bluuebunny/crossref_metadata_2025 huggingface dataset:
Rejection in early life is associated with high and long-lasting stress and higher incidence of infections in owl monkeys
Authors: Osman Mahdiyah , Olkun Aylin , Maldonado Angela M. , Lopez-Tremoleda Jordi , Sanchez-Perea Nofre , Paredes Ursula M.
Published: October 2020

1.

Background

The mothers of owl monkeys sometimes reject their new-borns. When this occurs in captive colonies, the rejected infants are manually raised by veterinarians, allowing them to survive. However, maternal rejection can induce chronic stress, which in turn is associated with infectious diseases. Rescued, rejected owl monkeys might experience high rates of stress and infections which go undetected.

Methodology

To test this hypothesis, we evaluated the connection between maternal rejection, stress and infections in owl monkeys (Aotus nancymaae) from the IVITA Center for Conservation and Reproduction of Primates (UNMSM, Peru). Specifically, we compared the stress rates and frequency of infection treatment in juveniles (19-24 months) rejected in the first month of life and controls. To assess stress, we compared cortisol levels in hair using a competitive ELISA and recorded behaviours using cameras. We analysed past medical treatments and medication to compare incidence of infection treatment in subjects. We then studied the correlation between the frequency of infection treatments and cortisol using a linear regression.

Results

Rejected owl monkeys showed significantly higher cortisol levels (p=0.0123), a higher incidence of stereotypical behaviour and overeating (pacing p=0.0159; head twirling p=0.0476, eating p=0.0238) compared to controls. Rejected owl monkeys also received significantly more treatment for infections than controls per month lived (p=0.0009). Moreover, infection rates observed in this population were positively although weakly associated with concentration of cortisol in hair (R2=0.307, p=0.0075).

Conclusion

Maternal rejection in the first month of life is associated with high and long-lasting stress levels and infections in the IVITA owl monkey colony. IVITA owl monkeys will be a useful model for studying the long-term effects of early life stress at the population level.
Integrating multimeric threading with high-throughput experiments for structural interactome ofEscherichia coli
Authors: Gong Weikang , Guerler Aysam , Zhang Chengxin , Warner Elisa , Li Chunhua , Zhang Yang
Published: October 2020

Genome-wide protein-protein interaction (PPI) determination remains a significant unsolved problem in structural biology. The difficulty is twofold since high-throughput experiments (HTEs) have often a high false-positive rate in assigning PPIs, and PPI quaternary structures are more difficult to solve than tertiary structures using traditional structural biology techniques. We proposed a uniform pipeline to address both problems, which first recognizes PPIs by combining multi-chain threading alignments with HTE results using naïve Bayesian classifiers, where the quaternary complex structures are then constructed by mapping the monomer models with the dimeric threading frameworks through interface-specific structural alignments. The pipeline was applied to theEscherichia coligenome and created 35,125 confident PPIs which is 4.5-fold higher than HTE alone. Graphic analyses of the PPI networks revealed a scale-free cluster size distribution, which was found critical to the robustness of genome evolution and the centrality of functionally important proteins that are essential toE. colisurvival. Furthermore, complex structure models were constructed for all predictedE. coliPPIs based on the quaternary threading alignments, where 6,771 of them were found to have a high confidence score that corresponds to the correct fold of the complexes with a TM-score >0.5 and 93 showed a close consistency with the later released experimental structures with an average TM-score=0.73. These results demonstrated the significant usefulness of threading-based homologous modeling in both genome-wide PPI network detection and complex structural construction.
Dynamic task-linked switching between brain networks - A Tri-Network perspective
Authors: Shaw Saurabh Bhaskar , McKinnon Margaret C. , Heisz Jennifer , Becker Suzanna
Published: October 2020

The highly influential tri-network model proposed by Menon integrates 3 key intrinsic brain networks — the central executive network (CEN), salience network (SN), and the default mode network (DMN), into a single cohesive model underlying normal behaviour and cognition. A large body of evidence suggests that abnormal intra- and inter- network connectivity between these three networks underlies the various behavioural and cognitive dysfunctions observed in patients with neuropsychiatric conditions such as PTSD and depression. An important prediction of the tri-network model is that the DMN and CEN networks are anti-correlated under the control of the SN, such that if a task engages one of the two, the SN inhibits the activation of the other. To date most of the evidence surrounding the functions of these three core networks comes from either resting state analyses or in the context of a single task with respect to rest. Few studies have investigated multiple tasks simultaneously or characterized the dynamics of task switching. Hence, a careful investigation of the temporal dynamics of network activity during task switching is warranted. To accomplish this we collected fMRI data from 14 participants that dynamically switched between a 2-back working memory task and an autobiographical memory retrieval task, designed to activate the CEN, DMN and the SN. The fMRI data were used to 1. identify nodes and sub-networks within the three major networks involved in task-linked dynamic network switching, 2. characterize the temporal pattern of activation of these nodes and sub-networks, and finally 3. investigate the causal influence that these nodes and sub-networks exerted on each other. Using a combination of multivariate neuroimaging analyses, timecourse analyses and multivariate Granger causality measures to study the tri-network dynamics, the current study found that the SN co-activates with the task-relevant network, providing a mechanistic insight into SN-mediated network selection in the context of explicit tasks. Our findings also indicate active involvement of the posterior insula and some medial temporal nodes in task-linked functions of the SN and DMN, warranting their inclusion as network nodes in future studies of the tri-network model. These results add to the growing body of evidence showing the complex interplay of CEN, DMN and SN nodes and sub-networks required for adequate task-switching, and characterizes a normative pattern of task-linked network dynamics within the context of Menon’s tri-network model.
Signatures of Selection in CompositeVrindavaniCattle of India
Authors: Singh Akansha , Mehrotra Arnav , Gondro Cedric , da Silva Romero Andrea Renata , Pandey Ashwni Kumar , Karthikeyan A , Bashir Aamir , Mishra B.P. , Dutt Triveni , Kumar Amit
Published: October 2020

