and other abundant cell types within the brain. Mfsd2a transports DHA and other polyunsaturated fatty acids (PUFAs) esterified to lysophosphatidylcholine (LPC-DHA). However, the function of Mfsd2a and DHA in brain development is incompletely understood. Here, we demonstrate, using vascular endothelial-specific and inducible vascular endothelial-specific deletion of Mfsd2a in mice, that Mfsd2a is uniquely required postnatally at the BBB for normal brain growth and DHA accretion, with DHA deficiency preceding the onset of microcephaly. In Mfsd2a-deficient mouse models, a lipidomic signature was identified that is indicative of increased de novo lipogenesis of PUFAs. Gene expression profiling analysis of these DHA-deficient brains indicated that sterol regulatory-element binding protein (Srebp)-1 and Srebp-2 pathways were highly elevated. Mechanistically, LPC-DHA treatment of primary neural stem cells down-regulated Srebp processing and activation in a Mfsd2a-dependent fashion, resulting in profound effects on phospholipid membrane saturation. In addition, Srebp regulated the expression of Mfsd2a. These data identify LPC-DHA transported by Mfsd2a as a physiological regulator of membrane phospholipid saturation acting in a feedback loop on Srebp activity during brain development.

Description: by Lizhen Wu, Jian Cao, Wesley L. Cai, Sabine M. Lang, John R. Horton, Daniel J. Jansen, Zongzhi Z. Liu, Jocelyn F. Chen, Meiling Zhang, Bryan T. Mott, Katherine Pohida, Ganesha Rai, Stephen C. Kales, Mark J. Henderson, Xin Hu, Ajit Jadhav, David J. Maloney, Anton Simeonov, Shu Zhu, Akiko Iwasaki, Matthew D. Hall, Xiaodong Cheng, Gerald S. Shadel, Qin Yan Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8 + T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy.

Description: by Joan M. Martínez-Láinez, David F. Moreno, Eva Parisi, Josep Clotet, Martí Aldea Cell size scales with ploidy in a great range of eukaryotes, but the underlying mechanisms remain unknown. Using various orthogonal single-cell approaches, we show that cell size increases linearly with centromere (CEN) copy number in budding yeast. This effect is due to a G1 delay mediated by increased degradation of Cln3, the most upstream G1 cyclin acting at Start, and specific centromeric signaling proteins, namely Mad3 and Bub3. Mad3 binds both Cln3 and Cdc4, the adaptor component of the Skp1/Cul1/F-box (SCF) complex that targets Cln3 for degradation, these interactions being essential for the CEN-dosage dependent effects on cell size. Our results reveal a pathway that modulates cell size as a function of CEN number, and we speculate that, in cooperation with other CEN-independent mechanisms, it could assist the cell to attain efficient mass/ploidy ratios.

Description: by Maria D. Sallee, Jennifer C. Zonka, Taylor D. Skokan, Brian C. Raftrey, Jessica L. Feldman Non-centrosomal microtubule organizing centers (ncMTOCs) are found in most differentiated cells, but how these structures regulate microtubule organization and dynamics is largely unknown. We optimized a tissue-specific degradation system to test the role of the essential centrosomal microtubule nucleators γ-tubulin ring complex (γ-TuRC) and AIR-1/Aurora A at the apical ncMTOC, where they both localize in Caenorhabditis elegans embryonic intestinal epithelial cells. As at the centrosome, the core γ-TuRC component GIP-1/GCP3 is required to recruit other γ-TuRC components to the apical ncMTOC, including MZT-1/MZT1, characterized here for the first time in animal development. In contrast, AIR-1 and MZT-1 were specifically required to recruit γ-TuRC to the centrosome, but not to centrioles or to the apical ncMTOC. Surprisingly, microtubules remain robustly organized at the apical ncMTOC upon γ-TuRC and AIR-1 co-depletion, and upon depletion of other known microtubule regulators, including TPXL-1/TPX2, ZYG-9/ch-TOG, PTRN-1/CAMSAP, and NOCA-1/Ninein. However, loss of GIP-1 removed a subset of dynamic EBP-2/EB1–marked microtubules, and the remaining dynamic microtubules grew faster. Together, these results suggest that different microtubule organizing centers (MTOCs) use discrete proteins for their function, and that the apical ncMTOC is composed of distinct populations of γ-TuRC-dependent and -independent microtubules that compete for a limited pool of resources.

Description: by Rui Zhang, Yuan Gao, Xiaotong Zhao, Mei Gao, Yanjun Wu, Yingying Han, Yuemei Qiao, Zheng Luo, Li Yang, Jianfeng Chen, Gaoxiang Ge Adipocyte progenitors reside in the stromal vascular fraction (SVF) of adipose tissues that are composed of fibroblasts, immune cells, and endothelial cells. It remains to be elucidated how the SVF regulates adipocyte progenitor fate determination and adipose homeostasis. Here, we report that fibroblast-specific protein-1 (FSP1) + fibroblasts in the SVF are essential to adipose homeostasis. FSP1 + fibroblasts, devoid of adipogenic potential, are adjacent to the preadipocytes in the SVF. Ablation of FSP1 + fibroblasts in mice severely diminishes fat content of adipose depots. Activation of canonical Wnt signaling in the FSP1 + fibroblasts results in gradual loss of adipose tissues and resistance to diet-induced obesity. Alterations in the FSP1 + fibroblasts reduce platelet-derived growth factor (PDGF)-BB signaling and result in the loss of preadipocytes. Reduced PDGF-BB signaling, meanwhile, impairs the adipogenic differentiation capability of preadipocytes by regulating matrix metalloproteinase (MMP) expression, extracellular matrix remodeling, and the activation of Yes-associated protein (YAP) signaling. Thus, FSP1 + fibroblasts are an important niche essential to the maintenance of the preadipocyte pool and its adipogenic potential in adipose homeostasis.

Description: by Alice Antia, Hasan Ahmed, Andreas Handel, Nichole E. Carlson, Ian J. Amanna, Rustom Antia, Mark Slifka Determining the duration of protective immunity requires quantifying the magnitude and rate of loss of antibodies to different virus and vaccine antigens. A key complication is heterogeneity in both the magnitude and decay rate of responses of different individuals to a given vaccine, as well as of a given individual to different vaccines. We analyzed longitudinal data on antibody titers in 45 individuals to characterize the extent of this heterogeneity and used models to determine how it affected the longevity of protective immunity to measles, rubella, vaccinia, tetanus, and diphtheria. Our analysis showed that the magnitude of responses in different individuals varied between 12- and 200-fold (95% coverage) depending on the antigen. Heterogeneity in the magnitude and decay rate contribute comparably to variation in the longevity of protective immunity between different individuals. We found that some individuals have, on average, slightly longer-lasting memory than others—on average, they have higher antibody levels with slower decay rates. We identified different patterns for the loss of protective levels of antibodies to different vaccine and virus antigens. Specifically, we found that for the first 25 to 50 years, virtually all individuals have protective antibody titers against diphtheria and tetanus, respectively, but about 10% of the population subsequently lose protective immunity per decade. In contrast, at the outset, not all individuals had protective titers against measles, rubella, and vaccinia. However, these antibody titers wane much more slowly, with a loss of protective immunity in only 1% to 3% of the population per decade. Our results highlight the importance of long-term longitudinal studies for estimating the duration of protective immunity and suggest both how vaccines might be improved and how boosting schedules might be reevaluated.

Description: by Marija Matejčić, Guillaume Salbreux, Caren Norden Tissue shape is often established early in development and needs to be scaled isotropically during growth. However, the cellular contributors and ways by which cells interact tissue-wide to enable coordinated isotropic tissue scaling are not yet understood. Here, we follow cell and tissue shape changes in the zebrafish retinal neuroepithelium, which forms a cup with a smooth surface early in development and maintains this architecture as it grows. By combining 3D analysis and theory, we show how a global increase in cell height can maintain tissue shape during growth. Timely cell height increase occurs concurrently with a non-cell-autonomous actin redistribution. Blocking actin redistribution and cell height increase perturbs isotropic scaling and leads to disturbed, folded tissue shape. Taken together, our data show how global changes in cell shape enable isotropic growth of the developing retinal neuroepithelium, a concept that could also apply to other systems.

Description: by Kenneth Allen Dyar, Michaël Jean Hubert, Ashfaq Ali Mir, Stefano Ciciliot, Dominik Lutter, Franziska Greulich, Fabiana Quagliarini, Maximilian Kleinert, Katrin Fischer, Thomas Oliver Eichmann, Lauren Emily Wright, Marcia Ivonne Peña Paz, Alberto Casarin, Vanessa Pertegato, Vanina Romanello, Mattia Albiero, Sara Mazzucco, Rosario Rizzuto, Leonardo Salviati, Gianni Biolo, Bert Blaauw, Stefano Schiaffino, N. Henriette Uhlenhaut Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover ( MuRF-1 , Atrogin-1 ). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations.

Description: by Theodore Clark Sex has consequences—indeed, where would we be without it? Yet for all its importance, remarkably little is known about how sex evolved, why it has persisted, or even what mechanisms allow sperm–egg fusion to occur. Fortunately, answers to these questions are beginning to emerge with studies of hapless 2/generative cell specific1 (HAP2/GCS1), a molecular machine that promotes gamete fusion in organisms ranging from protists to flowering plants and insects. In studies by Fedry and colleagues, key structural features of the HAP2 protein are revealed for the first time, lending new insights into its mode of action and reinforcing its relationship to viral proteins that accomplish a similar task and may be intimately linked to the origins of cell–cell fusion events (including sexual reproduction) across evolutionary time.

