bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 3D Reconstruction Algorithm for Real-time Simultaneous Multi-Source EIT Imaging for Lung Function Monitoring
Authors: Kao Tzu-Jen , Amm Bruce , Isaacson David , Newell Jonathan , Saulnier Gary , Mueller Jennifer L. 
Published: May 2020

AbstractMonitoring regional pulmonary ventilation and pulsatile perfusion changes in a 3D region of interest (ROI) of the lung is a promising application for electrical impedance tomography (EIT). This paper describes a 3D analytical reconstruction algorithm that was embedded in a prototype EIT system to enable a real-time image reconstruction at nearly 20 frames per second for monitoring impedance changes in the chest in real-time. The derivation and results of the 3D analytical forward solution and inverse solution and details of the real-time reconstruction algorithm are given. The algorithm and EIT system are validated with simulated data, in-vitro phantoms, and finally shown to be capable of imaging ventilation and pulsatile perfusion in human subjects. The human subject data was obtained using a high-precision, high-speed and simultaneous multiple current source (SMS-EIT) developed by GE Research. Data was collected using four rows of 8 electrodes for a healthy adult male subject and 2 rows of 16 electrodes for six healthy human female subjects, with one row placed above the breasts and a second row placed at the infra-mammary fold. Each of the female subjects performed a breathing maneuver with a volumetric incentive spirometer, and the volume of air inhaled was calculated from the EIT images. Pulsatile perfusion images were computed from this data, and regional lung filling was also analyzed.
Unexpected Specificity within Dynamic Transcriptional Protein-Protein Complexes
Authors: Henley Matthew J. , Linhares Brian M. , Morgan Brittany S. , Cierpicki Tomasz , Fierke Carol A. , Mapp Anna K. 
Published: May 2020

AbstractA key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and transcriptional coactivators. Seemingly incongruent with the tight regulation of transcription, many biochemical and biophysical studies suggest that activators use nonspecific hydrophobic and/or electrostatic interactions to bind to coactivators, with few if any specific contacts. Here a mechanistic dissection of a set of representative dynamic activator•coactivator complexes, comprised of the ETV/PEA3 family of activators and the coactivator Med25, reveals a different molecular recognition model. The data demonstrate that small sequence variations within an activator family significantly redistribute the conformational ensemble of the complex while not affecting overall affinity, and distal residues within the activator—not often considered as contributing to binding—play a key role in mediating conformational redistribution. The ETV/PEA3•Med25 ensembles are directed by specific contacts between the disordered activator and the Med25 interface, which is facilitated by structural shifts of the coactivator binding surface. Taken together, these data highlight the critical role coactivator plasticity plays in recognition of disordered activators, and indicates that molecular recognition models of disordered proteins must consider the ability of the binding partners to mediate specificity.
Structural basis for stereospecific inhibition of ASCT2 from rational design
Authors: Garibsingh Rachel-Ann A. , Ndaru Elias , Garaeva Alisa A. , Bonomi Massimiliano , Slotboom Dirk J. , Paulino Cristina , Grewer Christof , Schlessinger Avner 
Published: May 2020

ABSTRACTASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. ASCT2 is upregulated in cancer, where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides an emerging strategy for cancer therapy. Here, guided by a homology model of ASCT2 in an outward-facing conformation, we rationally designed novel inhibitors exploiting stereospecific pockets in the substrate binding site. A cryo-EM structure of ASCT2 in complex with inhibitor (Lc-BPE) validated our predictions and was subsequently refined based on computational analysis. The final structures, combined with MD simulations, show that the inhibitor samples multiple conformations in the ASCT2 binding site. Our results demonstrate the utility of combining computational modeling and cryo-EM for SLC ligand discovery, and a viable strategy for structure determination of druggable conformational states for challenging membrane protein targets.
Improved pure tone sensitivity after simulated hearing loss
Authors: Krauss Patrick 
Published: May 2020