Vrindavaniis an Indian composite cattle breed developed by crossbreeding taurine dairy breeds with native indicine cattle in the 1960s. About 190,000 semen doses ofVrindavanibulls have been distributed to the farmers till date. The animals are under artificial and natural selection for higher milk production and adaptation to the tropical climate, respectively. However, the selection response for production and adaptation traits in theVrindavanigenome is not explored. In this study, we provide the first overview of the selection signatures in theVrindavanigenome. 96Vrindavanicattle were genotyped using the BovineSNP50 BeadChip and the SNP genotype data of its constituent breeds were collected from a public database. Within-breed selection signatures in Vrindavani were investigated using the integrated haplotype score (iHS). Vrindavani was also compared to each of its parental breeds to discover between-population signatures of selection using two approaches, cross-population extended haplotype homozygosity (XP-EHH) and fixation index (FST). Selection of signature identifies 11 common region identified by more than one harbouring genes such asLRP1B,TNNI3K,APOB,CACNA2D1,FAM110B and SPATA17associated with production and adaptation. Overall, our results suggested stronger selective pressure on regions responsible for adaptation compared to milk yield.
A topic modelling analysis of TCGA breast and lung cancer transcriptomic data
Authors: Valle Filippo , Osella Matteo , Caselle Michele
Published: October 2020

Topic modelling is a widely used technique to extract relevant information from large arrays of data. The problem of finding a topic structure in a dataset was recently recognized to be analogous to the community detection problem in network theory. Leveraging on this analogy, a new class of topic modelling strategies has been introduced to overcome some of the limitations of classical methods. This paper applies these recent ideas to TCGA transcriptomic data on breast and lung cancer. The established cancer subtype organization is well reconstructed in the inferred latent topic structure. Moreover, we identify specific topics that are enriched in genes known to play a role in the corresponding disease and are strongly related to the survival probability of patients. Finally, we show that a simple neural network classifier operating in the low dimensional topic space is able to predict with high accuracy the cancer subtype of a test expression sample.
Functional Connectome Fingerprinting Using Shallow Feedforward Neural Networks
Authors: Sarar Gokce , Rao Bhaskar , Liu Thomas
Published: October 2020

Although individual subjects can be identified with high accuracy using correlation matrices computed from resting-state functional magnetic resonance imaging (rsfMRI) data, the performance significantly degrades as the scan duration is decreased. Recurrent neural networks can achieve high accuracy with short duration (72s) data segments but are designed to use temporal features not present in the correlation matrices. Here we show that shallow feedforward neural networks that rely solely on the information in rsfMRI correlation matrices can achieve state-of-the-art identification accuracies (≥ 99.5%) with data segments as short as 20s and across a range of input data-size combinations when the total number of data points (# regions × # time points) is on the order of 10,000.
Mice alternate between discrete strategies during perceptual decision-making
Authors: Ashwood Zoe C. , Roy Nicholas A. , Stone Iris R. ,   The International Brain Laboratory, Urai Anne E. , Churchland Anne K. , Pouget Alexandre , Pillow Jonathan W.
Published: October 2020

Classical models of perceptual decision-making assume that subjects use a single, consistent strategy to form decisions, or that strategies evolve slowly over time. Here we present new analyses suggesting that this common view is incorrect. We analyzed data from mouse and human decision-making experiments and found that choice behavior relies on an interplay between multiple interleaved strategies. These strategies, characterized by states in a hidden Markov model, persist for tens to hundreds of trials before switching, and may alternate multiple times within a session. The identified mouse decision-making strategies were highly consistent across individuals and comprised a single “engaged” state, in which decisions relied heavily on the sensory stimulus, and several biased states in which errors frequently occurred. These results provide a powerful alternate explanation for “lapses” often observed in rodent psychophysical experiments, and suggest that standard measures of performance mask the presence of dramatic changes in strategy across trials.
Population-based prevalence surveys during the COVID-19 pandemic: a systematic review
Authors: Franceschi Vinícius Bonetti , Santos Andressa Schneiders , Glaeser Andressa Barreto , Paiz Janini Cristina , Caldana Gabriel Dickin , Machado Lessa Carem Luana , de Menezes Mayer Amanda , Küchle Julia Gonçalves , Gazzola Zen Paulo Ricardo , Vigo Alvaro , Winck Ana Trindade , Rotta Liane Nanci , Thompson Claudia Elizabeth
Published: October 2020