Description: by Jacob A. Tennessen, Na Wei, Shannon Straub, Rajanikanth Govindarajulu, Aaron Liston, Tia-Lynn Ashman Turnovers of sex-determining systems represent important diversifying forces across eukaryotes. Shifts in sex chromosomes—but conservation of the master sex-determining genes—characterize distantly related animal lineages. Yet in plants, in which separate sexes have evolved repeatedly and sex chromosomes are typically homomorphic, we do not know whether such translocations drive sex-chromosome turnovers within closely related taxonomic groups. This phenomenon can only be demonstrated by identifying sex-associated nucleotide sequences, still largely unknown in plants. The wild North American octoploid strawberries ( Fragaria ) exhibit separate sexes (dioecy) with homomorphic, female heterogametic (ZW) inheritance, yet sex maps to three different chromosomes in different taxa. To characterize these turnovers, we identified sequences unique to females and assembled their reads into contigs. For most octoploid Fragaria taxa, a short (13 kb) sequence was observed in all females and never in males, implicating it as the sex-determining region (SDR). This female-specific “SDR cassette” contains both a gene with a known role in fruit and pollen production and a novel retrogene absent on Z and autosomal chromosomes. Phylogenetic comparison of SDR cassettes revealed three clades and a history of repeated translocation. Remarkably, the translocations can be ordered temporally due to the capture of adjacent sequence with each successive move. The accumulation of the “souvenir” sequence—and the resultant expansion of the hemizygous SDR over time—could have been adaptive by locking genes into linkage with sex. Terminal inverted repeats at the insertion borders suggest a means of movement. To our knowledge, this is the first plant SDR shown to be translocated, and it suggests a new mechanism (“move-lock-grow”) for expansion and diversification of incipient sex chromosomes.

Description: by Bryce A. Mendelsohn, Neal K. Bennett, Maxwell A. Darch, Katharine Yu, Mai K. Nguyen, Daniela Pucciarelli, Maxine Nelson, Max A. Horlbeck, Luke A. Gilbert, William Hyun, Martin Kampmann, Jean L. Nakamura, Ken Nakamura Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for regulating ATP levels are not systematically understood. We combined a pooled clustered regularly interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen to assay ATP concentrations in live human cells. We identified genes not known to be involved in energy metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-based therapies.

Description: by Aude Gilabert, Thomas D. Otto, Gavin G. Rutledge, Blaise Franzon, Benjamin Ollomo, Céline Arnathau, Patrick Durand, Nancy D. Moukodoum, Alain-Prince Okouga, Barthélémy Ngoubangoye, Boris Makanga, Larson Boundenga, Christophe Paupy, François Renaud, Franck Prugnolle, Virginie Rougeron Although Plasmodium vivax is responsible for the majority of malaria infections outside Africa, little is known about its evolution and pathway to humans. Its closest genetic relative, P . vivax -like, was discovered in African great apes and is hypothesized to have given rise to P . vivax in humans. To unravel the evolutionary history and adaptation of P . vivax to different host environments, we generated using long- and short-read sequence technologies 2 new P . vivax -like reference genomes and 9 additional P . vivax -like genotypes. Analyses show that the genomes of P . vivax and P . vivax -like are highly similar and colinear within the core regions. Phylogenetic analyses clearly show that P . vivax -like parasites form a genetically distinct clade from P . vivax . Concerning the relative divergence dating, we show that the evolution of P . vivax in humans did not occur at the same time as the other agents of human malaria, thus suggesting that the transfer of Plasmodium parasites to humans happened several times independently over the history of the Homo genus. We further identify several key genes that exhibit signatures of positive selection exclusively in the human P . vivax parasites. Two of these genes have been identified to also be under positive selection in the other main human malaria agent, P . falciparum , thus suggesting their key role in the evolution of the ability of these parasites to infect humans or their anthropophilic vectors. Finally, we demonstrate that some gene families important for red blood cell (RBC) invasion (a key step of the life cycle of these parasites) have undergone lineage-specific evolution in the human parasite (e.g., reticulocyte-binding proteins [RBPs]).

Description: by Wenhui Zong, Yan Wang, Quan Tang, Heng Zhang, Fengwei Yu Refinement of the nervous system depends on selective removal of excessive axons/dendrites, a process known as pruning. Drosophila ddaC sensory neurons prune their larval dendrites via endo-lysosomal degradation of the L1-type cell adhesion molecule (L1-CAM), Neuroglian (Nrg). Here, we have identified a novel gene, pruning defect 1 ( prd1 ), which governs dendrite pruning of ddaC neurons. We show that Prd1 colocalizes with the clathrin adaptor protein α-Adaptin (α-Ada) and the kinesin-3 immaculate connections (Imac)/Uncoordinated-104 (Unc-104) in dendrites. Moreover, Prd1 physically associates with α-Ada and Imac, which are both critical for dendrite pruning. Prd1, α-Ada, and Imac promote dendrite pruning via the regulation of endo-lysosomal degradation of Nrg. Importantly, genetic interactions among prd1 , α-adaptin , and imac indicate that they act in the same pathway to promote dendrite pruning. Our findings indicate that Prd1, α-Ada, and Imac act together to regulate discrete distribution of α-Ada/clathrin puncta, facilitate endo-lysosomal degradation, and thereby promote dendrite pruning in sensory neurons.

Description: by Jimena Barbeito-Andrés, Lavínia Schuler-Faccini, Patricia Pestana Garcez Zika virus (ZIKV) is a health burden due to the severe neurological abnormalities that arise after congenital infection. Although multiple experimental studies have linked ZIKV with neural birth defects, the scientific community has not been able to fully explain why Congenital Zika Syndrome (CZS) was only apparent after the virus entered the Americas and why these occurrences have an asymmetric geographic distribution. Here, we review the impact of ZIKV infection on human populations by exploring evolutionary changes in the virus’ genome as well as examining the diverse genetic and environmental cofactors of the human hosts.

Description: by Yuval Zur, Lior Rosenfeld, Chen Anna Keshelman, Nofar Dalal, Gali Guterman-Ram, Ayelet Orenbuch, Yulia Einav, Noam Levaot, Niv Papo There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and α v β 3 integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and α v β 3 integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and α v β 3 integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function.

Description: by Eric M. Erkenbrack, Jamie D. Maziarz, Oliver W. Griffith, Cong Liang, Arun R. Chavan, Mauris C. Nnamani, Günter P. Wagner Among animal species, cell types vary greatly in terms of number and kind. The number of cell types found within an organism differs considerably between species, and cell type diversity is a significant contributor to differences in organismal structure and function. These observations suggest that cell type origination is a significant source of evolutionary novelty. The molecular mechanisms that result in the evolution of novel cell types, however, are poorly understood. Here, we show that a novel cell type of eutherians mammals, the decidual stromal cell (DSC), evolved by rewiring an ancestral cellular stress response. We isolated the precursor cell type of DSCs, endometrial stromal fibroblasts (ESFs), from the opossum Monodelphis domestica . We show that, in opossum ESFs, the majority of decidual core regulatory genes respond to decidualizing signals but do not regulate decidual effector genes. Rather, in opossum ESFs, decidual transcription factors function in apoptotic and oxidative stress response. We propose that rewiring of cellular stress responses was an important mechanism for the evolution of the eutherian decidual cell type.

Description: by Bryce A. Mendelsohn, Neal K. Bennett, Maxwell A. Darch, Katharine Yu, Mai K. Nguyen, Daniela Pucciarelli, Maxine Nelson, Max A. Horlbeck, Luke A. Gilbert, William Hyun, Martin Kampmann, Jean L. Nakamura, Ken Nakamura Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for regulating ATP levels are not systematically understood. We combined a pooled clustered regularly interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen to assay ATP concentrations in live human cells. We identified genes not known to be involved in energy metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-based therapies.

Description: by Jacob A. Tennessen, Na Wei, Shannon Straub, Rajanikanth Govindarajulu, Aaron Liston, Tia-Lynn Ashman Turnovers of sex-determining systems represent important diversifying forces across eukaryotes. Shifts in sex chromosomes—but conservation of the master sex-determining genes—characterize distantly related animal lineages. Yet in plants, in which separate sexes have evolved repeatedly and sex chromosomes are typically homomorphic, we do not know whether such translocations drive sex-chromosome turnovers within closely related taxonomic groups. This phenomenon can only be demonstrated by identifying sex-associated nucleotide sequences, still largely unknown in plants. The wild North American octoploid strawberries ( Fragaria ) exhibit separate sexes (dioecy) with homomorphic, female heterogametic (ZW) inheritance, yet sex maps to three different chromosomes in different taxa. To characterize these turnovers, we identified sequences unique to females and assembled their reads into contigs. For most octoploid Fragaria taxa, a short (13 kb) sequence was observed in all females and never in males, implicating it as the sex-determining region (SDR). This female-specific “SDR cassette” contains both a gene with a known role in fruit and pollen production and a novel retrogene absent on Z and autosomal chromosomes. Phylogenetic comparison of SDR cassettes revealed three clades and a history of repeated translocation. Remarkably, the translocations can be ordered temporally due to the capture of adjacent sequence with each successive move. The accumulation of the “souvenir” sequence—and the resultant expansion of the hemizygous SDR over time—could have been adaptive by locking genes into linkage with sex. Terminal inverted repeats at the insertion borders suggest a means of movement. To our knowledge, this is the first plant SDR shown to be translocated, and it suggests a new mechanism (“move-lock-grow”) for expansion and diversification of incipient sex chromosomes.