AbstractRecently, it was proposed that a processing principle calledadaptive stochastic resonanceplays a major role in the auditory system, and serves to maintain optimal sensitivity even to highly variable sound pressure levels. As a side effect, in case of reduced auditory input, such as permanent hearing loss, this mechanism may eventually lead to the perception of phantom sounds like tinnitus or the Zwicker tone illusion. Using computational modeling, the biological plausibility of this processing principle was already demonstrated. Here, we provide empirical results that further support the stochastic resonance model of auditory perception. In particular, Mongolian gerbils were exposed to long-term notched noise, which mimics hearing loss for frequencies within the notch. Remarkably, the animals developed increased sensitivity, i.e. improved hearing thresholds, for the frequency centered within the notch, but nut for frequencies outside the notch. In addition, most animals treated with the new paradigm showed identical behavioral signs of phantom sound perception as animals with acoustic trauma induced tinnitus. In contrast, animals treated with broadband noise as a control condition did not show any significant threshold change, nor behavioral signs of phantom sound perception.
Development of an Ocean Protein Portal for Interactive Discovery and Education
Authors: Saito Mak A. , Saunders Jaclyn K. , Chagnon Michael , Gaylord David , Shepherd Adam , Held Noelle A. , Dupont Chris , Symmonds Nick , York Amber , Charron Matt , Kinkade Danie 
Published: May 2020

AbstractProteins are critical in catalyzing chemical reactions, forming key cellular structures, and in regulating cellular processes. Investigation of marine microbial proteins by metaproteomics methods enables the discovery of numerous aspects of microbial biogeochemistry processes. However, these datasets present big-data challenges as they often involve many samples collected across broad geospatial and temporal scales, resulting in thousands of protein identifications, abundances, and corresponding annotation information. The Ocean Protein Portal (OPP) was created to enable data sharing and discovery among multiple scientific domains and serve both research and education functions. The portal focuses on three use case questions: “Where is my protein of interest?”, “Who makes it?”, and “How much is there?”, and provides profile and section visualizations, real-time taxonomic analysis, and links to metadata, sequence analysis, and other external resources to enabling connections to be made between biogeochemical and proteomics datasets.
Deletion and overexpression of the scaffolding protein IQGAP1 promotes HCC
Authors: Delgado Evan R , Erickson Hanna L , Tao Junyan , Monga Satdarshan P , Duncan Andrew W , Anakk Sayeepriyadarshini 
Published: May 2020

AbstractIQ motif–containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with many pro-tumorigenic processes including cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective anti-tumor target. Therefore, we examined the role for IQGAP1 in tumor initiation and promotion during liver carcinogenesis. Unexpectedly, we found thatIqgap1-/-mice had a higher tumor burden thanIqgap1+/+andIqgap1+/-mice following DEN-induced liver carcinogenesis.Iqgap1-/-tumors as well as knocking downIQGAP1in hepatocellular carcinoma (HCC) cell lines resulted in increased MET activation and cellular proliferation. On the other hand, we uncovered IQGAP1 overexpression accelerates HCC development by YAP activation and subsequent NUAK2 expression. We demonstrate that increasing IQGAP1 expressionin vivodoes not alter β-catenin or MET activation. Taken together, we identify that both loss and gain of function of IQGAP1 promotes HCC development by two separate mechanisms in the liver. These results demonstrate that adequate amount of IQGAP1 is necessary to maintain a quiescent status of liver.
Spatially displaced excitation contributes to the encoding of interrupted motion by the retinal direction-selective circuit
Authors: Ding Jennifer , Chen Albert , Chung Janet , Ledesma Hector Acaron , Wu Mofei , Berson David M. , Palmer Stephanie E. , Wei Wei 
Published: May 2020

AbstractSpatially distributed excitation and inhibition collectively shape a visual neuron’s receptive field (RF) properties. In the direction-selective circuit of the mammalian retina, the role of strong null-direction inhibition of On-Off direction-selective ganglion cells (ON-OFF DSGCs) on their direction selectivity is well-studied. However, how excitatory inputs influence the On-Off DSGC’s visual response is underexplored. Here, we report that On-Off DSGCs have a spatially displaced glutamatergic receptive field along their preferred-null motion axis. This displaced receptive field contributes to DSGC null-direction spiking during interrupted motion trajectories. Theoretical analyses indicate that population responses during interrupted motion may help populations of On-Off DSGCs signal the spatial location of moving objects in complex, naturalistic visual environments. Our study highlights that the direction-selective circuit exploits separate sets of mechanisms under different stimulus conditions, and these mechanisms may help encode multiple visual features.
Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart
Authors: Dostal Vishantie , Wood Silas D. , Thomas Cody T. , Han Yu , Lau Edward , Lam Maggie P.Y. 
Published: May 2020