Population-based prevalence surveys of COVID-19 contribute to establish the burden and epidemiology of infection, the role of asymptomatic and mild infections in transmission, and allow more precise decisions about reopen policies. We performed a systematic review to evaluate qualitative aspects of these studies, their reliability, and biases. The available data described 37 surveys from 19 countries, mostly from Europe and America and using antibody testing. They reached highly heterogeneous sample sizes and prevalence estimates. Disproportional prevalence was observed in minority communities. Important risk of bias was detected in four domains: sample size, data analysis with sufficient coverage, measurements in standard way, and response rate. The correspondence analysis showed few consistent patterns for high risk of bias. Intermediate risk of bias was related to American and European studies, blood samples and prevalence >1%. Low risk of bias was related to Asian studies, RT-PCR tests and prevalence <1%.

One sentence summary

Population-based prevalence surveys of COVID-19 until September 2020 were mostly conducted in Europe and Americas, used antibody testing, and had important risks of bias.
Leveraging AutoML to provide NAFLD screening diagnosis: Proposed machine learning models
Authors: Bangash Ali Haider
Published: October 2020

NAFLD is reported to be the only hepatic ailment increasing in its prevalence concurrently with both; obesity & T2DM. In the wake of a massive strain on global health resources due to COVID 19 pandemic, NAFLD is bound to be neglected & shelved. Abdominal ultrasonography is done for NAFLD screening diagnosis which has a high monetary cost associated with it. We utilized MLjar, an autoML web platform, to propose machine learning models that require no coding whatsoever & take in only easy-to-measure anthropometric measures for coming up with a screening diagnosis for NAFLD with considerably high AUC. Further studies are suggested to validate the generalization of the presented models.
From miRNA target gene network to miRNA function: miR-375 might regulate apoptosis and actin dynamics in the heart muscle via Rho-GTPases-dependent pathways
Authors: Osmak German , Kiselev Ivan , Baulina Natalia , Favorova Olga
Published: October 2020

MicroRNAs (miRNAs) are short single-stranded non-coding RNA molecules, which are involved in regulation of main biological processes, such as apoptosis, cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myocardium), since this miRNA was previously shown to be associated with heart diseases and data on its function in myocardium are mostly unclear. We identifiedPIK3CA, RHOA, MAPK3, PAFAH1B1, CTNNB1, MYC, PRKCA, ERBB2, andCDC42as key genes in the miR-375 regulated network and predicted the possible function of miR-375 in the heart muscle, consisting mainly in the regulation of the Rho-GTPases-dependent signalling pathways.

We implemented our algorithm for miRNA function prediction into Python module, which is available at GitHub (https://github.com/GJOsmak/miRNET)
Molecular forms ofAnopheles subpictus s.l.andAnopheles sundaicus s.l.in the Indian subcontinent
Authors: Sindhania Ankita , Das Manoj K. , Sharma Gunjan , Surendran Sinnathamby N. , Kaushal B.R. , Lohani Himanshu P. , Singh Om P.
Published: October 2020

Background

Anopheles subpictus s.l.andAnopheles sundaicus s.l.are closely related species, each comprising of several sibling species. Ambiguities exist in the classification of these two nominal species and the specific status of members ofAn. subpictuscomplex. Identifying fixed molecular forms and mapping their spatial distribution will help in resolving the taxonomic ambiguities and understanding their relative epidemiological significance.

Methods

DNA sequencing of Internal Transcribed Spacer-2 (ITS2), 28S-rDNA (D1-to-D3 domains) andcytochrome oxidase-IIof morphologically identified specimens of two nominal species,An. subpictus s.l.andAn. sundaicus s.l.collected from the Indian subcontinent, was performed and subjected to genetic distance and molecular phylogenetic analyses.

Results

Molecular characterization of mosquitoes for rDNA revealed the presence of two molecular forms ofAn. sundaicus s.l.(identified asAn. epiroticus s.s.andAn. sundaicusD) and three molecular forms ofAn. subpictus s.l.(provisionally designated as Form A, B and C) in the Indian subcontinent. Phylogenetic analyses revealed two distinct clades: (i) subpictus clade, with a single molecular form ofAn. subpictus(Form A) prevalent in mainland India and Sri Lanka, and (ii) sundaicus clade, comprising of members of Sundaicus Complex., two molecular forms ofAn. subpictus s.l., (Form B and C) prevalent in coastal areas or islands, and molecular forms reported from Thailand and Indonesia. Based on the number of float-ridges on eggs, allAn. subpictusmolecular Form B were classified as Species B whereas majority (80%) of the molecular Form A were classified as sibling species C. Fixed intragenomic sequence variation in ITS2 with the presence of two haplotypes was found in molecular Form A throughout its distribution.