Description: by Aude Gilabert, Thomas D. Otto, Gavin G. Rutledge, Blaise Franzon, Benjamin Ollomo, Céline Arnathau, Patrick Durand, Nancy D. Moukodoum, Alain-Prince Okouga, Barthélémy Ngoubangoye, Boris Makanga, Larson Boundenga, Christophe Paupy, François Renaud, Franck Prugnolle, Virginie Rougeron Although Plasmodium vivax is responsible for the majority of malaria infections outside Africa, little is known about its evolution and pathway to humans. Its closest genetic relative, P . vivax -like, was discovered in African great apes and is hypothesized to have given rise to P . vivax in humans. To unravel the evolutionary history and adaptation of P . vivax to different host environments, we generated using long- and short-read sequence technologies 2 new P . vivax -like reference genomes and 9 additional P . vivax -like genotypes. Analyses show that the genomes of P . vivax and P . vivax -like are highly similar and colinear within the core regions. Phylogenetic analyses clearly show that P . vivax -like parasites form a genetically distinct clade from P . vivax . Concerning the relative divergence dating, we show that the evolution of P . vivax in humans did not occur at the same time as the other agents of human malaria, thus suggesting that the transfer of Plasmodium parasites to humans happened several times independently over the history of the Homo genus. We further identify several key genes that exhibit signatures of positive selection exclusively in the human P . vivax parasites. Two of these genes have been identified to also be under positive selection in the other main human malaria agent, P . falciparum , thus suggesting their key role in the evolution of the ability of these parasites to infect humans or their anthropophilic vectors. Finally, we demonstrate that some gene families important for red blood cell (RBC) invasion (a key step of the life cycle of these parasites) have undergone lineage-specific evolution in the human parasite (e.g., reticulocyte-binding proteins [RBPs]).

Description: by Wenhui Zong, Yan Wang, Quan Tang, Heng Zhang, Fengwei Yu Refinement of the nervous system depends on selective removal of excessive axons/dendrites, a process known as pruning. Drosophila ddaC sensory neurons prune their larval dendrites via endo-lysosomal degradation of the L1-type cell adhesion molecule (L1-CAM), Neuroglian (Nrg). Here, we have identified a novel gene, pruning defect 1 ( prd1 ), which governs dendrite pruning of ddaC neurons. We show that Prd1 colocalizes with the clathrin adaptor protein α-Adaptin (α-Ada) and the kinesin-3 immaculate connections (Imac)/Uncoordinated-104 (Unc-104) in dendrites. Moreover, Prd1 physically associates with α-Ada and Imac, which are both critical for dendrite pruning. Prd1, α-Ada, and Imac promote dendrite pruning via the regulation of endo-lysosomal degradation of Nrg. Importantly, genetic interactions among prd1 , α-adaptin , and imac indicate that they act in the same pathway to promote dendrite pruning. Our findings indicate that Prd1, α-Ada, and Imac act together to regulate discrete distribution of α-Ada/clathrin puncta, facilitate endo-lysosomal degradation, and thereby promote dendrite pruning in sensory neurons.

Description: by Yuval Zur, Lior Rosenfeld, Chen Anna Keshelman, Nofar Dalal, Gali Guterman-Ram, Ayelet Orenbuch, Yulia Einav, Noam Levaot, Niv Papo There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and α v β 3 integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and α v β 3 integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and α v β 3 integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function.

Description: by Peter J. Mumby, Karlo Hock, Scott A. Condie, Juan C. Ortiz, Nicholas H. Wolff, Kenneth R. N. Anthony, Paul G. Blackwell

Description: by Rodrigo P. P. Almeida The effective management of plant diseases is of fundamental importance for food production, forestry, and other plant-derived products, as well as for the sustainability of natural environments. When considering the impact of a plant pathogen, the financial costs incurred by an outbreak usually receive the most focus, but there are other much less understood consequences for the affected society, culture, and environment due to disease. This poorly studied layer of complexity is particularly relevant for emerging outbreaks, of which often only limited knowledge is available to devise management strategies, but decisions and actions must be made quickly. The recent outbreak of a bacterial plant pathogen in Europe illustrates how understanding not only the biology of an emerging pathogen but also the cultural context is critical for effectively communicating and engaging with stakeholders and policy makers in order to implement successful disease control strategies.

Description: by Norman R. Pace In the context of biology as a whole and of our own personal lives, seemingly small things can prove surprisingly influential. Here, I consider the powerful impact of small organisms—the inhabitants of the microbial world—and the small events that shaped my own development as a scientist. I reflect on the early days of the fields of molecular biology and microbial ecology and my own role in the origin story of what we now call “metagenomics”.

Description: by Mary Bushman, Rustom Antia, Venkatachalam Udhayakumar, Jacobus C. de Roode In the malaria parasite P . falciparum , drug resistance generally evolves first in low-transmission settings, such as Southeast Asia and South America. Resistance takes noticeably longer to appear in the high-transmission settings of sub-Saharan Africa, although it may spread rapidly thereafter. Here, we test the hypothesis that competitive suppression of drug-resistant parasites by drug-sensitive parasites may inhibit evolution of resistance in high-transmission settings, where mixed-strain infections are common. We employ a cross-scale model, which simulates within-host (infection) dynamics and between-host (transmission) dynamics of sensitive and resistant parasites for a population of humans and mosquitoes. Using this model, we examine the effects of transmission intensity, selection pressure, fitness costs of resistance, and cross-reactivity between strains on the establishment and spread of resistant parasites. We find that resistant parasites, introduced into the population at a low frequency, are more likely to go extinct in high-transmission settings, where drug-sensitive competitors and high levels of acquired immunity reduce the absolute fitness of the resistant parasites. Under strong selection from antimalarial drug use, however, resistance spreads faster in high-transmission settings than low-transmission ones. These contrasting results highlight the distinction between establishment and spread of resistance and suggest that the former but not the latter may be inhibited in high-transmission settings. Our results suggest that within-host competition is a key factor shaping the evolution of drug resistance in P . falciparum .

Description: by Michael Bode, Lance Bode, Severine Choukroun, Maurice K. James, Luciano B. Mason

Description: by Daniel Nunes, Thomas Kuner Dendrodendritic synaptic interactions between olfactory bulb mitral and granule cells represent a key neuronal mechanism of odor discrimination. Dendritic release of gamma-aminobutyric acid (GABA) from granule cells contributes to stimulus-dependent, rapid, and accurate odor discrimination, yet the physiological mechanisms governing this release and its behavioral relevance are unknown. Here, we show that granule cells express the voltage-gated sodium channel α-subunit Na V 1.2 in clusters distributed throughout the cell surface including dendritic spines. Deletion of Na V 1.2 in granule cells abolished spiking and GABA release as well as inhibition of synaptically connected mitral cells (MCs). As a consequence, mice required more time to discriminate highly similar odorant mixtures, while odor discrimination learning remained unaffected. In conclusion, we show that expression of Na V 1.2 in granule cells is crucial for physiological dendritic GABA release and rapid discrimination of similar odorants with high accuracy. Hence, our data indicate that neurotransmitter-releasing dendritic spines function just like axon terminals.

Description: by Adam J. Kucharski, Justin Lessler, Derek A. T. Cummings, Steven Riley Human immunity influences the evolution and impact of influenza strains. Because individuals are infected with multiple influenza strains during their lifetime, and each virus can generate a cross-reactive antibody response, it is challenging to quantify the processes that shape observed immune responses or to reliably detect recent infection from serological samples. Using a Bayesian model of antibody dynamics at multiple timescales, we explain complex cross-reactive antibody landscapes by inferring participants’ histories of infection with serological data from cross-sectional and longitudinal studies of influenza A/H3N2 in southern China and Vietnam. We find that individual-level influenza antibody profiles can be explained by a short-lived, broadly cross-reactive response that decays within a year to leave a smaller long-term response acting against a narrower range of strains. We also demonstrate that accounting for dynamic immune responses alongside infection history can provide a more accurate alternative to traditional definitions of seroconversion for the estimation of infection attack rates. Our work provides a general model for quantifying aspects of influenza immunity acting at multiple timescales based on contemporary serological data and suggests a two-armed immune response to influenza infection consistent with competitive dynamics between B cell populations. This approach to analysing multiple timescales for antigenic responses could also be applied to other multistrain pathogens such as dengue and related flaviviruses.

Description: by Toshitaka N. Suzuki, David Wheatcroft, Michael Griesser Syntax is the set of rules for combining words into phrases, providing the basis for the generative power of linguistic expressions. In human language, the principle of compositionality governs how words are combined into a larger unit, the meaning of which depends on both the meanings of the words and the way in which they are combined. This linguistic capability, i.e., compositional syntax, has long been considered a trait unique to human language. Here, we review recent studies on call combinations in a passerine bird, the Japanese tit ( Parus minor ), that provide the first firm evidence for compositional syntax in a nonhuman animal. While it has been suggested that the findings of these studies fail to provide evidence for compositionality in Japanese tits, this criticism is based on misunderstanding of experimental design, misrepresentation of the importance of word order in human syntax, and necessitating linguistic capabilities beyond those given by the standard definition of compositionality. We argue that research on avian call combinations has provided the first steps in elucidating how compositional expressions could have emerged in animal communication systems.

