bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural mechanisms of regulation of empathy and altruism by beliefs of others’ pain
Authors: Wu Taoyu , Han Shihui
Published: January 2021

Perceived cues signaling others’ pain induce empathy that in turn motivates altruistic behavior toward those who appear suffering. This perception-emotion-behavior reactivity is the core of human altruism but does not always occur in real life situations. Here, by integrating behavioral and multimodal neuroimaging measures, we investigate neural mechanisms underlying the functional role of beliefs of others’ pain in modulating empathy and altruism. We show evidence that decreasing (or enhancing) beliefs of others’ pain reduces (or increases) subjective estimation of others’ painful emotional states and monetary donations to those who show pain expressions. Moreover, decreasing beliefs of others’ pain attenuates neural responses to perceived cues signaling others’ pain within 200 ms after stimulus onset and modulate neural responses to others’ pain in the frontal cortices and temporoparietal junction. Our findings highlight beliefs of others’ pain as a fundamental cognitive basis of human empathy and altruism and unravel the intermediate neural architecture.
Association between COVID-19 Outcomes and Mask Mandates, Adherence, and Attitudes
Authors: Adjodah Dhaval , Dinakar Karthik , Chinazzi Matteo , Fraiberger Samuel P. , Pentland Alex , Bates Samantha , Staller Kyle , Vespignani Alessandro , Bhatt Deepak L.
Published: January 2021

We extend previous studies on the impact of masks on COVID-19 outcomes by investigating an unprecedented breadth and depth of health outcomes, geographical resolutions, types of mask mandates, early versus later waves and controlling for other government interventions, mobility testing rate and weather. We show that mask mandates are associated with a statistically significant decrease in new cases (-3.55 per 100K), deaths (-0.13 per 100K), and the proportion of hospital admissions (-2.38 percentage points) up to 40 days after the introduction of mask mandates both at the state and county level. These effects are large, corresponding to 14% of the highest recorded number of cases, 13% of deaths, and 7% of admission proportion. We also find that mask mandates are linked to a 23.4 percentage point increase in mask adherence in four diverse states. Lastly, using a large novel survey dataset of almost half a million people in 68 countries, we introduce the novel results that community mask adherence and community attitudes towards masks are associated with a reduction in COVID-19 cases and deaths. Our results have policy implications for reinforcing the need to maintain and encourage mask-wearing by the public, especially in light of some states starting to remove their mask mandates.
Fecal biomarkers of environmental enteric dysfunction and the gut microbiota of rural Malawian children: an observational study
Authors: Chaima David , Pickering Harry , Hart John D. , Burr Sarah E. , Maleta Kenneth M. , Kalua Khumbo , Bailey Robin L. , Holland Martin J.
Published: January 2021

Environmental enteric dysfunction (EED) is a subclinical condition of the gut characterized by changes in morphology and function with underlying chronic inflammatory responses. This study characterized composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. Fecal samples were collected from children aged 1-59 months. Neopterin, myeloperoxidase and alpha-1 antitrypsin concentrations were quantified by ELISA and combined to form a composite EED score using principal component analysis. DNA was extracted from fecal samples and V4-16S rRNA sequencing was used to characterize the gut microbiota. The concentrations of all three biomarkers decreased with increasing age, which is consistent with other studies of children living in similar low-income settings. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. Increased alpha diversity was associated with a reduction in neopterin concentration. Microbiota composition was associated with the composite EED score. Increased abundance of Succinivibrio was associated with reduced composite EED scores.

Highlights

In Malawian children, fecal concentrations of myeloperoxidase, alpha-1 antitrypsin and neopterin decreased with age

A marginal negative association was found between alpha diversity of the gut microbiota and fecal neopterin concentration

A higher abundance of Succinivibrio was found in children with lower concentrations of biomarker of environmental enteric dysfunction

Fatty acid biosynthesis, tetrapyrrole biosynthesis and pyrimidine nucleotide degradation pathways were associated with environmental enteric dysfunction biomarker score
Myocardial BDNF regulates cardiac bioenergetics through the transcription factor Yin Yang 1
Authors: Yang Xue , Zhang Manling , Xie Bingxian , Zimmerman Raymond , Wang Qin , Wei An-chi , Peng Zishan , Khalifa Moustafa , Reynolds Michael , Om Matthew , Zhu Guangshuo , Bedja Djahida , Jiang Hong , Jurczak Michael , Shiva Sruti , Scott Iain , O’Rourke Brian , Kass David A. , Paolocci Nazareno , Feng Ning
Published: January 2021

Circulating Brain-derived Neurotrophic Factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, Tropomyosin Related Kinase Receptor (TrkB), are expressed in cardiomyocytes, however the role of myocardial BDNF signaling in cardiac pathophysiology is poorly understood. We found that cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). The cTrkB KO mice developed an exacerbated heart failure progression with transaortic constriction. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.
Shape analysis of gamma rhythm supports a superlinear inhibitory regime in an inhibition-stabilized network
Authors: Krishnakumaran R , Raees Mohammed , Ray Supratim
Published: January 2021