Conclusion

A total of three molecular forms ofAn. subpictus s.l.and two molecular forms ofAn. sundaicus s.l.were recorded in the Indian subcontinent. Phylogenetically, two forms ofAn. subpictus s.l., (Form B and C) prevalent in coastal areas or islands in the Indian subcontinent and molecular forms reported from Southeast Asia are members of Sundaicus Complex. Molecular Form A ofAn. subpictusis distantly related to all other forms and deserve a distinct specific status. Presence ofAn. epiroticusin Indian territory is recorded for the first time.
Dual-view light-sheet imaging through tilted glass interface using a deformable mirror
Authors: Vladimirov N , Preusser F , Wisniewski J , Yaniv Z , Desai RA , Woehler A , Preibisch S
Published: October 2020

Light-sheet microscopy has become one of the primary tools for imaging live developing organisms because of its high speed, low phototoxicity, and optical sectioning capabilities. Detection from multiple sides (multi-view imaging) additionally allows nearly isotropic resolution via computational merging of the views. However, conventional light-sheet microscopes require that the sample is suspended in a gel to allow optical access from two or more sides. At the same time, the use of microfluidic devices is highly desirable for many experiments, but geometric constrains and strong optical aberrations caused by the coverslip titled relative to objectives make the use of multi-view lightsheet challenging for microfluidics.

In this paper we describe the use of adaptive optics (AO) to enable multi-view light-sheet microscopy in such microfluidic setup by correcting optical aberrations introduced by the tilted coverslip. The optimal shape of deformable mirror is computed by an iterative stochastic gradient-descent algorithm that optimizes PSF in two orthogonal planes simultaneously. Simultaneous AO correction in two optical arms is achieved via a knife-edge mirror that splits excitation path and combines the detection path.

We characterize the performance of this novel microscope setup and, by dual-view light-sheet imaging ofC.elegansinside a microfluidic channel, demonstrate a drastic improvement of image quality due to AO and dual-view reconstruction. Our microscope design allows multi-view light-sheet microscopy with microfluidic devices for precisely controlled experimental conditions and high-content screening.
ESCO: single cell expression simulation incorporating gene co-expression
Authors: Tian Jinjin , Wang Jiebiao , Roeder Kathryn
Published: October 2020

Motivation

Gene-gene co-expression networks (GCN) are of biological interest for the useful information they provide for understanding gene-gene interactions. The advent of single cell RNA-sequencing allows us to examine more subtle gene co-expression occurring within a cell type. Many imputation and denoising methods have been developed to deal with the technical challenges observed in single cell data; meanwhile, several simulators have been developed for benchmarking and assessing these methods. Most of these simulators, however, either do not incorporate gene co-expression or generate co-expression in an inconvenient manner.

Results

Therefore, with the focus on gene co-expression, we propose a new simulator, ESCO, which adopts the idea of the copula to impose gene co-expression, while preserving the highlights of available simulators, which perform well for simulation of gene expression marginally. Using ESCO, we assess the performance of imputation methods on GCN recovery and find that imputation generally helps GCN recovery when the data are not too sparse, and the ensemble imputation method works best among leading methods. In contrast, imputation fails to help in the presence of an excessive fraction of zero counts, where simple data aggregating methods are a better choice. These findings are further verified with mouse and human brain cell data.

Availability

The ESCO implementation is available as R packageSplatterESCO(https://github.com/JINJINT/SplatterESCO).

Contact

roeder@andrew.cmu.edu
Mutational meltdown of microbial altruists inStreptomyces coelicolorcolonies
Authors: Zhang Zheren , Shitut Shraddha , Claushuis Bart , Claessen Dennis , Rozen Daniel E.
Published: October 2020

In colonies of the filamentous multicellular bacteriumStreptomyces coelicolor, a sub-population of cells arise that hyper-produce metabolically costly antibiotics, resulting in division of labor that maximizes colony fitness. Because these cells contain large genomic deletions that cause massive reductions to individual fitness, their behavior is altruistic, much like worker castes in social insects or somatic cells in multicellular organisms. To understand the reproductive and genomic fate of these mutant cells after their emergence, we use experimental evolution by serially transferring populations via spore-to-spore transfer for 25 cycles, reflective of the natural mode of bottlenecked transmission for these spore-forming bacteria. We show that, in contrast to wild-type cells, altruistic mutant cells continue to significantly decline in fitness during transfer while they delete larger and larger fragments from their chromosome ends. In addition, altruistic mutants acquire a roughly 10-fold increase in their base-substitution rates possibly due to mutations in genes for DNA replication and repair. Ecological damage, caused by reduced sporulation, coupled with irreversible DNA damage due to point mutations and deletions, leads to an inevitable and irreversible type of mutational meltdown in these cells. Taken together, these results suggest that the altruistic cells arising in this division of labor are analogous to reproductively sterile castes of social insects.
Asymmetries around the visual field: From retina to cortex to behavior
Authors: Kupers Eline R. , Benson Noah C. , Carrasco Marisa , Winawer Jonathan
Published: October 2020

