bluuebunny/crossref_metadata_2025 huggingface dataset:
A cysteine protease inhibitor blocks SARS-CoV-2 infection of human and monkey cells
Authors: Mellott Drake M. , Tseng Chien-Te , Drelich Aleksandra , Fajtová Pavla , Chenna Bala C. , Kostomiris Demetrios H. , Hsu Jason , Zhu Jiyun , Taylor Zane W. , Tat Vivian , Katzfuss Ardala , Li Linfeng , Giardini Miriam A. , Skinner Danielle , Hirata Ken , Beck Sungjun , Carlin Aaron F. , Clark Alex E. , Beretta Laura , Maneval Daniel , Frueh Felix , Hurst Brett L. , Wang Hong , Kocurek Klaudia I. , Raushel Frank M. , O’Donoghue Anthony J. , de Siqueira-Neto Jair Lage , Meek Thomas D. , McKerrow James H.
Published: October 2020

K777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ACE2, Caco-2, A549/ACE2, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ACE2, and 4 nM for HeLa/ACE2 cells. In contrast, Calu-3 and Caco-2 cells had EC50 values in the low micromolar range. No toxicity of K777 was observed for any of the host cells at 10-100 μM inhibitor. K777 did not inhibit activity of the papain-like cysteine protease and 3CL cysteine protease, encoded by SARS-CoV-2 at concentrations of ≤ 100 μM. These results suggested that K777 exerts its potent anti-viral activity by inactivation of mammalian cysteine proteases which are essential to viral infectivity. Using a propargyl derivative of K777 as an activity-based probe, K777 selectively targeted cathepsin B and cathepsin L in Vero E6 cells. However only cathepsin L cleaved the SARS-CoV-2 spike protein and K777 blocked this proteolysis. The site of spike protein cleavage by cathepsin L was in the S1 domain of SARS-CoV-2, differing from the cleavage site observed in the SARS CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of viral spike protein processing.

SIGNIFICANCE

The virus causing COVID-19 is highly infectious and has resulted in a global pandemic. We confirm that a cysteine protease inhibitor, approved by the FDA as a clinical-stage compound, inhibits SARS-CoV-2 infection of several human and monkey cell lines with notable(nanomolar) efficacy. The mechanism of action of this inhibitor is identified as a specific inhibition of host cell cathepsin L. This in turn inhibits host cell processing of the coronaviral spike protein, a step required for cell entry. Neither of the coronaviral proteases are inhibited, and the cleavage site of spike protein processing is different from that reported in other coronaviruses. Hypotheses to explain the differential activity of the inhibitor with different cell types are discussed.
Alleloscope: Integrative single cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer
Authors: Wu Chi-Yun , Lau Billy T. , Kim Heon Seok , Sathe Anuja , Grimes Susan M. , Ji Hanlee P. , Zhang Nancy R.
Published: October 2020

Cancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single cell DNA and ATAC sequencing data, either separately or in combination. This approach allows for integrative multi-omic analysis of allele-specific copy number and chromatin accessibility on the same cell. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with extensive validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. The contributions of such allele-specific events to intratumor heterogeneity have been under-reported and under-studied due to the lack of methods for their detection. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling the dissection of the contributions of chromosomal instability and chromatin remodeling in tumor evolution.
Dynamical interactions reconfigure the gradient of cortical timescales
Authors: Sorrentino P , Rabuffo G , Baselice F , Troisi Lopez E , Liparoti M , Quarantelli M , Sorrentino G , Bernard C , Jirsa V
Published: October 2020

A hierarchy of local timescales with a back (sensory)-to-front (prefrontal) gradient reflects brain region specialization. However, cognitive processes emerge from the coordinated activity across regions, and the corresponding timescales should refer to the interactions rather than to regional activity. Using edgewise connectivity on magnetoencephalography signals, we demonstrate a reverse front-to-back gradient when non-local interactions are prominent. Thus, the timescales are dynamic and reconfigure between back-to-front and front-to-back patterns.
Dysregulated gene expression of imprinted and X-linked genes: a link to poor development of bovine haploid androgenetic embryos
Authors: Aguila Luis , Therrien Jacinthe , Suzuki Joao , García Mónica , Trindade Amanda , Smith Lawrence C.
Published: October 2020

Mammalian uniparental embryos are efficient models for genome imprinting research and allow studies on the contribution of the paternal and maternal genome to early embryonic development. In this study, we analyzed different methodologies for production of bovine haploid androgenetic embryos (hAE) to elucidate the causes behind their poor developmental potential. The results showed that hAE can be efficiently generated by using intracytoplasmic sperm injection and oocyte enucleation at telophase II. Although haploidy does not disturb early development up to around the 3rdmitotic division, androgenetic development is disturbed after the time of zygote genome activation those that reach the morula stage are less capable to become a blastocyst. Analysis of gene expression indicated abnormal levels of methyltransferase 3B and key long non-coding RNAs involved in X-chromosome inactivation and genomic imprinting of the KCNQ1 locus, which is associated to the methylation status of imprinted control regions of XIST and KCNQ1OT1. Thus, our results seem to exclude micromanipulation consequences and chromosomal abnormalities as major factors in developmental restriction, suggesting that their early developmental constraint is regulated at an epigenetic level.
Insight into the origin of 5’UTR and source of CpG reduction in SARS-CoV-2 genome
Authors: Afrasiabi Ali , Alinejad-Rokny Hamid , Lovell Nigel , Xu Zhenming , Ebrahimi Diako
Published: October 2020