AbstractThe heart is sensitive to oxidative damage but a global view on how the cardiac proteome responds to oxidative stressors has yet to fully emerge. Using quantitative tandem mass spectrometry, we assessed the effects of acute exposure of the oxidative stress inducer paraquat on protein expression in mouse hearts. We observed widespread protein expression changes in the paraquat-exposed heart especially in organelle-containing subcellular fractions. During cardiac response to acute oxidative stress, proteome changes are consistent with a rapid reduction of mitochondrial metabolism, coupled with activation of multiple antioxidant proteins, reduction of protein synthesis and remediation of proteostasis. In addition to differential expression, we saw evidence of spatial reorganizations of the cardiac proteome including the translocation of hexokinase 2 to more soluble fractions. Treatment with the antioxidants Tempol and MitoTEMPO reversed many proteomic signatures of paraquat but this reversal was incomplete. We also identified a number of proteins with unknown function in the heart to be triggered by paraquat, suggesting they may have functions in oxidative stress response. Surprisingly, protein expression changes in the heart correlate poorly with those in the lung, consistent with differential sensitivity or stress response in these two organs. The results provide insights into oxidative stress responses in the heart and may avail the search for new therapeutic targets.
COVID-3D: An online resource to explore the structural distribution of genetic variation in SARS-CoV-2 and its implication on therapeutic development
Authors: Portelli Stephanie , Olshansky Moshe , Rodrigues Carlos H.M. , D’Souza Elston N. , Myung Yoochan , Silk Michael , Alavi Azadeh , Pires Douglas E.V. , Ascher David B. 
Published: May 2020

SUMMARYThe emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms, to inform effective vaccine and drug development. Despite viral novelty, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implications of SARS-CoV-2 mutations on infection, host immunity and drug development we have developed COVID-3D (http://biosig.unimelb.edu.au/covid3d/).
Inferences on a Multidimensional Social Hierarchy Use a Grid-like Code
Authors: Park Seongmin A. , Miller Douglas S. , Boorman Erie D. 
Published: May 2020

AbstractGeneralizing experiences to guide decision making in novel situations is a hallmark of flexible behavior. It has been hypothesized such flexibility depends on a cognitive map of an environment or task, but directly linking the two has proven elusive. Here, we find that discretely sampled abstract relationships between entities in an unseen two-dimensional (2-D) social hierarchy are reconstructed into a unitary 2-D cognitive map in the hippocampus and entorhinal cortex. We further show that humans utilize a grid-like code in several brain regions, including entorhinal cortex and medial prefrontal cortex, forinferreddirect trajectories between entities in the reconstructed abstract space during discrete decisions. Moreover, these neural grid-like codes in the entorhinal cortex are associated with neural decision value computations in the medial prefrontal cortex and temporoparietal junction area during choice. Collectively, these findings show that grid-like codes are used by the human brain to infer novel solutions, even in abstract and discrete problems, and suggest a general mechanism underpinning flexible decision making and generalization.
Influence of isolation by environment and landscape heterogeneity on genetic structure of wild riceZizania latifoliaalong a latitudinal gradient
Authors: Wagutu Godfrey Kinyori , Fan Xiangrong , Fu Wenlong , Li Wei , Chen Yuanyuan 
Published: May 2020