Visual performance varies around the visual field. It is best near the fovea compared to the periphery, and at iso-eccentric locations it is best on the horizontal, intermediate on the lower, and poorest on the upper meridian. The fovea-to-periphery performance decline is linked to the decreases in cone density, retinal ganglion cell (RGC) density, and V1 cortical magnification factor (CMF) as eccentricity increases. The origins of polar angle asymmetries are not well understood. Optical quality and cone density vary across the retina, but recent computational modeling has shown that these factors can only account for a small percentage of behavior. Here, we investigate how visual processing beyond the cone photon absorptions contributes to polar angle asymmetries in performance. First, we quantify the extent of asymmetries in cone density, midget RGC density, and V1 CMF. We find that both polar angle asymmetries and eccentricity gradients increase from cones to mRGCs, and from mRGCs to cortex. Second, we extend our previously published computational observer model to quantify the contribution of phototransduction by the cones and spatial filtering by mRGCs to behavioral asymmetries. Starting with photons emitted by a visual display, the model simulates the effect of human optics, cone isomerizations, phototransduction, and mRGC spatial filtering. The model performs a forced choice orientation discrimination task on mRGC responses using a linear support vector machine classifier. The model shows that asymmetries in a decision-maker’s performance across polar angle are greater when assessing the photocurrents than when assessing isomerizations and are greater still when assessing mRGC signals. Nonetheless, the polar angle asymmetries of the mRGC outputs are still considerably smaller than those observed from human performance. We conclude that cone isomerizations, phototransduction and the spatial filtering properties of mRGCs contribute to polar angle performance differences, but that a full account of these differences will entail additional contribution from cortical representations.
Speech categorization is better described by induced rather than evoked neural activity
Authors: Mahmud Md Sultan , Yeasin Mohammed , Bidelman Gavin M.
Published: October 2020

Categorical perception (CP) describes how the human brain categorizes speech despite inherent acoustic variability. We examined neural correlates of CP in both evoked and induced EEG activity to evaluate which mode best describes the process of speech categorization. Using source reconstructed EEG, we used band-specific evoked and induced neural activity to build parameter optimized support vector machine (SVMs) model to assess how well listeners’ speech categorization could be decoded via whole-brain and hemisphere-specific responses. We found whole-brain evoked β-band activity decoded prototypical from ambiguous speech sounds with ~70% accuracy. However, induced γ-band oscillations showed better decoding of speech categories with ~95% accuracy compared to evoked β-band activity (~70% accuracy). Induced high frequency (γ-band) oscillations dominated CP decoding in the left hemisphere, whereas lower frequency (θ-band) dominated decoding in the right hemisphere. Moreover, feature selection identified 14 brain regions carrying induced activity and 22 regions of evoked activity that were most salient in describing category-level speech representations. Among the areas and neural regimes explored, we found that induced γ-band modulations were most strongly associated with listeners’ behavioral CP. Our data suggest that the category-level organization of speech is dominated by relatively high frequency induced brain rhythms.
Epistatic interactions shape the interplay between beneficial alleles and gain or loss of pathways in the evolution of novel metabolism
Authors: Bruger Eric L. , Chubiz Lon M. , Rojas Echenique José I. , Renshaw Caleb J. , Espericueta N. Victoria , Draghi Jeremy A. , Marx Christopher J.
Published: October 2020

Fitness landscapes are often invoked to interpret the effects of allele substitutions and their interactions; however, evolution also includes larger changes like gene loss and acquisition. Previous work with the methylotrophic bacteriumMethylorubrum extorquensAM1 identified strongly beneficial mutations in a strain evolved to utilize a novel,Foreignpathway in place of its native central metabolic pathway for growth on methanol. These mutations were consistently beneficial, regardless of the order in which they arose. Here we extend this analysis to consider loss or acquisition of metabolic pathways by examining strains relying upon either theNativepathway, or both (‘Dual’) pathways present. Unlike in theForeignpathway context in which they evolved, these alleles were often deleterious in these alternative genetic backgrounds, following patterns that were strongly contingent on the specific pathways and other evolved alleles present. Landscapes for these alternative pathway backgrounds altered which genotypes correspond to local fitness peaks and would restrict the set of accessible evolutionary trajectories. These epistatic interactions negatively impact the probability of maintaining multiple degenerate pathways, making it more difficult for these pathways to coevolve. Together, our results highlight the uncertainty of retaining novel functions acquired via horizontal gene transfer (HGT), and that the potential for cells to either adopt novel functions or to maintain degenerate pathways together in a genome is heavily dependent upon the underlying epistatic interactions between them.

Author Summary

The evolution of physiology in microbes has important impacts ranging from global cycling of elements to the emergence and spread of pathogens and their resistance to antibiotics. While genetic interactions between mutations in evolving lineages of microbes have been investigated, these have not included the acquisition of novel genes on elements like plasmids, and thus how these elements interact with existing alleles. The dynamics of novel gene retention are of interest from both positive (e.g., biotechnology) and negative (e.g., antimicrobial resistance) practical impacts. We find that the patterns of interactions between evolved alleles appear substantially different, and generally much less positive, when moved into novel genetic backgrounds. Additionally, these preexisting alleles were found to have strong impacts on the ability of genotypes to maintain – and in rare cases coevolve with – novel genes and pathways. These results show that even though they evolved separately, the particular alleles in a genetic background, and importantly the physiological impacts they confer, weigh heavily on whether genes for novel metabolic processes are maintained.
orfipy: a fast and flexible tool for extracting ORFs
Authors: Singh Urminder , Wurtele Eve Syrkin
Published: October 2020

Searching for ORFs in transcripts is a critical step prior to annotating coding regions in newly-sequenced genomes and to search for alternative reading frames within known genes. With the tremendous increase in RNA-Seq data, faster tools are needed to handle large input datasets. These tools should be versatile enough to fine-tune search criteria and allow efficient downstream analysis. Here we present a new python based tool,orfipy, which allows the user to flexibly search for open reading frames in fasta sequences. The search is rapid and is fully customizable, with a choice of Fasta and BED output formats.