Visual inspection of stimulus-induced gamma oscillations (30-70 Hz) often reveals a non-sinusoidal shape. Such distortions are a hallmark of non-linear systems and are also observed in mean-field models of gamma oscillations. A thorough characterization of the shape of the gamma cycle can therefore provide additional constraints on the operating regime of such models. However, the gamma waveform has not been quantitatively characterized, partially because the first harmonic of gamma, which arises because of the non-sinusoidal nature of the signal, is typically weak and gets masked due to a broadband increase in power related to spiking. To address this, we recorded local field potential (LFP) from the primary visual cortex (V1) of two awake female macaques while presenting full-field gratings or iso-luminant chromatic hues that produced huge gamma oscillations with prominent peaks at harmonic frequencies in the power spectra. We found that gamma and its first harmonic always maintained a specific phase relationship, resulting in a distinctive shape with a sharp trough and a shallow peak. Interestingly, a Wilson-Cowan (WC) model operating in an inhibition stabilized mode could replicate this shape, but only when the inhibitory population operated in the super-linear regime, as predicted recently. However, another recently developed model of gamma that operates in a linear regime driven by stochastic noise failed to produce salient harmonics or the observed shape. Our results impose additional constraints on models that generate gamma oscillations and their operating regimes.
Biochemical and Structural Characterization of Two Cif-Like Epoxide Hydrolases fromBurkholderia cenocepacia
Authors: Taher Noor M. , Hvorecny Kelli L. , Burke Cassandra M. , Gilman Morgan S.A. , Heussler Gary E. , Adolf-Bryfogle Jared , Bahl Christopher D. , O’Toole George A. , Madden Dean R.
Published: January 2021

Epoxide hydrolases catalyze the conversion of epoxides to vicinal diols in a range of cellular processes such as signaling, detoxification, and virulence. These enzymes typically utilize a pair of tyrosine residues to orient the substrate epoxide ring in the active site and stabilize the hydrolysis intermediate. A new subclass of epoxide hydrolases that utilize a histidine in place of one of the tyrosines was established with the discovery of the CFTR Inhibitory Factor (Cif) fromPseudomonas aeruginosa. Although the presence of such Cif-like epoxide hydrolases was predicted in other opportunistic pathogens based on sequence analyses, only Cif and its homologue aCif fromAcinetobacter nosocomialishave been characterized. Here we report the biochemical and structural characteristics of Cfl1 and Cfl2, twoCif-like epoxide hydrolases fromBurkholderia cenocepacia. Cfl1 is able to hydrolyze xenobiotic as well as biological epoxides that might be encountered in the environment or during infection. In contrast, Cfl2 shows very low activity against a diverse set of epoxides. The crystal structures of the two proteins reveal quaternary structures that build on the well-known dimeric assembly of the α/β hydrolase domain, but broaden our understanding of the structural diversity encoded in novel oligomer interfaces. Analysis of the interfaces reveals both similarities and key differences in sequence conservation between the two assemblies, and between the canonical dimer and the novel oligomer interfaces of each assembly. Finally, we discuss the effects of these higher-order assemblies on the intra-monomer flexibility of Cfl1 and Cfl2 and their possible roles in regulating enzymatic activity.
Hyperoxia Inhibits the Growth of Mouse Forebrain Oligodendrocyte Progenitors
Authors: Moore Lisamarie , McLane Lauren E. , Wahl Stacey , Ornelas Isis M. , Wood Teresa L. , Canoll Peter , Levison Steven W.
Published: January 2021

NG2 chondroitin sulfate proteoglycan positive oligodendrocyte progenitor cells (OPCs) reside throughout the brain. They divide asymmetrically and differentiate into myelinating oligodendrocytes throughout adulthood. OPCs have been successfully isolated from rodents using several techniques including magnetic beads, immunopanning and exploiting differential centripetal adhesion. Whereas rat OPCs are relatively simple to propagatein vitro, it has been difficult to expand mouse OPCs. Therefore, we evaluated the effects of oxygen levels, growth factors and extracellular matrix components to produce a simple and reproducible method to prepare large numbers of nearly homogenous cultures of primary mouse OPCs from postnatal day 0-2 mouse telencephala. Using the McCarthy and de Vellis mechanical separation method OPCs were separated from mixed culture of glial cells. When the OPCs were plated onto fibronectin coated tissue culture plates in a biochemically defined medium that contained fibroblast growth factor-2 (FGF-2) and platelet derived growth factor AA (PDGFAA), and they were maintained in a standard tissue culture incubator, they proliferated very slowly. By contrast, mouse OPCs doubled approximately every 7 days when maintained in a 2% oxygen, nitrogen buffered environment. After 3 passages, greater than 99% of these OPCs were NG2+/PDGFRα+. In medium containing only FGF-2, mouse OPCs progressed to late stage OPCs whereupon A2B5 expression decreased and O4 expression increased. When these cells were differentiated between passages 1 and 3, the majority of the OPCs differentiated into MBP+ mature oligodendrocytes However, cells that were repeatedly passaged beyond 4 passages progressed to a late O4+ OPC (even with mitogens present) and when differentiated by mitogen removal a minority of the OPCs differentiated into MBP+ cells. These studies reveal significant differences between mouse and rat OPCs and an inhibitory role for oxygen in mouse OPC proliferation.
Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis through dye-functionalized lipid nanocarriers
Authors: Press Adrian T. , Babic Petra , Hoffmann Bianca , Müller Tina , Foo Wanling , Hauswald Walter , Benecke Jovana , Beretta Martina , Cseresnyés Zoltán , Hoeppener Stephanie , Nischang Ivo , Coldewey Sina M. , Gräler Markus H. , Bauer Reinhard , Gonnert Falk , Gaßler Nikolaus , Wetzker Reinhard , Figge Marc Thilo , Schubert Ulrich S. , Bauer Michael
Published: January 2021

Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.

One-Sentence Summary

Dye-functionalized liposomes allow delivery of a PI3Kγ inhibitor to hepatocytes to resolve sepsis-related liver failure without ‘off-target’ effects on immunity.

Graphical Abstract

Targeting PI3Kγ in hepatocytes by dye-functionalized liposomes to resolve sepsis-related liver failure without ‘off-target’ effects on immunity.
Molecular mechanism for kinesin-1 direct membrane recognition
Authors: Antón Zuriñe , Weijman Johannes F. , Williams Christopher , Moody Edmund R.R. , Mantell Judith , Yip Yan Y. , Cross Jessica A. , Williams Tom A. , Steiner Roberto A. , Crump Matthew , Woolfson Derek N. , Dodding Mark P.
Published: January 2021

The cargo-binding capabilities of cytoskeletal motor proteins have expanded during evolution through both gene duplication and alternative splicing. For the light chains of the kinesin-1 family of microtubule motors, this has resulted in an array of carboxy-terminal domain sequences of unknown molecular function. Here, combining phylogenetic analyses with biophysical, biochemical and cell biology approaches we identify a highly conserved membrane-induced curvature-sensitive amphipathic helix within this region of a newly defined subset of long kinesin light chain paralogues and splice isoforms. This helix mediates the direct binding of kinesin-1 to lipid membranes. Membrane binding requires specific anionic phospholipids and is important for kinesin-1 dependent lysosome positioning, a canonical activity that until now has been attributed exclusively the recognition of organelle-associated cargo adaptor proteins. This leads us to propose a new protein-lipid coincidence detection framework for kinesin-1 mediated organelle transport.
DevKidCC allows for robust classification and direct comparisons of kidney organoid datasets
Authors: Wilson Sean B. , Howden Sara E. , Vanslambrouck Jessica M. , Dorison Aude , Alquicira-Hernandez Jose , Powell Joseph E. , Little Melissa H.
Published: January 2021

Kidney organoids provide a valuable resource to understand kidney development and disease. Clustering algorithms and marker genes fail to accurately and robustly classify cellular identity between human pluripotent stem cell (hPSC)-derived organoid datasets. Here we present a new method able to accurately classify kidney cell subtypes, a hierarchical machine learning model trained using comprehensive reference data from single cell RNA-sequencing of human fetal kidney (HFK). We demonstrate the tool’s (DevKidCC) performance by application to all published kidney organoid datasets and a novel dataset.DevKidCCis available on Github and can be used on any kidney single cell RNA-sequence data.
Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection
Authors: Sohail Aaqib , Iqbal Azeem A. , Sahini Nishika , Tantawy Mohamed , Winterhoff Moritz , Ebensen Thomas , Geffers Robert , Schughart Klaus , Chen Fangfang , Preusse Matthias , Pils Marina C. , Guzman Carlos A. , Mostafa Ahmed , Pleschka Stephan , Falk Christine , Michelucci Alessandro , Pessler Frank
Published: January 2021

Itaconate has recently emerged as a metabolite with immunomodulatory properties. We evaluated effects of endogenous itaconate and exogenous itaconate, dimethyl-, and 4-octyl-itaconate on host responses to influenza A virus infection. Infection inducedACOD1(the enzyme catalyzing itaconate synthesis) mRNA in monocytes and macrophages, which correlated with viral replication and was abrogated by itaconate treatment. Pulmonary inflammation and weight loss were greater inAcod1-/-than wild-type mice, and ectopic synthesis of itaconate in human epithelial cells reduced infection-induced inflammation. The compounds induced different recruitment programs in infected human macrophages, and transcriptome profiling revealed that they reversed infection-triggered interferon responses and modulated inflammation in cell lines, PBMC, and lung tissue. Single-cell RNA sequencing of PBMC revealed that infection inducedACOD1exclusively in monocytes, whereas treatment silenced IFN-responses in monocytes, lymphocytes, and NK cells. Viral replication did not increase under treatment despite the dramatically repressed IFN responses, but 4-octyl itaconate inhibited viral transcription in PBMC. The results reveal dramatic reprogramming of host responses by itaconate and derivatives and their potential as adjunct treatments for hyperinflammation in viral infection.
Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis
Authors: Ricker Edd , Manni Michela , Flores-Castro Danny , Jenkins Daniel , Gupta Sanjay , Rivera-Correa Juan , Meng Wenzhao , Rosenfeld Aaron M. , Pannellini Tania , Bachu Mahesh , Chinenov Yurii , Sculco Peter K. , Jessberger Rolf , Prak Eline T. Luning , Pernis Alessandra B.
Published: January 2021