Description: by Jimena Barbeito-Andrés, Lavínia Schuler-Faccini, Patricia Pestana Garcez Zika virus (ZIKV) is a health burden due to the severe neurological abnormalities that arise after congenital infection. Although multiple experimental studies have linked ZIKV with neural birth defects, the scientific community has not been able to fully explain why Congenital Zika Syndrome (CZS) was only apparent after the virus entered the Americas and why these occurrences have an asymmetric geographic distribution. Here, we review the impact of ZIKV infection on human populations by exploring evolutionary changes in the virus’ genome as well as examining the diverse genetic and environmental cofactors of the human hosts.

Description: by Eric M. Erkenbrack, Jamie D. Maziarz, Oliver W. Griffith, Cong Liang, Arun R. Chavan, Mauris C. Nnamani, Günter P. Wagner Among animal species, cell types vary greatly in terms of number and kind. The number of cell types found within an organism differs considerably between species, and cell type diversity is a significant contributor to differences in organismal structure and function. These observations suggest that cell type origination is a significant source of evolutionary novelty. The molecular mechanisms that result in the evolution of novel cell types, however, are poorly understood. Here, we show that a novel cell type of eutherians mammals, the decidual stromal cell (DSC), evolved by rewiring an ancestral cellular stress response. We isolated the precursor cell type of DSCs, endometrial stromal fibroblasts (ESFs), from the opossum Monodelphis domestica . We show that, in opossum ESFs, the majority of decidual core regulatory genes respond to decidualizing signals but do not regulate decidual effector genes. Rather, in opossum ESFs, decidual transcription factors function in apoptotic and oxidative stress response. We propose that rewiring of cellular stress responses was an important mechanism for the evolution of the eutherian decidual cell type.

Description: by Jane Nielsen, Tania Bubela, Don R. C. Chalmers, Amber Johns, Linda Kahl, Joanne Kamens, Charles Lawson, John Liddicoat, Rebekah McWhirter, Ann Monotti, James Scheibner, Tess Whitton, Dianne Nicol Whereas biological materials were once transferred freely, there has been a marked shift in the formalisation of exchanges involving these materials, primarily through the use of Material Transfer Agreements (MTAs). This paper considers how risk aversion dominates MTA negotiations and the impact it may have on scientific progress. Risk aversion is often based on unwarranted fears of incurring liability through the use of a material or loss of control or missing out on commercialisation opportunities. Evidence to date has suggested that complexity tends to permeate even straightforward transactions despite extensive efforts to implement simple, standard MTAs. We argue that in most cases, MTAs need do little more than establish provenance, and any attempt to extend MTAs beyond this simple function constitutes stifling behaviour. Drawing on available examples of favourable practice, we point to a number of strategies that may usefully be employed to reduce risk-averse tendencies, including the promotion of simplicity, education of those engaged in the MTA process, and achieving a cultural shift in the way in which technology transfer office (TTO) success is measured in institutions employing MTAs.

Description: by Theodore Clark Sex has consequences—indeed, where would we be without it? Yet for all its importance, remarkably little is known about how sex evolved, why it has persisted, or even what mechanisms allow sperm–egg fusion to occur. Fortunately, answers to these questions are beginning to emerge with studies of hapless 2/generative cell specific1 (HAP2/GCS1), a molecular machine that promotes gamete fusion in organisms ranging from protists to flowering plants and insects. In studies by Fedry and colleagues, key structural features of the HAP2 protein are revealed for the first time, lending new insights into its mode of action and reinforcing its relationship to viral proteins that accomplish a similar task and may be intimately linked to the origins of cell–cell fusion events (including sexual reproduction) across evolutionary time.

Description: by Simon W. Townsend, Sabrina Engesser, Sabine Stoll, Klaus Zuberbühler, Balthasar Bickel A key step in understanding the evolution of human language involves unravelling the origins of language’s syntactic structure. One approach seeks to reduce the core of syntax in humans to a single principle of recursive combination, merge, for which there is no evidence in other species. We argue for an alternative approach. We review evidence that beneath the staggering complexity of human syntax, there is an extensive layer of nonproductive, nonhierarchical syntax that can be fruitfully compared to animal call combinations. This is the essential groundwork that must be explored and integrated before we can elucidate, with sufficient precision, what exactly made it possible for human language to explode its syntactic capacity, transitioning from simple nonproductive combinations to the unrivalled complexity that we now have.

Description: by Gabriel Byrne, Sara M. O’Rourke, David L. Alexander, Bin Yu, Rachel C. Doran, Meredith Wright, Qiushi Chen, Parastoo Azadi, Phillip W. Berman Over the last decade, multiple broadly neutralizing monoclonal antibodies (bN-mAbs) to the HIV-1 envelope protein (Env) gp120 have been described. Many of these recognize epitopes consisting of both amino acid and glycan residues. Moreover, the glycans required for binding of these bN-mAbs are early intermediates in the N-linked glycosylation pathway. This type of glycosylation substantially alters the mass and net charge of Envs compared to molecules with the same amino acid sequence but possessing mature, complex (sialic acid–containing) carbohydrates. Since cell lines suitable for biopharmaceutical production that limit N-linked glycosylation to mannose-5 (Man 5 ) or earlier intermediates are not readily available, the production of vaccine immunogens displaying these glycan-dependent epitopes has been challenging. Here, we report the development of a stable suspension-adapted Chinese hamster ovary (CHO) cell line that limits glycosylation to Man 5 and earlier intermediates. This cell line was created using the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing system and contains a mutation that inactivates the gene encoding Mannosyl (Alpha-1,3-)-Glycoprotein Beta-1,2-N-Acetylglucosaminyltransferase (MGAT1). Monomeric gp120s produced in the MGAT1 − CHO cell line exhibit improved binding to prototypic glycan-dependent bN-mAbs directed to the V1/V2 domain (e.g., PG9) and the V3 stem (e.g., PGT128 and 10–1074) while preserving the structure of the important glycan-independent epitopes (e.g., VRC01). The ability of the MGAT1 − CHO cell line to limit glycosylation to early intermediates in the N-linked glycosylation pathway without impairing the doubling time or ability to grow at high cell densities suggests that it will be a useful substrate for the biopharmaceutical production of HIV-1 vaccine immunogens.

Description: by Imke Spöring, Vincent A. Martinez, Christian Hotz, Jana Schwarz-Linek, Keara L. Grady, Josué M. Nava-Sedeño, Teun Vissers, Hanna M. Singer, Manfred Rohde, Carole Bourquin, Haralampos Hatzikirou, Wilson C. K. Poon, Yann S. Dufour, Marc Erhardt Most bacteria swim in liquid environments by rotating one or several flagella. The long external filament of the flagellum is connected to a membrane-embedded basal body by a flexible universal joint, the hook, which allows the transmission of motor torque to the filament. The length of the hook is controlled on a nanometer scale by a sophisticated molecular ruler mechanism. However, why its length is stringently controlled has remained elusive. We engineered and studied a diverse set of hook-length variants of Salmonella enterica . Measurements of plate-assay motility, single-cell swimming speed, and directional persistence in quasi-2D and population-averaged swimming speed and body angular velocity in 3D revealed that the motility performance is optimal around the wild-type hook length. We conclude that too-short hooks may be too stiff to function as a junction and too-long hooks may buckle and create instability in the flagellar bundle. Accordingly, peritrichously flagellated bacteria move most efficiently as the distance travelled per body rotation is maximal and body wobbling is minimized. Thus, our results suggest that the molecular ruler mechanism evolved to control flagellar hook growth to the optimal length consistent with efficient bundle formation. The hook-length control mechanism is therefore a prime example of how bacteria evolved elegant but robust mechanisms to maximize their fitness under specific environmental constraints.

Description: by Angela M. Phillips, Anna I. Ponomarenko, Kenny Chen, Orr Ashenberg, Jiayuan Miao, Sean M. McHugh, Vincent L. Butty, Charles A. Whittaker, Christopher L. Moore, Jesse D. Bloom, Yu-Shan Lin, Matthew D. Shoulders The threat of viral pandemics demands a comprehensive understanding of evolution at the host–pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition–mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.

Description: by Tara D. Fischer, Pramod K. Dash, Jun Liu, M. Neal Waxham Neurons project axons to local and distal sites and can display heterogeneous morphologies with limited physical dimensions that may influence the structure of large organelles such as mitochondria. Using cryo-electron tomography (cryo-ET), we characterized native environments within axons and presynaptic varicosities to examine whether spatial restrictions within these compartments influence the morphology of mitochondria. Segmented tomographic reconstructions revealed distinctive morphological characteristics of mitochondria residing at the narrowed boundary between presynaptic varicosities and axons with limited physical dimensions (approximately 80 nm), compared to mitochondria in nonspatially restricted environments. Furthermore, segmentation of the tomograms revealed discrete organizations between the inner and outer membranes, suggesting possible independent remodeling of each membrane in mitochondria at spatially restricted axonal/varicosity boundaries. Thus, cryo-ET of mitochondria within axonal subcompartments reveals that spatial restrictions do not obstruct mitochondria from residing within them, but limited available space can influence their gross morphology and the organization of the inner and outer membranes. These findings offer new perspectives on the influence of physical and spatial characteristics of cellular environments on mitochondrial morphology and highlight the potential for remarkable structural plasticity of mitochondria to adapt to spatial restrictions within axons.