Availability and implementation

orfipyis implemented in python and is compatible with python v3.6 and higher. Source code:https://github.com/urmi-21/orfipy. Installation: from the source, or via PyPi (https://pypi.org/project/orfipy) or bioconda (https://anaconda.org/bioconda/orfipy).

Contact

usingh@iastate.edu,mash@iastate.edu

Supplementary information

Supplementary data are available athttps://github.com/urmi-21/orfipy
Direct visualization of epithelial microvilli biogenesis
Authors: Gaeta Isabella M. , Meenderink Leslie M. , Postema Meagan M. , Cencer Caroline S. , Tyska Matthew J.
Published: October 2020

Microvilli are actin bundle supported surface protrusions that play essential roles in diverse epithelial cell functions. To develop our understanding of microvilli biogenesis, we used live imaging to directly visualize protrusion growth at early stages of epithelial differentiation. Time-lapse data revealed that an “initiation complex” enriched in EPS8 and IRTKS appears at future sites of microvillus growth minutes before core actin bundle assembly. Elongation of a new core bundle occurs in parallel with the arrival of EZRIN and plasma membrane encapsulation. In addition tode novogrowth, we also observed that new microvilli emerge from pre-existing protrusions. Additionally, we found that new microvilli can also collapse, characterized first by loss of membrane wrapping and Ezrin enrichment, followed by a sharp decrease in distal tip EPS8 and IRTKS. These studies are the first to offer a temporally resolved microvillus growth mechanism and highlight critical factors that drive this process.
The cowboy effect: robot gaze influences human decisions
Authors: Belkaid Marwen , Kompatsiari Kyveli , de Tommaso Davide , Zablith Ingrid , Wykowska Agnieszka
Published: October 2020

In most everyday life situations, the brain needs to engage not only in making decisions, but also in anticipating and predicting the behavior of others. In such contexts, gaze can be highly informative about others’ intentions, goals and upcoming decisions. Here, we investigated whether a humanoid robot’s gaze (mutual or averted) influences the way people strategically reason in a social decisionmaking context. Specifically, participants played a strategic game with the robot iCub while we measured their behavior and neural (EEG) activity. Participants were slower to respond when iCub established mutual gaze prior to their decision, relative to averted gaze. This was associated with a higher decision threshold in the drift diffusion model and accompanied by more synchronized EEG alpha activity. In addition, we found that participants reasoned about the robot’s actions in both conditions. However, those who mostly experienced the averted gaze were more likely to adopt a self-oriented strategy and their neural activity showed higher sensitivity to outcome. Altogether, these findings suggest that robot gaze acts as a strong social signal for humans, modulating response times, decision threshold, neural synchronization, as well as choice strategies and sensitivity outcomes. This has strong implications for all contexts involving human-robot interaction, from robotics to clinical applications.
The molecular coupling between substrate recognition and ATP turnover in a AAA+ hexameric helicase loader
Authors: Puri Neha , Fernandez Amy J. , Murray Valerie L. O’Shea , McMillan Sarah , Keck James L. , Berger James M.
Published: October 2020

In many bacteria and in eukaryotes, replication fork establishment requires the controlled loading of hexameric, ring-shaped helicases around DNA by AAA+ ATPases. How loading factors use ATP to control helicase deposition is poorly understood. Here, we dissect how specific ATPase elements ofE. coliDnaC, an archetypal loader for the bacterial DnaB helicase, play distinct roles in helicase loading and the activation of DNA unwinding. We identify a new element, the arginine-coupler, which regulates the switch-like behavior of DnaC to prevent futile ATPase cycling and maintains loader responsiveness to replication restart systems. Our data help explain how the ATPase cycle of a AAA+-family helicase loader is channeled into productive action on its target; comparative studies indicate elements analogous to the Arg-coupler are present in related, switch-like AAA+ proteins that control replicative helicase loading in eukaryotes, as well as polymerase clamp loading and certain classes of DNA transposases.
Robust Mendelian randomization in the presence of residual population stratification, batch effects and horizontal pleiotropy
Authors: Cinelli Carlos , LaPierre Nathan , Hill Brian L. , Sankararaman Sriram , Eskin Eleazar
Published: October 2020