Sex differences characterize immune responses to viruses and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+T-bet+B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+and CD11c-effector populations with pathogenic and proinflammatory potential.Tlr7duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.
The extinction and survival of sharks across the end-Cretaceous mass extinction
Authors: Bazzi Mohamad , Campione Nicolás E. , Ahlberg Per E. , Blom Henning , Kear Benjamin P.
Published: January 2021

Sharks (Selachimorpha) are iconic marine predators that have survived multiple mass extinctions over geologic time. Their fossil record is represented by an abundance of teeth, which traditionally formed the basis for reconstructing large-scale diversity changes among different selachimorph clades. By contrast, corresponding patterns in shark ecology, as measured through morphological disparity, have received comparatively limited analytical attention. Here, we use a geometric morphometric approach to comprehensively examine the dental morphology of multiple shark lineages traversing the catastrophic end-Cretaceous mass extinction — this event terminated the Mesozoic Era 66 million years ago. Our results show that selachimorphs maintained virtually static levels of dental disparity in most of their constituent clades during the Cretaceous/Paleogene transition. Nevertheless, selective extinctions did impact on apex predator lineages characterized by triangular blade-like teeth, and in particular, lamniforms including the dominant Cretaceous anacoracids. Other groups, such as, triakid carcharhiniforms, squalids, and hexanchids, were seemingly unaffected. Finally, while some lamniform lineages experienced morphological depletion, others underwent a post-extinction disparity increase, especially odontaspidids, which are typified by narrow-cusped teeth adapted for feeding on fishes. This disparity shift coincides with the early Paleogene radiation of teleosts, a possible prey source, as well as the geographic relocation of shark disparity ‘hotspots’, perhaps indicating a regionally disjunct pattern of extinction recovery. Ultimately, our study reveals a complex morphological response to the end-Cretaceous mass extinction event, the dynamics of which we are only just beginning to understand.
Multivariable Association Discovery in Population-scale Meta-omics Studies
Authors: Mallick Himel , Rahnavard Ali , McIver Lauren J. , Ma Siyuan , Zhang Yancong , Nguyen Long H. , Tickle Timothy L. , Weingart George , Ren Boyu , Schwager Emma H. , Chatterjee Suvo , Thompson Kelsey N. , Wilkinson Jeremy E. , Subramanian Ayshwarya , Lu Yiren , Waldron Levi , Paulson Joseph N. , Franzosa Eric A. , Bravo Hector Corrada , Huttenhower Curtis
Published: January 2021

It is challenging to associate features such as human health outcomes, diet, environmental conditions, or other metadata to microbial community measurements, due in part to their quantitative properties. Microbiome multi-omics are typically noisy, sparse (zero-inflated), high-dimensional, extremely non-normal, and often in the form of count or compositional measurements. Here we introduce an optimized combination of novel and established methodology to assess multivariable association of microbial community features with complex metadata in population-scale observational studies. Our approach, MaAsLin 2 (Microbiome Multivariable Associations with Linear Models), uses general linear models to accommodate a wide variety of modern epidemiological studies, including cross-sectional and longitudinal designs, as well as a variety of data types (e.g. counts and relative abundances) with or without covariates and repeated measurements. To construct this method, we conducted a large-scale evaluation of a broad range of scenarios under which straightforward identification of meta-omics associations can be challenging. These simulation studies reveal that MaAsLin 2’s linear model preserves statistical power in the presence of repeated measures and multiple covariates, while accounting for the nuances of meta-omics features and controlling false discovery. We also applied MaAsLin 2 to a microbial multi-omics dataset from the Integrative Human Microbiome (HMP2) project which, in addition to reproducing established results, revealed a unique, integrated landscape of inflammatory bowel disease (IBD) across multiple time points and omics profiles.
Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining
Authors: Cabello-Lobato Maria Jose , Jenner Matthew , Loch Christian M. , Jackson Stephen P. , Wu Qian , Cliff Matthew J. , Schmidt Christine K.
Published: January 2021