Description: by Michael Eitel, Warren R. Francis, Frédérique Varoqueaux, Jean Daraspe, Hans-Jürgen Osigus, Stefan Krebs, Sergio Vargas, Helmut Blum, Gray A. Williams, Bernd Schierwater, Gert Wörheide

Description: by Britt Koskella Host populations are under continual selection by parasites due to reduced fitness of infected individuals relative to uninfected individuals. This should select for host resistance against parasites, and ample evidence from the laboratory and natural populations demonstrates that hosts can respond rapidly to parasitism by evolving resistance. Why then do parasites still exist? In part, this is due to ongoing arms races as parasites evolve counteradaptations to overcome resistance and to the presence of spatial structure and refuges. However, host–parasite coexistence can also be explained through loss of resistance over time due either to selection against costly resistance mechanisms or constant loss of resistance via reversion mutations.

Description: by Hélène Chabas, Sébastien Lion, Antoine Nicot, Sean Meaden, Stineke van Houte, Sylvain Moineau, Lindi M. Wahl, Edze R. Westra, Sylvain Gandon The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pathogens to escape host resistance may boost pathogen spread and promote emergence. Yet, the ecological factors that govern such evolutionary emergence remain elusive because of the lack of ecological realism of current theoretical frameworks and the difficulty of experimentally testing their predictions. Here, we develop a theoretical model to explore the effects of the heterogeneity of the host population on the probability of pathogen emergence, with or without pathogen evolution. We show that evolutionary emergence and the spread of escape mutations in the pathogen population is more likely to occur when the host population contains an intermediate proportion of resistant hosts. We also show that the probability of pathogen emergence rapidly declines with the diversity of resistance in the host population. Experimental tests using lytic bacteriophages infecting their bacterial hosts containing Clustered Regularly Interspaced Short Palindromic Repeat and CRISPR-associated (CRISPR-Cas) immune defenses confirm these theoretical predictions. These results suggest effective strategies for cross-species spillover and for the management of emerging infectious diseases.

Description: by Tobias Grossmann, Manuela Missana, Kathleen M. Krol Altruistic behavior is considered a key feature of the human cooperative makeup, with deep ontogenetic roots. The tendency to engage in altruistic behavior varies between individuals and has been linked to differences in responding to fearful faces. The current study tests the hypothesis that this link exists from early in human ontogeny. Using eye tracking, we examined whether attentional responses to fear in others at 7 months of age predict altruistic behavior at 14 months of age. Our analysis revealed that altruistic behavior in toddlerhood was predicted by infants’ attention to fearful faces but not happy or angry faces. Specifically, infants who showed heightened initial attention to (i.e., prolonged first look) followed by greater disengagement (i.e., reduced attentional bias over 15 seconds) from fearful faces at 7 months displayed greater prosocial behavior at 14 months of age. Our data further show that infants’ attentional bias to fearful faces and their altruistic behavior was predicted by brain responses in the dorsolateral prefrontal cortex (dlPFC), measured through functional near-infrared spectroscopy (fNIRS). This suggests that, from early in ontogeny, variability in altruistic helping behavior is linked to our responsiveness to seeing others in distress and brain processes implicated in attentional control. These findings critically advance our understanding of the emergence of altruism in humans by identifying responsiveness to fear in others as an early precursor contributing to variability in prosocial behavior.

Description: by Salah Mahmoudi, Sofia Henriksson, Irene Weibrecht, Stephen Smith, Ola Söderberg, Staffan Strömblad, Klas G. Wiman, Marianne Farnebo

Description: by Christoph Grundner Tuberculosis (TB) is now the leading cause of death from infectious disease. On September 26, 2018, the United Nations (UN) General Assembly holds its first high-level meeting on TB, a once-in-a-lifetime chance to commit governments around the world to redouble their TB control efforts. Here I share impressions from a preparatory meeting at the UN in June and make the case for basic research as a central component of any future TB control strategy. The pathogen that causes TB, Mycobacterium tuberculosis , is still largely a mystery. But if we do not understand the basic, fundamental workings of the pathogen, we cannot hope to develop 21st century interventions for the disease.

Description: by Min Pan, Henrik Schinke, Elke Luxenburger, Gisela Kranz, Julius Shakhtour, Darko Libl, Yuanchi Huang, Aljaž Gaber, Miha Pavšič, Brigita Lenarčič, Julia Kitz, Mark Jakob, Sabina Schwenk-Zieger, Martin Canis, Julia Hess, Kristian Unger, Philipp Baumeister, Olivier Gires Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFR low /EpCAM high HNSCC patients ( n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain extracellular domain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.

Description: by Lukas Landler, David A. Keays Over the last three decades, evidence has emerged that low-intensity magnetic fields can influence biological systems. It is now well established that migratory birds have the capacity to detect the Earth's magnetic field; it has been reported that power lines are associated with childhood leukemia and that pulsed magnetic fields increase the production of reactive oxidative species (ROS) in cellular systems. Justifiably, studies in this field have been viewed with skepticism, as the underlying molecular mechanisms are unknown. In the accompanying paper, Sherrard and colleagues report that low-flux pulsed electromagnetic fields (PEMFs) result in aversive behavior in Drosophila larvae and ROS production in cell culture. They further report that these responses require the presence of cryptochrome, a putative magnetoreceptor. If correct, it is conceivable that carcinogenesis associated with power lines, PEMF-induced ROS generation, and animal magnetoreception share a common mechanistic basis.

Description: by Lauren A. Richardson In this Open Highlight, Senior Editor Lauren Richardson features exciting new Open Access research into how species evolve their characteristic traits.

Description: by Paul Wolff Mitchell The discovery of nearly 180-year-old cranial measurements in the archives of 19th century American physician and naturalist Samuel George Morton can address a lingering debate, begun in the late 20th century by paleontologist and historian of science Stephen Jay Gould, about the unconscious bias alleged in Morton’s comparative data of brain size in human racial groups. Analysis of Morton’s lost data and the records of his studies does not support Gould’s arguments about Morton’s biased data collection. However, historical contextualization of Morton with his scientific peers, especially German anatomist Friedrich Tiedemann, suggests that, while Morton’s data may have been unbiased, his cranial race science was not. Tiedemann and Morton independently produced similar data about human brain size in different racial groups but analyzed and interpreted their nearly equivalent results in dramatically different ways: Tiedemann using them to argue for equality and the abolition of slavery, and Morton using them to entrench racial divisions and hierarchy. These differences draw attention to the epistemic limitations of data and the pervasive role of bias within the broader historical, social, and cultural context of science.

Description: by Gheylen Daghfous, François Auclair, Felix Clotten, Jean-Luc Létourneau, Elias Atallah, Jean-Patrick Millette, Dominique Derjean, Richard Robitaille, Barbara S. Zielinski, Réjean Dubuc Odor-guided behaviors, including homing, predator avoidance, or food and mate searching, are ubiquitous in animals. It is only recently that the neural substrate underlying olfactomotor behaviors in vertebrates was uncovered in lampreys. It consists of a neural pathway extending from the medial part of the olfactory bulb (medOB) to locomotor control centers in the brainstem via a single relay in the caudal diencephalon. This hardwired olfactomotor pathway is present throughout life and may be responsible for the olfactory-induced motor behaviors seen at all life stages. We investigated modulatory mechanisms acting on this pathway by conducting anatomical (tract tracing and immunohistochemistry) and physiological (intracellular recordings and calcium imaging) experiments on lamprey brain preparations. We show that the GABAergic circuitry of the olfactory bulb (OB) acts as a gatekeeper of this hardwired sensorimotor pathway. We also demonstrate the presence of a novel olfactomotor pathway that originates in the non-medOB and consists of a projection to the lateral pallium (LPal) that, in turn, projects to the caudal diencephalon and to the mesencephalic locomotor region (MLR). Our results indicate that olfactory inputs can induce behavioral responses by activating brain locomotor centers via two distinct pathways that are strongly modulated by GABA in the OB. The existence of segregated olfactory subsystems in lampreys suggests that the organization of the olfactory system in functional clusters may be a common ancestral trait of vertebrates.

Description: by Liza Gross This Editorial introduces a Collection of articles in which the authors explore the challenges and pitfalls of communicating the science of climate change in an atmosphere where evidence doesn't matter.

Description: by Edward B. Chuong The co-option of endogenous retroviruses (ERVs) is increasingly recognized as a recurrent theme in placental biology, which has far-reaching implications for our understanding of mammalian evolution and reproductive health. Most research in this area has focused on ERV-derived proteins, which have been repeatedly co-opted to promote cell–cell fusion and immune modulation in the placenta. ERVs also harbor regulatory sequences that can potentially control placental gene expression, but there has been limited evidence to support this role. In a recent study, Dunn-Fletcher and colleagues discover a striking example of an ERV-derived enhancer element that has been co-opted to regulate a gene important for human pregnancy. Using genomic and experimental approaches, they firmly establish that a primate-specific ERV functions as a placenta-specific enhancer for corticotropin-releasing hormone ( CRH ), a hormone linked to the control of birth timing in humans. Their findings implicate an extensive yet understudied role for retroviruses in shaping the evolution of placental gene regulatory networks.

Description: by Michael F. Dahlstrom, Dietram A. Scheufele Compelling stories about science can motivate people to engage and respond to relevant problems facing society. While science plays a unique role in society, providing the best available evidence for policy choices, understanding the world, and informing citizens’ daily lives, it does not hold any intrinsic advantage in creating captivating stories for mass audiences. Instead, science must compete with other storytellers, many of whom are not bound to scientific evidence. This presents a paradox—how can science preserve its credibility as curator of knowledge while engaging audiences with a communication format that is agnostic to truth?