Mendelian Randomization (MR) exploits genetic variants as instrumental variables to estimate the causal effect of an “exposure” trait on an “outcome” trait from observational data. However, the validity of such studies is threatened by population stratification, batch effects, and horizontal pleiotropy. Although a variety of methods have been proposed to partially mitigate those problems, residual biases may still remain, leading to highly statistically significant false positives in large genetic databases. Here, we describe a suite of sensitivity analysis tools for MR that enables investigators to properly quantify the robustness of their findings against these (and other) unobserved validity threats. Specifically, we propose the routine reporting of sensitivity statistics that can be used to readily quantify the robustness of a MR result: (i) the partialR2of the genetic instrument with the exposure and the outcome traits; and, (ii) therobustness valueof both genetic associations. These statistics quantify theminimal strengthof violations of the MR assumptions that would be necessary to explain away the MR causal effect estimate. We also provide intuitive displays to visualize the sensitivity of the MR estimate to any degree of violation, and formal methods tobound the worst-case biascaused by violations in terms of multiples of the observed strength of principal components, batch effects, as well as putative pleiotropic pathways. We demonstrate how these tools can aid researchers in distinguishing robust from fragile findings, by showing that the MR estimate of the causal effect of body mass index (BMI) on diastolic blood pressure is relatively robust, whereas the MR estimate of the causal effect of BMI on Townsend deprivation index is relatively fragile.
Plant Scaffolds Support Motor Recovery and Regeneration in Rats after Traumatic Spinal Cord Injury
Authors: Modulevsky Daniel J. , Cuerrier Charles M. , Leblanc-Latour Maxime , Hickey Ryan J. , Obhi Ras-Jeevan K. , Shore Isabel , Galuta Ahmad , Walker Krystal L. A. , Tsai Eve C. , Pelling Andrew E.
Published: October 2020

As of yet, no standard of care incorporates biomaterials to treat traumatic spinal cord injury (SCI). However, intense development of biomaterials for treating SCI has focused on fabricating microscale channels to support the regrowth of axons while minimizing scar formation. We previously demonstrated that plant tissues could be decellularized and processed to form sterile, biocompatible and implantable biomaterials that support cell infiltration and vascularizationin vivo. Vascularized plant tissues contain continuous microscale channels with geometries relevant for supporting neural regeneration. We hypothesized that decellularized vascular bundles would support neural regeneration and motor recovery in SCI. Sprague Dawley rats received a complete T8-T9 spinal cord transection and were implanted with acellular plant-derived scaffolds and allowed to recover over 28 weeks. Animals that received the scaffolds alone, with no other therapeutic compounds, demonstrated a significant and stable partial improvement in motor function compared to control animals as early as week 4 post-injury. Hind-limb motor function did not deteriorate over the remaining 28 weeks. Histological analysis revealed minimal astrocyte scarring at the spinal cord - scaffold interface, aligned axonal projection through the scaffolds, populations of serotonergic neurons and Schwann cells, laminin and collagen deposition and the presence of blood vessels. Axonal reconnection via the scaffold was also confirmed by Fluro-gold retrograde tracing. Taken together, our work defines a novel route for building upon naturally occurring plant microarchitectures to support the repair of the spinal cord post-injury. Notably, these results were achieved without the use of growth factors, stem/progenitor cells, or any other interventions.
Integrated Single Cell Atlas of Endothelial Cells of the Human Lung
Authors: Schupp Jonas C. , Adams Taylor S. , Cosme Carlos , Raredon Micha Sam Brickman , Omote Norihito , De Frias Sergio Poli , Rose Kadi-Ann , Manning Edward , Sauler Maor , DeIuliis Giuseppe , Ahangari Farida , Neumark Nir , Yuan Yifan , Habermann Arun C. , Gutierrez Austin J. , Bui Linh T. , Meyer Kerstin B. , Nawijn Martijn C. , Teichmann Sarah A. , Banovich Nicholas E. , Kropski Jonathan A. , Niklason Laura E. , Pe’er Dana , Yan Xiting , Homer Robert , Rosas Ivan O. , Kaminski Naftali
Published: October 2020

Background

Despite its importance in health and disease, the cellular diversity of the lung endothelium has not been systematically characterized in humans. Here we provide a reference atlas of human lung endothelial cells (ECs), to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium, both in health and disease.

Methods

We reprocessed control single cell RNA sequencing (scRNAseq) data from five datasets of whole lungs that were used for the analysis of pan-endothelial markers, we later included a sixth dataset of sorted control EC for the vascular subpopulation analysis. EC populations were characterized through iterative clustering with subsequent differential expression analysis. Marker genes were validated by immunohistochemistry andin situhybridization. Signaling network between different lung cell types was studied using connectomic analysis. For cross species analysis we applied the same methods to scRNAseq data obtained from mouse lungs.

Results

The six lung scRNAseq datasets were reanalyzed and annotated to identify over 15,000 vascular EC cells from 73 individuals. Differential expression analysis of EC revealed signatures corresponding to endothelial lineage, including pan-endothelial, pan-vascular and subpopulation-specific marker gene sets. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous ECs we found previously indistinguishable subpopulations; among venous EC we identified two previously indistinguishable populations, pulmonary-venous ECs (COL15A1neg) localized to the lung parenchyma and systemic-venous ECs (COL15A1pos) localized to the airways and the visceral pleura; among capillary EC we confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1 and TBX2 and general capillary EC. We confirmed that all six endothelial cell types, including the systemic-venous EC and aerocytes are present in mice and identified endothelial marker genes conserved in humans and mice. Ligand-Receptor connectome analysis revealed important homeostatic crosstalk of EC with other lung resident cell types. Our manuscript is accompanied by an online data mining tool (www.LungEndothelialCellAtlas.com).