SUMOylation is critical for a plethora of cellular signalling pathways including the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Based on systematic proteome microarray screening combined with widely applicable carbene footprinting and high-resolution structural profiling, we define two non-conventional SUMO2-binding modules on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ). Mechanistically, interaction of SUMO2 with XRCC4 is incompatible with XRCC4 binding to at least two other NHEJ proteins – XLF and DNA ligase 4 (LIG4). These findings are consistent with SUMO2 interactions of XRCC4 acting as backup pathways at different stages of NHEJ, in the absence of these factors or their dysfunctioning. Such scenarios are not only relevant for carcinogenesis, but also for the design of precision anti-cancer medicines and the optimisation of CRISPR/Cas9-based gene editing. This work reveals insights into topology-specific SUMO recognition and its potential for modulating DSB repair by NHEJ. Moreover, it provides a rich resource on binary SUMO receptors that can be exploited for uncovering regulatory layers in a wide array of cellular processes.
Modulations of local synchrony over time lead to resting-state functional connectivity in a parsimonious large-scale brain model
Authors: Portoles Oscar , Qin Yuzhen , Hadida Jonathan , Woolrich Mark , Cao Ming , van Vugt Marieke
Published: January 2021

Biophysical models of large-scale brain activity are a fundamental tool for understanding the mechanisms underlying the patterns observed with neuroimaging. These models combine a macroscopic description of the within- and between-ensemble dynamics of neurons within a single architecture. A challenge for these models is accounting for modulations of within-ensemble synchrony over time. Such modulations in local synchrony are fundamental for modeling behavioral tasks and resting-state activity. Another challenge comes from the difficulty in parametrizing large scale brain models which hinders researching principles related with between-ensembles differences. Here we derive a parsimonious large scale brain model that can describe fluctuations of local synchrony. Crucially, we do not reduce within-ensemble dynamics to macroscopic variables first, instead we consider within and between-ensemble interactions similarly while preserving their physiological differences. The dynamics of within-ensemble synchrony can be tuned with a parameter which manipulates local connectivity strength. We simulated resting-state static and time-resolved functional connectivity of alpha band envelopes in models with identical and dissimilar local connectivities. We show that functional connectivity emerges when there are high fluctuations of local and global synchrony simultaneously (i.e. metastable dynamics). We also show that for most ensembles, leaning towards local asynchrony or synchrony correlates with the functional connectivity with other ensembles, with the exception of some regions belonging to the default-mode network.

Author summary

Here we present and evaluate a parsimonious model of large-scale brain activity. The model represents the brain as a network-of-networks structure. The sub-networks describe the neural activity within a brain region, and the global network encodes interactions between brain regions. Unlike other models, it capture progressive changes of local synchrony and local dynamics can be tuned with one parameter. Therefore the model could be used not only to model resting-state, but also behavioural tasks. Furthermore, we describe a simple framework that can deal with the arduous task of identifying global and local parameters.
High throughput imaging of nanoscale extracellular vesicles by scanning electron microscopy for accurate size-based profiling and morphological analysis
Authors: Cavallaro Sara , Hååg Petra , Viktorsson Kristina , Krozer Anatol , Fogel Kristina , Lewensohn Rolf , Linnros Jan , Dev Apurba
Published: January 2021

Nanoscale extracellular vesicle (EVs) have been found to play a key role in intercellular communication, offering opportunities for both diagnostics and therapeutics. However, lying below the diffraction limit and also being highly heterogeneous in their size, morphology and abundance, these vesicles pose significant challenges for their physical characterization. Here, we present a direct visual approach for their accurate morphological and size-based profiling by using scanning electron microscopy (SEM). To achieve that, we methodically examined various process steps and developed a protocol to improve the throughput, conformity and image quality while preserving the shape of EVs. The investigation was performed with small EVs (sEVs) isolated from a non-small cell lung cancer (NSCLC) cell line H1975 as well as from a human serum, and the results were compared with those obtained from nanoparticle tracking analysis (NTA). While the comparison of the sEV size distributions showed good agreement between the two methods for large sEVs (diameter >70 nm), the microscopy based approach showed a better capacity for analyses on smaller vesicles, with higher sEV counts compared to NTA. In addition, we demonstrated the possibility of identifying non-EV particles based on size and morphological features. The study also showed process steps that can generate artifacts bearing resemblance with sEVs. The results therefore present a simple way to use a widely available microscopy tool for accurate and high throughput physical characterization of EVs.
Actin fence therapy with exogenous V12Rac1 protects against Acute Lung Injury
Authors: Gusarova Galina A. , Das Shonit R. , Islam Mohammad N. , Westphalen Kristin , Jin Guangchun , O.Shmarakov Igor , Li Li , Bhattacharya Sunita , Bhattacharya Jahar
Published: January 2021