Description: by Sue E. Moore, Randall R. Reeves Global warming is significantly altering arctic marine ecosystems. Specifically, the precipitous loss of sea ice is creating a dichotomy between ice-dependent polar bears and pinnipeds that are losing habitat and some cetaceans that are gaining habitat. While final outcomes are hard to predict for the many and varied marine mammal populations that rely on arctic habitats, we suggest a simplified framework to assess status, based upon ranking a population’s size, range, behavior, and health. This basic approach is proposed as a means to prioritize and expedite conservation and management efforts in an era of rapid ecosystem alteration.

Description: by Tom Maloney, Ryan Phelan, Naira Simmons Horseshoe crabs have been integral to the safe production of vaccines and injectable medications for the past 40 years. The bleeding of live horseshoe crabs, a process that leaves thousands dead annually, is an ecologically unsustainable practice for all four species of horseshoe crab and the shorebirds that rely on their eggs as a primary food source during spring migration. Populations of both horseshoe crabs and shorebirds are in decline. This study confirms the efficacy of recombinant Factor C (rFC), a synthetic alternative that eliminates the need for animal products in endotoxin detection. Furthermore, our findings confirm that the biomedical industry can achieve a 90% reduction in the use of reagents derived from horseshoe crabs by using the synthetic alternative for the testing of water and other common materials used in the manufacturing process. This represents an extraordinary opportunity for the biomedical and pharmaceutical industries to significantly contribute to the conservation of horseshoe crabs and the birds that depend on them.

Description: by The PLOS Biology Staff Editors As we celebrate our anniversary, the PLOS Biology editors discuss recent initiatives taken by the journal (meta-research, complementary research policy, preprint posting, short reports, methods and resources, data policy, protocols.io) and look ahead to the next fifteen years.

Description: by Eric Verschooten, Christian Desloovere, Philip X. Joris Frequency tuning and phase-locking are two fundamental properties generated in the cochlea, enabling but also limiting the coding of sounds by the auditory nerve (AN). In humans, these limits are unknown, but high resolution has been postulated for both properties. Electrophysiological recordings from the AN of normal-hearing volunteers indicate that human frequency tuning, but not phase-locking, exceeds the resolution observed in animal models.

Description: by Rosangela Follmann, Christopher John Goldsmith, Wolfgang Stein A ubiquitous feature of the nervous system is the processing of simultaneously arriving sensory inputs from different modalities. Yet, because of the difficulties of monitoring large populations of neurons with the single resolution required to determine their sensory responses, the cellular mechanisms of how populations of neurons encode different sensory modalities often remain enigmatic. We studied multimodal information encoding in a small sensorimotor system of the crustacean stomatogastric nervous system that drives rhythmic motor activity for the processing of food. This system is experimentally advantageous, as it produces a fictive behavioral output in vitro, and distinct sensory modalities can be selectively activated. It has the additional advantage that all sensory information is routed through a hub ganglion, the commissural ganglion, a structure with fewer than 220 neurons. Using optical imaging of a population of commissural neurons to track each individual neuron's response across sensory modalities, we provide evidence that multimodal information is encoded via a combinatorial code of recruited neurons. By selectively stimulating chemosensory and mechanosensory inputs that are functionally important for processing of food, we find that these two modalities were processed in a distributed network comprising the majority of commissural neurons imaged. In a total of 12 commissural ganglia, we show that 98% of all imaged neurons were involved in sensory processing, with the two modalities being processed by a highly overlapping set of neurons. Of these, 80% were multimodal, 18% were unimodal, and only 2% of the neurons did not respond to either modality. Differences between modalities were represented by the identities of the neurons participating in each sensory condition and by differences in response sign (excitation versus inhibition), with 46% changing their responses in the other modality. Consistent with the hypothesis that the commissural network encodes different sensory conditions in the combination of activated neurons, a new combination of excitation and inhibition was found when both pathways were activated simultaneously. The responses to this bimodal condition were distinct from either unimodal condition, and for 30% of the neurons, they were not predictive from the individual unimodal responses. Thus, in a sensorimotor network, different sensory modalities are encoded using a combinatorial code of neurons that are activated or inhibited. This provides motor networks with the ability to differentially respond to categorically different sensory conditions and may serve as a model to understand higher-level processing of multimodal information.

Description: by Crispin Y. Jordan

Description: by Stanley E. Lazic, Charlie J. Clarke-Williams, Marcus R. Munafò This Formal Comment responds to Jordan et al., and stresses that if scientific findings are to be robust, training in experimental design and statistics is critical to ensure that research questions, design considerations, and analyses are aligned.

Description: by Chad M. Eliason Animal signals—involving combinations of acoustic, chemical, visual, and behavioral cues—are among the most diverse traits in nature. Testing hypotheses about signal evolution has been hampered by difficulties with comparing highly divergent signals among species. In this Primer, I describe recent advances in capturing signals and studying their evolution. I highlight new findings using an information-theory–based approach to quantifying signal variation in the diverse birds-of-paradise. Growing access to signal databases in tandem with development of new analytical tools will open up new avenues for studying the proximate mechanisms and ultimate evolutionary causes of signal variation, both within and among species.

Description: by Stephanie Lauer, Grace Avecilla, Pieter Spealman, Gunjan Sethia, Nathan Brandt, Sasha F. Levy, David Gresham Copy number variants (CNVs) are a pervasive source of genetic variation and evolutionary potential, but the dynamics and diversity of CNVs within evolving populations remain unclear. Long-term evolution experiments in chemostats provide an ideal system for studying the molecular processes underlying CNV formation and the temporal dynamics with which they are generated, selected, and maintained. Here, we developed a fluorescent CNV reporter to detect de novo gene amplifications and deletions in individual cells. We used the CNV reporter in Saccharomyces cerevisiae to study CNV formation at the GAP1 locus, which encodes the general amino acid permease, in different nutrient-limited chemostat conditions. We find that under strong selection, GAP1 CNVs are repeatedly generated and selected during the early stages of adaptive evolution, resulting in predictable dynamics. Molecular characterization of CNV-containing lineages shows that the CNV reporter detects different classes of CNVs, including aneuploidies, nonreciprocal translocations, tandem duplications, and complex CNVs. Despite GAP1 ’s proximity to repeat sequences that facilitate intrachromosomal recombination, breakpoint analysis revealed that short inverted repeat sequences mediate formation of at least 50% of GAP1 CNVs. Inverted repeat sequences are also found at breakpoints at the DUR3 locus, where CNVs are selected in urea-limited chemostats. Analysis of 28 CNV breakpoints indicates that inverted repeats are typically 8 nucleotides in length and separated by 40 bases. The features of these CNVs are consistent with origin-dependent inverted-repeat amplification (ODIRA), suggesting that replication-based mechanisms of CNV formation may be a common source of gene amplification. We combined the CNV reporter with barcode lineage tracking and found that 10 2 –10 4 independent CNV-containing lineages initially compete within populations, resulting in extreme clonal interference. However, only a small number (18–21) of CNV lineages ever constitute more than 1% of the CNV subpopulation, and as selection progresses, the diversity of CNV lineages declines. Our study introduces a novel means of studying CNVs in heterogeneous cell populations and provides insight into their dynamics, diversity, and formation mechanisms in the context of adaptive evolution.

Description: by Kun Zhu, Yi Tang, Xuan Xu, Hien Dang, Liu-Ya Tang, Xiang Wang, Xin Wei Wang, Ying E. Zhang Nonalcoholic fatty liver disease (NAFLD) is characterized by abnormal accumulation of triglycerides (TG) in the liver and other metabolic syndrome symptoms, but its molecular genetic causes are not completely understood. Here, we show that mice deficient for ubiquitin ligase (E3) Smad ubiquitin regulatory factor 1 (Smurf1) spontaneously develop hepatic steatosis as they age and exhibit the exacerbated phenotype under a high-fat diet (HFD). Our data indicate that loss of Smurf1 up-regulates the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes involved in lipid synthesis and fatty acid uptake. We further show that PPARγ is a direct substrate of Smurf1-mediated non-proteolytic lysine 63 (K63)-linked ubiquitin modification that suppresses its transcriptional activity, and treatment of Smurf1-deficient mice with a PPARγ antagonist, GW9662, completely reversed the lipid accumulation in the liver. Finally, we demonstrate an inverse correlation of low SMURF1 expression to high body mass index (BMI) values in human patients, thus revealing a new role of SMURF1 in NAFLD pathogenesis.

Description: by Dan Xu, Minghui Yao, Yaqing Wang, Ling Yuan, Joerg D. Hoeck, Jingwen Yu, Liang Liu, Yvonne Y. C. Yeap, Weiya Zhang, Feng Zhang, Yinghang Feng, Tiantian Ma, Yujie Wang, Dominic C. H. Ng, Xiaoyin Niu, Bing Su, Axel Behrens, Zhiheng Xu Mutations of WD repeat domain 62 ( WDR62 ) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3 , Wdr62 , or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1 . Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development.

Description: by Kenneth W. Wachter Newman questions recent claims about a plateau in mortality rates for Italians beyond age 105 on the basis of a hypothetical model. His model implies implausibly high error rates for extreme ages. For individuals over 110, for whom birth certificates have been collected, the form in which Italian births were registered precludes the kinds of clerical errors in year of birth that Newman assumes.