AbstractGlobal aquatic habitats are undergoing rapid degradation and fragmentation as a result of land-use change and climate change. Understanding the genetic variability and adaptive potential of aquatic plant species is thus important for conservation purposes. In this study, we investigated the role of environment, landscape heterogeneity and geographical distance in shaping the genetic structure of 28 natural populations ofZizania latifolia(Griseb.) Turcz. Ex Stapf in China based on 25 microsatellite markers. Genetic structure was investigated by analysis of molecular variance (AMOVA), estimation ofFST, Bayesian clustering and Thermodynamic Integration (TI) methods. Isolation by environment (IBE), isolation by resistance (IBR) and isolation by distance (IBD) hypotheses were compared using a reciprocal causal model (RCM). Further, generalized linear models and spatially explicit mixed models, by using geographic, landscape and genetic variables, were developed to elucidate the role of environment in drivingZ. latifoliagenetic diversity. The genetic differentiation across all populations was high:FST= 0.579; Øpt= 0.578. RCM exclusively supported IBE in shaping genetic structuring, only partial support for IBR, but not for IBD. Maximum temperature of the warmest month and precipitation seasonality were the plausible parameters responsible for genetic diversity. After controlling for spatial effect and landscape complexity, precipitation seasonality was significantly associated with genetic diversity. Based on these findings, genetic structure ofZ. latifoliaacross China seem to be as a result of local adaptation. Environmental gradient and topographical barriers, rather than geographical isolation, influence genetic differentiation of aquatic species across China resulting in instances of local adaptation.
SoxS represses flagellar gene expression through RflP inSalmonella entericaSerovar Typhimurium
Authors: Thota Srinivas S. , Henry Brittany N. , Chubiz Lon M. 
Published: May 2020

ABSTRACTFlagellar gene expression is subject to regulation by many global transcription factors in response to environmental and nutritional signals. One of the primary ways this occurs inSalmonella entericaserovar Typhimurium, and its close relatives, is through controlling levels of FlhD4C2(the flagellar master regulator) via transcriptional, post-transcriptional, and post-translational mechanisms. Recently, we found the homologous transcription factors MarA, Rob, and SoxS repressflhDCexpression by distinct mechanisms. MarA and Rob, regulators involved in inducible multidrug resistance, repressedflhDCtranscription by interacting directly with theflhDCpromoter. Alternatively, SoxS, the oxidative stress response regulator, altered FlhD4C2levels independent offlhDCtranscription by post-transcriptional or post-translational mechanism. Here, using a forward genetic screen, we discovered that SoxS-dependent repression of flagellar gene expression occurs through RflP, an anti-FlhD4C2factor that targets FlhD4C2for proteolytic degradation. ElevatedsoxSexpression resulted in concomitant increases inrflPexpression, indicating SoxS may work through RflP at the level ofrflPtranscription. Mapping of therflPpromoter and a bioinformatic search yielded a putative SoxS binding site proximal to therflPtranscription start site. Comparison of therflPpromoter region inS. Typhimurium andEscherichia coliindicate substantial differences, providing a possible mechanism for differential expression ofrflPbetween these species.IMPORTANCESalmonella entericais a major cause of foodborne illness. Understanding environmental and intracellular signals used bySalmonellato control expression of virulence-associated traits is critical to advancing treatment and prevention ofSalmonella-related disease. Reduced expression of flagella at key points duringSalmonellainfection aids in evasion of the host innate immune system. Within macrophagesSalmonellais non-flagellated and exposed to oxidative stress. SoxS-dependent repression of flagellar genes may provide a potential link between oxidative stress and reductions in flagellar expression.
Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia
Authors: Lencz Todd , Yu Jin , Rashid Khan Raiyan , Carmi Shai , Lam Max , Ben-Avraham Danny , Barzilai Nir , Bressman Susan , Darvasi Ariel , Cho Judy H. , Clark Lorraine N. , Gümüş Zeynep H. , Vijai Joseph , Klein Robert J. , Lipkin Steven , Offit Kenneth , Ostrer Harry , Ozelius Laurie J. , Peter Inga , Malhotra Anil K. , Atzmon Gil , Pe’er Itsik 
Published: May 2020