High mortality in Acute Lung Injury (ALI) results from sustained proinflammatory signaling by alveolar receptors, such as TNFα receptor type 1 (TNFR1). Factors that determine the sustained signaling are not known. Unexpectedly, optical imaging of live alveoli revealed a major TNFα-induced surge of alveolar TNFR1 due to a Ca2+-dependent mechanism that decreased the cortical actin fence. Mouse mortality due to inhaled LPS was associated with cofilin activation, actin loss and the TNFR1 surge. The constitutively active form of the GTPase, Rac1 (V12Rac1), given intranasally as a non-covalent construct with a cell-permeable peptide, enhanced alveolar F-actin and blocked the TNFR1 surge. V12Rac1 also protected against ALI-induced mortality resulting from intranasal (i.n.) instillation of LPS, or ofPseudomonas aeruginosa. We propose a new therapeutic paradigm in which actin enhancement by exogenous Rac1 strengthens the alveolar actin fence, protecting against proinflammatory receptor hyperexpression, hence blocking ALI.
The VTA-BLA-NAc circuit for sex reward inhibited by VTA GABAergic neurons under stress in male mice
Authors: Sun Linshan , You Jingjing , Cui Minghu , Sun Fengjiao , Wang Jiangong , Wang Wentao , Wang Dan , Liu Dunjiang , Xu Zhicheng , Qiu Changyun , Liu Bin , Yan Haijing
Published: January 2021

Anhedonia, inability to experience pleasure from rewarding or enjoyable activities, is the prominent symptom of depression that involves dysfunction of the reward processing system. Both genetic predisposition and life events are thought to increase the risk for depression, in particular life stress. The cellular mechanism underlying stress modulating the reward processing neural circuits and subsequently disrupting reward-related behaviors remains elusive. We identify the VTA-BLA-NAc pathway as being activated by sex reward. Blockade of this circuit induces depressive-like behaviors, while reactivation of VTA neurons associated with sexual rewarding experience acutely ameliorates the impairment of reward-seeking behaviors induced by chronic restraint stress. Our histological and electrophysiological results show that the VTA neuron subpopulation responding to restraint stress inhibits the responsiveness of the VTA dopaminergic neurons to sexual reward. Together, these results reveal the cellular mechanism by which stress influences the brain reward processing system and provide a potential target for depression treatment.
In-silico studies of Neurocognitive and Neuropharmacological effect of Bacopa monnieri (L.)
Authors: Sangeet Satyam , Khan Arshad
Published: January 2021

Different Indian therapeutic plants have picked up consideration for their restorative properties against neurodevelopmental disorders lately.Bacopa monnieri (B. monnieri), being one of them, finds its utilization significantly in the treatment of cognition and learning. Despite the fact that it possesses such great capacity to treat neurological issues, how precisely it confers its influence is muddled. This study makes a stride towards knowing which phytochemical is significantly associated with grantingB. monnieriwith therapeutic properties. The docking investigation and the molecular simulation studies proposes that there is no single phytochemical included that impartsB. monnieria significant medicinal effect. It is really the blend of dominant part of natural phytochemicals present inB. monnierithat bestows the anti-neurological activity toB. monnieri.The ADME studies shows the convergence of properties of phytochemicals ofB. monnieriwith that of commercially available drugs which suggests that phytochemicals ofB. monnierican used as a potential drug source to treat neurodegenerative and neurodevelopmental disorders.
Nuclear stabilisation of p53 requires a functional nucleolar surveillance pathway
Authors: Hannan Katherine M. , Soo Priscilla , Wong Mei S. , Lee Justine K. , Hein Nadine , Evers Maurits , Wysoke Kira D. , Williams Tobias D. , Montellese Christian , Smith Lorey K. , Al-Obaidi Sheren J. , Núñez-Villacís Lorena , Poh Perlita , Pavy Megan , He Jin-Shu , Parsons Kate M. , Diesch Jeannine , Burgio Gaetan , Ferreira Rita , Feng Zhi-Ping , Gould Cathryn M. , Madhamshettiwar Piyush B. , Flygare Johan , Gonda Thomas J. , Simpson Kaylene J. , Kutay Ulrike , Pearson Richard B. , Engel Christoph , Watkins Nicholas J. , Hannan Ross D. , George Amee J.
Published: January 2021

The nucleolar surveillance pathway (NSP) monitors nucleolar fidelity and responds to nucleolar stresses (i.e., inactivation of ribosome biogenesis) by mediating the inhibitory binding of ribosomal proteins (RPs) to mouse double minute 2 homolog (MDM2), a nuclear-localised E3 ubiquitin ligase, which results in p53 accumulation. Inappropriate activation of the NSP has been implicated in the pathogenesis of collection of human diseases termed “ribosomopathies”, while drugs that selectively activate the NSP are now in trials for cancer. Despite the clinical significance, the precise molecular mechanism(s) regulating the NSP remain poorly understood. Using genome-wide loss of function screens, we demonstrate the ribosome biogenesis (RiBi) axis as the most potent class of genes whose disruption stabilises p53. Furthermore, we identified a novel suite of genes critical for the NSP, including a novel mammalian protein implicated in 5S ribonucleoprotein particle (5S-RNP) biogenesis, HEATR3. By selectively disabling the NSP, we unexpectedly demonstrate that a functional NSP is required for the ability of all nuclear acting stresses tested, including DNA damage, to robustly induce p53 accumulation. Together, our data demonstrates that the NSP has evolved as the dominant central integrator of stresses that regulate nuclear p53 abundance, thus ensuring RiBi is hardwired to cellular proliferative capacity.
Hearing loss is associated with delayed neural responses to continuous speech
Authors: Gillis Marlies , Decruy Lien , Vanthornhout Jonas , Francart Tom
Published: January 2021

We investigated the impact of hearing loss on the neural processing of speech. Using a forward modeling approach, we compared the neural responses to continuous speech of 14 adults with sensorineural hearing loss with those of age-matched normal-hearing peers.