Description: by Farah H. Bardai, Dalila G. Ordonez, Rachel M. Bailey, Matthew Hamm, Jada Lewis, Mel B. Feany Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson disease. Genetics and neuropathology link Parkinson disease with the microtubule-binding protein tau, but the mechanism of action of LRRK2 mutations and the molecular connection between tau and Parkinson disease are unclear. Here, we investigate the interaction of LRRK and tau in Drosophila and mouse models of tauopathy. We find that either increasing or decreasing the level of fly Lrrk enhances tau neurotoxicity, which is further exacerbated by expressing Lrrk with dominantly acting Parkinson disease—associated mutations. At the cellular level, altering Lrrk expression promotes tau neurotoxicity via excess stabilization of filamentous actin (F-actin) and subsequent mislocalization of the critical mitochondrial fission protein dynamin-1-like protein (Drp1). Biochemically, monomeric LRRK2 exhibits actin-severing activity, which is reduced as increasing concentrations of wild-type LRRK2, or expression of mutant forms of LRRK2 promote oligomerization of the protein. Overall, our findings provide a potential mechanistic basis for a dominant negative mechanism in LRRK2-mediated Parkinson disease, suggest a common molecular pathway with other familial forms of Parkinson disease linked to abnormalities of mitochondrial dynamics and quality control, and raise the possibility of new therapeutic approaches to Parkinson disease and related disorders.

Description: by Saul Justin Newman Several organisms, including humans, display a deceleration in mortality rates at advanced ages. This mortality deceleration is sufficiently rapid to allow late-life mortality to plateau in old age in several species, causing the apparent cessation of biological ageing. Here, it is shown that late-life mortality deceleration (LLMD) and late-life plateaus are caused by common demographic errors. Age estimation and cohort blending errors introduced at rates below 1 in 10,000 are sufficient to cause LLMD and plateaus. In humans, observed error rates of birth and death registration predict the magnitude of LLMD. Correction for these sources of demographic error using a mixed linear model eliminates LLMD and late-life mortality plateaus (LLMPs) without recourse to biological or evolutionary models. These results suggest models developed to explain LLMD have been fitted to an error distribution, that ageing does not slow or stop during old age in humans, and that there is a finite limit to human longevity.

Description: by Saul Justin Newman This study highlights how the mortality plateau in Barbi and colleagues can be generated by low-frequency, randomly distributed age-misreporting errors. Furthermore, sensitivity of the late-life mortality plateau in Barbi and colleagues to the particular age range selected for regression is illustrated. Collectively, the simulation of age-misreporting errors in late-life human mortality data and a less-specific model choice than that of Barbi and colleagues highlight a clear alternative hypothesis to explanations based on evolution, the cessation of ageing, and population heterogeneity.

Description: by Jennifer C. Swart, Michael J. Frank, Jessica I. Määttä, Ole Jensen, Roshan Cools, Hanneke E. M. den Ouden Motivation exerts control over behavior by eliciting Pavlovian responses, which can either match or conflict with instrumental action. We can overcome maladaptive motivational influences putatively through frontal cognitive control. However, the neurocomputational mechanisms subserving this control are unclear; does control entail up-regulating instrumental systems, down-regulating Pavlovian systems, or both? We combined electroencephalography (EEG) recordings with a motivational Go/NoGo learning task ( N = 34), in which multiple Go options enabled us to disentangle selective action learning from nonselective Pavlovian responses. Midfrontal theta-band (4 Hz–8 Hz) activity covaried with the level of Pavlovian conflict and was associated with reduced Pavlovian biases rather than reduced instrumental learning biases. Motor and lateral prefrontal regions synchronized to the midfrontal cortex, and these network dynamics predicted the reduction of Pavlovian biases over and above local, midfrontal theta activity. This work links midfrontal processing to detecting Pavlovian conflict and highlights the importance of network processing in reducing the impact of maladaptive, Pavlovian biases.

Description: by Jason Boehme, Natacha Le Moan, Rebecca J. Kameny, Alexandra Loucks, Michael J. Johengen, Amy L. Lesneski, Wenhui Gong, Tina Davis, Kevin Tanaka, Andrew Davis, Youping He, Janel Long-Boyle, Vijay Ivaturi, Jogarao V. S. Gobburu, Jonathan A. Winger, Stephen P. Cary, Sanjeev A. Datar, Jeffrey R. Fineman, Ana Krtolica, Emin Maltepe The heart exhibits the highest basal oxygen (O 2 ) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O 2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O 2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX–based variants effectively deliver O 2 to hypoxic tissues, but not those at physiologic O 2 tension. Additionally, H-NOX–based variants exhibit tunable binding that is specific for O 2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O 2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O 2 . Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) ( p 〈 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV–treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O 2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.

Description: by Christine Häger, Lydia M. Keubler, Steven R. Talbot, Svenja Biernot, Nora Weegh, Stephanie Buchheister, Manuela Buettner, Silke Glage, André Bleich The fine-scale grading of the severity experienced by animals used in research constitutes a key element of the 3Rs (replace, reduce, and refine) principles and a legal requirement in the European Union Directive 2010/63/EU. Particularly, the exact assessment of all signs of pain, suffering, and distress experienced by laboratory animals represents a prerequisite to develop refinement strategies. However, minimal and noninvasive methods for an evidence-based severity assessment are scarce. Therefore, we investigated whether voluntary wheel running (VWR) provides an observer-independent behaviour-centred approach to grade severity experienced by C57BL/6J mice undergoing various treatments. In a mouse model of chemically induced acute colitis, VWR behaviour was directly related to colitis severity, whereas clinical scoring did not sensitively reflect severity but rather indicated marginal signs of compromised welfare. Unsupervised k-means algorithm–based cluster analysis of body weight and VWR data enabled the discrimination of cluster borders and distinct levels of severity. The validity of the cluster analysis was affirmed in a mouse model of acute restraint stress. This method was also applicable to uncover and grade the impact of serial blood sampling on the animal’s welfare, underlined by increased histological scores in the colitis model. To reflect the entirety of severity in a multidimensional model, the presented approach may have to be calibrated and validated in other animal models requiring the integration of further parameters. In this experimental set up, however, the automated assessment of an emotional/motivational driven behaviour and subsequent integration of the data into a mathematical model enabled unbiased individual severity grading in laboratory mice, thereby providing an essential contribution to the 3Rs principles.

Description: by Chiyu Li, Xuanming Liu, Xiaonan Qiang, Xiaoyan Li, Xiushan Li, Sirui Zhu, Long Wang, Yuan Wang, Hongdong Liao, Sheng Luan, Feng Yu FERONIA (FER), a plasma membrane receptor-like kinase, is a central regulator of cell growth that integrates environmental and endogenous signals. A peptide ligand rapid alkalinization factor 1 (RALF1) binds to FER and triggers a series of downstream events, including inhibition of Arabidopsis H + -ATPase 2 activity at the cell surface and regulation of gene expression in the nucleus. We report here that, upon RALF1 binding, FER first promotes ErbB3-binding protein 1 ( EBP1 ) mRNA translation and then interacts with and phosphorylates the EBP1 protein, leading to EBP1 accumulation in the nucleus. There, EBP1 associates with the promoters of previously identified RALF1-regulated genes, such as CML38 , and regulates gene transcription in response to RALF1 signaling. EBP1 appears to inhibit the RALF1 peptide response, thus forming a transcription–translation feedback loop (TTFL) similar to that found in circadian rhythm control. The plant RALF1-FER-EBP1 axis is reminiscent of animal epidermal growth factor receptor (EGFR) signaling, in which EGF peptide induces EGFR to interact with and phosphorylate EBP1, promoting EBP1 nuclear accumulation to control cell growth. Thus, we suggest that in response to peptide signals, plant FER and animal EGFR use the conserved key regulator EBP1 to control cell growth in the nucleus.

Description: by Susanna C. Weber, Thorsten Kahnt, Boris B. Quednow, Philippe N. Tobler The value of rewards arises from multiple hedonic and motivational dimensions. Reward-encoding brain regions such as the ventral striatum (VS) are known to process these dimensions. However, the mechanism whereby distinct reward dimensions are selected for neural processing and guiding behavior remains unclear. Here, we used functional imaging to investigate how human individuals make either hedonic (liking) or motivational (wanting) evaluations of everyday items. We found that the two types of evaluations were differently modulated depending on whether participants won or lost these items. Neural activity in the VS encoded both hedonic and motivational dimensions of reward, whereas ventromedial prefrontal activity encoded primarily motivational evaluations and central orbitofrontal activity encoded predominantly hedonic evaluations. These distinct prefrontal representations arose regardless of which judgment was currently relevant for behavior. Critically, the VS preferentially processed the reward dimension currently being evaluated and showed judgment-specific functional connectivity with the dimension-specific prefrontal areas. Thus, our data are in keeping with a gating mechanism by which prefrontal cortex (PFC)–VS pathways flexibly encode reward dimensions depending on their behavioral relevance. These findings provide a prototype for a generalized information selection mechanism through content-tailored frontostriatal communication.