SummaryIdentification of rare genetic variants associated with schizophrenia has proven challenging due to multiple sources of heterogeneity, which may be reduced in founder populations. We examined ultra-rare exonic variants in 786 patients with schizophrenia and 463 healthy comparison subjects, all drawn from the Ashkenazi Jewish population. Cases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls. Characterizing 141 “case-only” genes (in which ≥ 3 cases in our dataset had MisLoF variants with none found in controls), we identified cadherins as a novel gene set associated with schizophrenia, including a recurrent mutation in PCDHA3. Modeling the effects of purifying selection demonstrated that deleterious ultra-rare variants are greatly over-represented in the Ashkenazi population, resulting in enhanced power for rare variant association. Identification of cell adhesion genes in the cadherin/protocadherin family helps specify the synaptic abnormalities central to the disorder, and suggests novel potential treatment strategies.
COVID-19 :Determinants of Hospitalization, ICU and Death among 20,293 reported cases in Portugal
Authors: Ricoca Peixoto Vasco , Vieira André , Aguiar Pedro , Sousa Paulo , Carvalho Carlos , Thomas Daniel , Abrantes Alexandre , Nunes Carla 
Published: May 2020

SummaryIntroductionDeterminants of hospitalization, intensive care unit (ICU) admission and death are still unclear for Covid-19 and only a few studies have adjusted for confounding for different clinical outcomes including all reported cases in a country. We used routine surveillance data from Portugal to identify risk factors for COVID-19 outcomes, in order to support risk stratification, clinical and public health interventions, and scenarios to plan health care resources.MethodsWe conducted a retrospective cohort study including 20,293 laboratory confirmed cases of COVID-19 in Portugal extracted in April 28 2020, electronically through the National Epidemic Surveillance System of the Directorate-General of Health(DGS). We calculated absolute risks, relative risks (RR) and adjusted relative risks (aRR) to identify demographic and clinical factors associated with hospitalization, admission to ICU and death using Poisson regressions.ResultsIncreasing age after 60 years was the greatest determinant for all outcomes. Assuming 0–50 years as reference, being aged 80–89 years was the strongest determinant of hospital admission (aRR-5.7), 70–79 years for ICU(aRR-10.4) and > 90 years for death(aRR-226.8) with an aRR of 112.7 in those 70–79. Among comorbidities, Immunodeficiency, cardiac disease, kidney disease, and neurologic disease were independent risk factors for hospitalization (aRR 1.83,1.79,1.56, 1.82), for ICU these were cardiac, Immunodeficiency, kidney and lung disease (aRR 4.33, 2.76, 2.43, 2.04), and for death they were kidney, cardiac and chronic neurological disease (aRR: 2.9, 2.6, 2.0) Male gender was a risk factor for all outcomes. There were small statistically significant differences for the 3 outcomes between regions.Discussion and ConclusionsOlder age stands out as the strongest risk factor for all outcomes specially for death as absolute is risk was small for those younger than 50. These findings have implications in terms of risk stratified public health measures that should prioritize protecting older people although preventive behavior is needed in all ages. Epidemiologic scenarios and clinical guidelines may consider these estimated risks, even though under-ascertainment of mild and asymptomatic cases should be considered.
Digital proximity tracing on empirical contact networks for pandemic control
Authors: Cencetti G. , Santin G. , Longa A. , Pigani E. , Barrat A. , Cattuto C. , Lehmann S. , Salathé M. , Lepri B. 
Published: May 2020

ABSTRACTDigital contact tracing is a relevant tool to control infectious disease outbreaks, including the COVID-19 epidemic. Early work evaluating digital contact tracing omitted important features and heterogeneities of real-world contact patterns influencing contagion dynamics. We fill this gap with a modeling framework informed by empirical high-resolution contact data to analyze the impact of digital contact tracing in the COVID-19 pandemic. We investigate how well contact tracing apps, coupled with the quarantine of identified contacts, can mitigate the spread in real environments. We find that restrictive policies are more effective in containing the epidemic but come at the cost of unnecessary large-scale quarantines. Policy evaluation through their efficiency and cost results in optimized solutions which only consider contacts longer than 15-20 minutes and closer than 2-3 meters to be at risk. Our results show that isolation and tracing can help control re-emerging outbreaks when some conditions are met: (i) a reduction of the reproductive number through masks and physical distance; (ii) a low-delay isolation of infected individuals; (iii) a high compliance. Finally, we observe the inefficacy of a less privacy-preserving tracing involving second order contacts. Our results may inform digital contact tracing efforts currently being implemented across several countries worldwide.