Compared to their normal-hearing peers, hearing-impaired listeners had increased neural tracking and delayed neural responses to continuous speech in quiet. The latency also increased with the degree of hearing loss. As speech understanding decreased, neural tracking decreased in both populations; however, a significantly different trend was observed for the latency of the neural responses. For normal-hearing listeners, the latency increased with increasing background noise level. However, for hearing-impaired listeners, this increase was not observed.

Our results support the idea that the neural response latency indicates the efficiency of neural speech processing. Hearing-impaired listeners process speech in silence less efficiently than normal-hearing listeners. Our results suggest that this reduction in neural speech processing efficiency is a gradual effect which occurs as hearing deteriorates. Moreover, the efficiency of neural speech processing in hearing-impaired listeners is already at its lowest level when listening to speech in quiet, while normal-hearing listeners show a further decrease in efficiency when the noise level increases.

From our results, it is apparent that sound amplification does not solve hearing loss. Even when listing to speech in silence at a comfortable loudness, hearing-impaired listeners process speech less efficiently.
α-catenin links integrin adhesions to F-actin to regulate ECM mechanosensing and rigidity-dependence
Authors: Mukherjee Abhishek , Melamed Shay , Damouny-Khoury Hana , Amer Malak , Feld Lea , Nadjar-Boger Elisabeth , Sheetz Michael P. , Wolfenson Haguy
Published: January 2021

Both cell-cell and cell-matrix adhesions are regulated by mechanical signals, but the mechanobiological processes that mediate the crosstalk between these structures are poorly understood. Here we show that α- catenin, a mechanosensitive protein that is classically associated with cadherin-based adhesions, directly interacts with and regulates integrin adhesions. α-catenin is recruited to the edges of mesenchymal cells, where it interacts with F-actin. This is followed by mutual retrograde flow of α-catenin and F-actin from the cell edge, during which α-catenin interacts with vinculin within integrin adhesions. This interaction affects adhesion maturation, stress-fiber assembly, and force transmission to the matrix. In epithelial cells, α-catenin is present in cell-cell adhesions and absent from cell-matrix adhesions. However, when these cells undergo epithelial-to-mesenchymal transition, α-catenin transitions to cell-matrix adhesions, where it facilitates proper mechanosensing. This is highlighted by the ability of α-catenin-depleted cells to grow on soft matrices. These results suggest a dual role of α-catenin in mechanosensing, through both cell-cell and cell-matrix adhesions.
The pseudouridine synthase dyskerin binds to cytoplasmic H/ACA-box snoRNA retaining transcripts affecting nuclear hormone receptor dependence
Authors: Zacchini Federico , Venturi Giulia , De Sanctis Veronica , Bertorelli Roberto , Ceccarelli Claudio , Santini Donatella , Taffurelli Mario , Penzo Marianna , Treré Davide , Inga Alberto , Dassi Erik , Montanaro Lorenzo
Published: January 2021

Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. Since its defective function induces specific alterations in gene expression, we sought to unbiasedly identify mRNAs regulated by dyskerin. We found that dyskerin depletion affects the expression or the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin and can interact with cytoplasmic ribosomes. We then characterized the cytoplasmic dyskerin RNA interactome finding both H/ACA box snoRTs and protein-coding transcripts. Since a fraction of these latter transcripts is involved in the nuclear hormone receptor binding, we tested to see if this specific activity is affected by dyskerin. Results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer. Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions.
Different autotrophic enrichments yield efficient inocula for biocathodic applications
Authors: Gülay Arda , Jensen Marlene Mark , Sicheritz-Pontén Thomas , Smets Barth F.
Published: January 2021

The uptake of extracellular electrons from cathodes by microbes is a recently discovered phenomenon. However, current knowledge on the diversity of microbes accepting extracellular electrons and populating biocathodes is scarce. Research is required to explore the distribution of extracellular electron uptake metabolism in the tree of life across microbial guilds. Here we characterize the electron uptake ability of microbial guilds enriched on H2, S2O32-, or CH4and NH4+from the same inoculum taken from a groundwater treatment sand-filter. We hypothesized that functional microbes having dense outer membrane cytochromes in their native pathway, such as pathways of NH4+, CH4, S2O32-and H2, can perform extracellular electron uptake. We aimed of addressing the following questions: (1) Are there any known microbial member of anticipated function performing extracellular electron transfer? (2) How does electron uptake efficiency vary between the different functional guilds? (3) How is the dissipated electron energy distributed across metabolisms? We developed and applied a novel pipeline to identify taxa utilizing direct electron energy and utilizing secondary microbial products. We report the putative direct electron uptake metabolism of types belonging toMethylomonas, UBA6140, andNitrosomonas. Furthermore, members ofStreptococcaceae, Rhizobiaceae, Streptococcus, Brevundimonas, Chryseobacterium, andPseudomonasare detected as electroactive taxa. Our results reveal novel insights into the diversity, electrochemical activity, and metabolism of taxa performing direct electron uptake.
Dosage-sensitive functions in embryonic development drove the survival of genes on sex-specific chromosomes in snakes, birds, and mammals
Authors: Bellott Daniel W. , Page David C.
Published: January 2021