Description: by Jia Chen, Aram-Christopher Sayadian, Nick Lowe, Holly E. Lovegrove, Daniel St Johnston Apical–basal polarity is essential for the formation and function of epithelial tissues, whereas loss of polarity is a hallmark of tumours. Studies in Drosophila have identified conserved polarity factors that define the apical (Crumbs, Stardust, Par-6, atypical protein kinase C [aPKC]), junctional (Bazooka [Baz]/Par-3), and basolateral (Scribbled [Scrib], Discs large [Dlg], Lethal [2] giant larvae [Lgl]) domains of epithelial cells. Because these conserved factors mark equivalent domains in diverse types of vertebrate and invertebrate epithelia, it is generally assumed that this system underlies polarity in all epithelia. Here, we show that this is not the case, as none of these canonical factors are required for the polarisation of the endodermal epithelium of the Drosophila adult midgut. Furthermore, like vertebrate epithelia but not other Drosophila epithelia, the midgut epithelium forms occluding junctions above adherens junctions (AJs) and requires the integrin adhesion complex for polarity. Thus, Drosophila contains two types of epithelia that polarise by fundamentally different mechanisms. This diversity of epithelial types may reflect their different developmental origins, junctional arrangement, or whether they polarise in an apical–basal direction or vice versa. Since knock-outs of canonical polarity factors in vertebrates often have little or no effect on epithelial polarity and the Drosophila midgut shares several common features with vertebrate epithelia, this diversity of polarity mechanisms is likely to be conserved in other animals.

Description: by The PLOS Biology Staff

Description: by Fengying Duan, Ricardo F. H. Giehl, Niko Geldner, David E. Salt, Nicolaus von Wirén In plants, nutrient provision of shoots depends on the uptake and transport of nutrients across the root tissue to the vascular system. Nutrient delivery to the vasculature is mediated via the apoplastic transport pathway (ATP), which uses the free space in the cell walls and is controlled by apoplastic barriers and nutrient transporters at the endodermis, or via the symplastic transport pathway (STP). However, the relative importance of these transport routes remains elusive. Here, we show that the STP, mediated by the epidermal ammonium transporter 1;3 (AMT1;3), dominates the radial movement of ammonium across the root tissue when external ammonium is low, whereas apoplastic transport controlled by AMT1;2 at the endodermis prevails at high external ammonium. Then, AMT1;2 favors nitrogen (N) allocation to the shoot, revealing a major importance of the ATP for nutrient partitioning to shoots. When an endodermal bypass was introduced by abolishing Casparian strip (CS) formation, apoplastic ammonium transport decreased. By contrast, symplastic transport was increased, indicating synergism between the STP and the endodermal bypass. We further establish that the formation of apoplastic barriers alters the cell type–specific localization of AMTs and determines STP and ATP contributions. These results show how radial transport pathways vary along the longitudinal gradient of the root axis and contribute to nutrient partitioning between roots and shoots.

Description: by Erin S. Kelleher, Jaweria Jaweria, Uchechukwu Akoma, Lily Ortega, Wenpei Tang Transposable elements (TEs) are obligate genetic parasites that propagate in host genomes by replicating in germline nuclei, thereby ensuring transmission to offspring. This selfish replication not only produces deleterious mutations—in extreme cases, TE mobilization induces genotoxic stress that prohibits the production of viable gametes. Host genomes could reduce these fitness effects in two ways: resistance and tolerance. Resistance to TE propagation is enacted by germline-specific small-RNA-mediated silencing pathways, such as the Piwi-interacting RNA (piRNA) pathway, and is studied extensively. However, it remains entirely unknown whether host genomes may also evolve tolerance by desensitizing gametogenesis to the harmful effects of TEs. In part, the absence of research on tolerance reflects a lack of opportunity, as small-RNA-mediated silencing evolves rapidly after a new TE invades, thereby masking existing variation in tolerance. We have exploited the recent historical invasion of the Drosophila melanogaster genome by P -element DNA transposons in order to study tolerance of TE activity. In the absence of piRNA-mediated silencing, the genotoxic stress imposed by P -elements disrupts oogenesis and, in extreme cases, leads to atrophied ovaries that completely lack germline cells. By performing quantitative trait locus (QTL) mapping on a panel of recombinant inbred lines (RILs) that lack piRNA-mediated silencing of P -elements, we uncovered multiple QTL that are associated with differences in tolerance of oogenesis to P -element transposition. We localized the most significant QTL to a small 230-kb euchromatic region, with the logarithm of the odds (LOD) peak occurring in the bruno locus, which codes for a critical and well-studied developmental regulator of oogenesis. Genetic, cytological, and expression analyses suggest that bruno dosage modulates germline stem cell (GSC) loss in the presence of P -element activity. Our observations reveal segregating variation in TE tolerance for the first time, and implicate gametogenic regulators as a source of tolerant variants in natural populations.

Description: by Martin Stegmann Controlling organ growth and development is crucial for all multicellular organisms and is controlled by plasma membrane localized receptor kinases (RKs) across kingdoms, including animals and plants. A central RK in plants is FERONIA (FER), which perceives endogenous rapid alkalinization factor (RALF) peptides to regulate a plethora of biological responses, including growth and development. However, it remained largely unknown how RALF sensing by FER at the plasma membrane is translated into a nuclear response. A key step forward is presented by Li and colleagues, who show that FER increases ERBB3 binding protein 1 ( EBP1 ) mRNA translation and directly phosphorylates EBP1 to shift its subcellular localization from the cytoplasm to the nucleus where it controls growth and development through its regulation of transcription. Importantly, EBP1 is described as a transcriptional and translational regulator in mammals by acting downstream of epidermal growth factor receptor (EGFR) signaling, suggesting that animals and plants use similar conserved pathways to fine-tune growth and development. Furthermore, this work highlights the importance of protein translation as a direct output of RK signaling, a mechanism that is largely unknown in plants.

Description: by Peng Tan, Youqiong Ye, Lian He, Jiansheng Xie, Ji Jing, Guolin Ma, Hongming Pan, Leng Han, Weidong Han, Yubin Zhou Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 KDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer.

Description: by Zhuan Qin, Jiagang Tu, Tao Lin, Steven J. Norris, Chunhao Li, Md A. Motaleb, Jun Liu Periplasmic flagella are essential for the distinct morphology and motility of spirochetes. A flagella-specific type III secretion system (fT3SS) composed of a membrane-bound export apparatus and a cytosolic ATPase complex is responsible for the assembly of the periplasmic flagella. Here, we deployed cryo-electron tomography (cryo-ET) to visualize the fT3SS machine in the Lyme disease spirochete Borrelia burgdorferi . We show, for the first time, that the cytosolic ATPase complex is attached to the flagellar C-ring through multiple spokes to form the “spoke and hub” structure in B . burgdorferi . This structure not only strengthens structural rigidity of the round-shaped C-ring but also appears to rotate with the C-ring. Our studies provide structural insights into the unique mechanisms underlying assembly and rotation of the periplasmic flagella and may provide the basis for the development of novel therapeutic strategies against several pathogenic spirochetes.

Description: by David W. Rogers, Ellen McConnell, Jasmine Ono, Duncan Greig Genome-wide sequence divergence between populations can cause hybrid sterility through the action of the anti-recombination system, which rejects crossover repair of double strand breaks between nonidentical sequences. Because crossovers are necessary to ensure proper segregation of homologous chromosomes during meiosis, the reduced recombination rate in hybrids can result in high levels of nondisjunction and therefore low gamete viability. Hybrid sterility in interspecific crosses of Saccharomyces yeasts is known to be associated with such segregation errors, but estimates of the importance of nondisjunction to postzygotic reproductive isolation have been hampered by difficulties in accurately measuring nondisjunction frequencies. Here, we use spore-autonomous fluorescent protein expression to quantify nondisjunction in both interspecific and intraspecific yeast hybrids. We show that segregation is near random in interspecific hybrids. The observed rates of nondisjunction can explain most of the sterility observed in interspecific hybrids through the failure of gametes to inherit at least one copy of each chromosome. Partially impairing the anti-recombination system by preventing expression of the RecQ helicase SGS1 during meiosis cuts nondisjunction frequencies in half. We further show that chromosome loss through nondisjunction can explain nearly all of the sterility observed in hybrids formed between two populations of a single species. The rate of meiotic nondisjunction of each homologous pair was negatively correlated with chromosome size in these intraspecific hybrids. Our results demonstrate that sequence divergence is not only associated with the sterility of hybrids formed between distantly related species but may also be a direct cause of reproductive isolation in incipient species.

Description: by Jun Guo, Youhua Zhang, Hua Li, Huiying Chu, Qinshu Wang, Shutan Jiang, Yan Li, Hongbin Shen, Guohui Li, Jianfeng Chen, Chenqi Xu Protein transmembrane domains (TMDs) are generally hydrophobic, but our bioinformatics analysis shows that many TMDs contain basic residues at terminal regions. Physiological functions of these membrane-snorkeling basic residues are largely unclear. Here, we show that a membrane-snorkeling Lys residue in integrin αLβ2 (also known as lymphocyte function-associated antigen 1 [LFA-1]) regulates transmembrane heterodimer formation and integrin adhesion through ionic interplay with acidic phospholipids and calcium ions (Ca 2+ ) in T cells. The amino group of the conserved Lys ionically interacts with the phosphate group of acidic phospholipids to stabilize αLβ2 transmembrane association, thus keeping the integrin at low-affinity conformation. Intracellular Ca 2+ uses its charge to directly disrupt this ionic interaction, leading to the transmembrane separation and the subsequent extracellular domain extension to increase adhesion activity. This Ca 2+ -mediated regulation is independent on the canonical Ca 2+ signaling or integrin inside-out signaling. Our work therefore showcases the importance of intramembrane ionic protein–lipid interaction and provides a new mechanism of integrin activation.