Conclusion

Our integrated analysis provides the comprehensive and well-crafted reference atlas of lung endothelial cells in the normal lung and confirms and describes in detail previously unrecognized endothelial populations across a large number of humans and mice.
The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway
Authors: Li Xinzhi , Yuan Bingchuan , Yao Zhicheng , Sun Xu , Guo Weixiang , Chen Zheng
Published: October 2020

Hepatocyte death triggers liver inflammation, liver injury, and fibrosis, which contributes to non-alcoholic steatohepatitis (NASH) pathogenesis. However, whether RNA processing regulates death signaling pathway during NASH progression is not investigated. In this study, we show that HuR, a widely expressed RNA-binding protein, promotes NASH progression by increasing DR5/caspase8/caspase3-mediated hepatocyte death. Cytosolic HuR levels are abnormally elevated in human patients with NASH. Hepatocyte-specific deletion ofHuRprotects against MCD-induced NASH by decreasing liver steatosis, inflammation and cell death, whereas hepatic overexpression of HuR induces liver injury by increasing DR5-induced hepatocyte death. Furthermore, in primary hepatocytes, HuR deficiency ameliorates PA&TNFα-induced hepatocyte death due to decreased DR5/caspase8/caspase 3 signaling pathway while overexpression of HuR induces hepatocyte death by increasing DR5/caspase8/caspase 3 signaling pathway. Mechanistically, HuR directly binds to 3′-UTR of DR5 transcript and promotes its mRNA stability, contributing to the hepatocyte death during NASH progression. Our data reveal a novel mechanism by which HuR promotes mRNA stability of DR5, which contributes to NASH progression.
Inhibitory interneurons show early dysfunction in a SOD1 mouse model of amyotrophic lateral sclerosis
Authors: Cavarsan C. F. , Steele P. R. , Genry L. T. , Reedich E.J. , McCane L. M. , LaPre K. J. , Puritz A. C. , Manuel M. , Katenka N. , Quinlan K. A.
Published: October 2020

Few studies in amyotrophic lateral sclerosis (ALS) measure effects of the disease on inhibitory interneurons synapsing onto motoneurons (MNs). However, inhibitory interneurons could contribute to dysfunction, particularly if altered before MN neuropathology, and establish a long-term imbalance of inhibition / excitation. We directly assessed excitability and morphology of glycinergic (GlyT2 expressing) ventral lumbar interneurons from SOD1G93AGlyT2eGFP (SOD1) and wildtype GlyT2eGFP (WT) mice on postnatal days 6-10. Patch clamp revealed dampened excitability in SOD1 interneurons, including depolarized persistent inward currents (PICs), increased voltage and current threshold for firing action potentials, along with a marginal decrease in afterhyperpolarization (AHP) duration. Primary neurites of ventral SOD1 inhibitory interneurons were larger in volume and surface area than WT. GlyT2 interneurons were then divided into 3 subgroups based on location: (1) interneurons within 100 μm of the ventral white matter, where Renshaw cells (RCs) are located, (2) interneurons interspersed with MNs in lamina IX, and (3) interneurons in the intermediate ventral area including laminae VII and VIII. Ventral interneurons in the RC area were the most profoundly affected, exhibiting more depolarized PICs and larger primary neurites. Interneurons in lamina IX had depolarized PIC onset. In lamina VII-VIII, interneurons were least affected. In summary, inhibitory interneurons show very early region-specific perturbations poised to impact excitatory / inhibitory balance of MNs, modify motor output, and provide early biomarkers of ALS. Therapeutics like riluzole which universally reduce CNS excitability could exacerbate the inhibitory dysfunction described here.

Abstract Figure

Abstract Figure:

SOD1 glycinergic interneurons in the ventral horn show altered morphology and excitability, including depolarization of PICs, depolarized threshold, shorter AHPs, smaller somata and larger primary neurites. Ventrally located interneurons are the most prominently affected.

Key Points Summary

Spinal inhibitory interneurons could contribute to amyotrophic lateral sclerosis (ALS) pathology, but their excitability has never been directly measured.

We studied the excitability and morphology of glycinergic interneurons in early postnatal transgenic mice (SOD1G93AGlyT2eGFP).

Interneurons were less excitable and had marginally smaller somas but larger primary neurites in SOD1 mice.

GlyT2 interneurons were analyzed according to their localization within the ventral spinal cord. Interestingly, the greatest differences were observed in the most ventrally-located interneurons.

We conclude that inhibitory interneurons show presymptomatic changes that may contribute to excitatory / inhibitory imbalance in ALS.
Computational study of the effect of hypoxia on cancer response to radiation treatment
Authors: Korhonen T. , Lagerlöf J. H. , Muntean A.
Published: October 2020

We perform a computational study of the propagation of the oxygen concentration within a two-dimensional slice of a heterogeneous tumour region where the position and shape of the blood vessels are known. Exploiting the parameters space, we explore which effect is noticeable what concerns the formation of hypoxic zones. We use this information to anticipate a patient-specific radiation treatment with controlled response of the cancer growth.