Different ancestral autosomes independently evolved into sex chromosomes in snakes, birds, and mammals. In snakes and birds, females are ZW and males are ZZ; in mammals, females are XX and males are XY. Although X and Z Chromosomes retain nearly all ancestral genes, sex-specific W and Y Chromosomes suffered extensive genetic decay. In both birds and mammals, the genes that survived on sex-specific chromosomes are enriched for broadly expressed, dosage-sensitive regulators of gene expression, subject to strong purifying selection. To gain deeper insight into the processes that govern survival on sex-specific chromosomes, we carried out a meta-analysis of survival across 41 species—three snakes, 24 birds, and 14 mammals—doubling the number of ancestral genes under investigation and increasing our power to detect enrichments among survivors relative to nonsurvivors. Of 2564 ancestral genes, representing an eighth of the ancestral amniote genome, only 324 survive on present-day sex-specific chromosomes. Survivors are enriched for dosage-sensitive developmental processes, particularly development of neural crest–derived structures, such as the face. However, there was no enrichment for expression in sex-specific tissues, involvement in sex determination or gonadogenesis pathways, or conserved sex-biased expression. Broad expression and dosage sensitivity contributed independently to gene survival, suggesting that pleiotropy imposes additional constraints on the evolution of dosage compensation. We propose that maintaining the viability of the heterogametic sex drove gene survival on amniote sex-specific chromosomes, and that subtle modulation of the expression of survivor genes and their autosomal orthologs has disproportionately large effects on development and disease.
Combined scanning small-angle X-ray scattering and holography probes multiple length scales in cell nuclei
Authors: Wittmeier Andrew , Cassini Chiara , Töpperwien Mareike , Denz Manuela , Hagemann Johannes , Osterhoff Markus , Salditt Tim , Köster Sarah
Published: January 2021

X-rays are emerging as a complementary probe to visible-light photons and electrons for imaging biological cells. By exploiting their small wavelength and high penetration depth, it is possible to image whole, intact cells and resolve subcellular structures at nanometer resolution. A variety of X-ray methods for cell imaging have been devised for probing different properties of biological matter, opening up various opportunities for fully exploiting different views of the same sample. Here, a combined approach is employed to study cell nuclei of NIH-3T3 fibroblasts. Scanning small-angle X-ray scattering is combined with X-ray holography to quantify length scales, aggregation state, and projected electron and mass densities of the nuclear material. Only by joining all this information is it possible to spatially localize nucleoli, heterochromatin and euchromatin, and physically characterize them. It is thus shown that for complex biological systems, like the cell nucleus, combined imaging approaches are highly valuable.
Aggressive Boards and CEO Turnover
Authors: AGHAMOLLA CYRUS , HASHIMOTO TADASHI
Published: January 2021

This study investigates a communication game between a CEO and a board of directors where the CEO's career concerns can potentially impede value‐increasing informative communication. By adopting a policy of aggressive boards (excessive replacement), shareholders can facilitate communication between the CEO and the board. The results are in contrast to the multitude of models which generally find that management‐friendly boards improve communication, and help to explain empirical results concerning CEO turnover. The results also provide the following novel predictions concerning variation in CEO turnover: (1) there is greater CEO turnover in firms or industries where CEO performance is relatively more difficult to assess; (2) the board is more aggressive in their replacement of the CEO in industries or firms where the board's advisory role is more salient; and (3) there is comparatively less CEO turnover in firms or industries where the variance of CEO talent is high.
Emergency physicians' role in telemedicine care during the coronavirus disease pandemic: Experiences from Taiwan
Authors: Chu Chien‐Ming , Wang Tsung‐Hsi , Lee Hsin‐Chung , Lin Chaou‐Shune , Feng Cho‐Chao
Published: January 2021

Taiwan's response to the coronavirus disease pandemic received international recognition. Among various epidemic control measures, telemedicine services are provided for people under home quarantine. Although this service presents no policy, cost or equipment problems, the medical needs of people under home quarantine are diverse. Further, there are no clear guidelines regarding which specialists should be included in a multidisciplinary team. Moreover, many physicians are unwilling to participate in telemedicine, creating a big challenge for hospitals providing these services. Emergency physicians (EPs) have unique experiences in crisis management and can provide a number of effective public health measures. We advocate that EPs should be the first specialists to contact patients in a multidisciplinary team. Currently, there is a lack of literature on this subject, and Taiwan's epidemic control experience is used as an example to prove our viewpoint and provide recommendations for future EPs.