SARS-CoV-2, the causative agent of COVID-19, has an RNA genome, which is, overall, closely related to the bat coronavirus sequence RaTG13. However, the ACE2-binding domain of this virus is more similar to a coronavirus isolated from a Guangdong pangolin. In addition to this unique feature, the genome of SARS-CoV-2 (and its closely related coronaviruses) has a low CpG content. This has been postulated to be the signature of an evolutionary pressure exerted by the host antiviral protein ZAP. Here, we analyzed the sequences of a wide range of viruses using both alignment-based and alignment free approaches to investigate the origin of SARS-CoV-2 genome. Our analyses revealed a high level of similarity between the 5’UTR of SARS-CoV-2 and that of the Guangdong pangolin coronavirus. This suggests bat and pangolin coronaviruses might have recombined at least twice (in the 5’UTR and ACE2 binding regions) to seed the formation of SARS-CoV-2. An alternative hypothesis is that the lineage preceding SARS-CoV-2 is a yet to be sampled bat coronavirus whose ACE2 binding domain and 5’UTR are distinct from other known bat coronaviruses. Additionally, we performed a detailed analysis of viral genome compositions as well as expression and RNA binding data of ZAP to show that the low CpG abundance in SARS-CoV-2 is not related to an evolutionary pressure from ZAP.
A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior
Authors: Gildawie Kelsea R. , Ryll Lilly M. , Hexter Jessica C. , Peterzell Shayna , Valentine Alissa A. , Brenhouse Heather C.
Published: October 2020

Adversity early in life substantially impacts prefrontal cortex (PFC) development and vulnerability to later-life psychopathology. Importantly, repeated adverse experiences throughout childhood increase the risk for PFC-mediated behavioral deficits more commonly in women. Evidence from animal models points to effects of adversity on later-life neural and behavioral dysfunction; however, few studies have investigated the neurobiological underpinnings of sex-specific, long term consequences of multiple developmental stressors. We modeled early life adversity in rats via maternal separation (postnatal day (P)2-20) and juvenile social isolation (P21-35). Adult (P85) male and female rats were assessed for differences in the presence and structural integrity of PFC perineuronal nets (PNNs) enwrapping parvalbumin (PV)-expressing interneurons. PNNs are extracellular matrix structures formed during critical periods in postnatal development that play a key role in the plasticity of PV cells. Females – but not males – exposed to multiple hits of adversity demonstrated a reduction in PFC PV cells in adulthood. We also observed a sex-specific, potentiated reduction in PV+ PNN structural integrity. Moreover, correlations between neural disruption and hyperactivity/risk-assessment behavior were altered by adversity differently in males and females. These findings suggest a sex-specific impact of repeated adversity on neurostructural development and implicate PNNs as a contributor to associated behavioral dysfunction.
High precision in microRNA prediction: a novel genome-wide approach based on convolutional deep residual networks
Authors: Yones C. , Raad J. , Bugnon L.A. , Milone D.H. , Stegmayer G.
Published: October 2020

Motivation

MicroRNAs (miRNAs) are small non-coding RNAs that have a key role in the regulation of gene expression. The importance of miRNAs is widely acknowledged by the community nowadays, and the precise prediction of novel candidates with computational methods is still very needed. This could be done by searching homologous with sequence alignment tools, but this will be restricted only to sequences very similar to the known miRNA precursors (pre-miRNAs). Further-more, other important properties of pre-miRNAs, such as the secondary structure, are not taken into account by these methods. Many machine learning approaches were proposed in the last years to fill this gap, but these methods were tested in very controlled conditions, which are not fulfilled, for example, when predicting in newly sequenced genomes, where no miRNAs are known. If these methods are used under real conditions, the precision achieved is far from the one published.

Results

This work provides a novel approach for dealing with the computational prediction of pre-miRNAs: a convolutional deep residual neural network. The proposed model has been tested on several complete genomes of animals and plants, achieving a precision up to 5 times higher than other approaches at the same recall rates. Also, a novel validation methodology is used to ensure that the performance reported can be achieved when using the method on new unknown species.

Availability

To provide fast an easy access to mirDNN, a web demo is availablehere. It can process fasta files with multiple sequences to calculate the prediction scores, and can generate the nucleotide importance plots. The full source code of this project is availablehereandhere.

Contact

cyones@sinc.unl.edu.ar
Free-living psychrophilic bacteria of the genusPsychrobacterare descendants of pathobionts
Authors: Welter Daphne K. , Ruaud Albane , Henseler Zachariah M. , De Jong Hannah N. , van Coeverden de Groot Peter , Michaux Johan , Gormezano Linda , Waters Jillian L. , Youngblut Nicholas D. , Ley Ruth E.
Published: October 2020

Host-adapted microbiota are generally thought to have evolved from free-living ancestors. This process is in principle reversible, but examples are few. The genusPsychrobacter(familyMoraxellaceae, phylumGamma-Proteobacteria) includes species inhabiting diverse and mostly polar environments, such as sea ice and marine animals. To probePsychrobacter’sevolutionary history, we analyzed 85Psychrobacterstrains by comparative genomics and phenotyping under 24 different growth conditions. Genome-based phylogeny showsPsychrobacterare derived fromMoraxella, which are warm-adapted pathobionts.Psychrobacterstrains form two ecotypes based on growth temperature: flexible (FE, growth at 4 - 37°C), and restricted (RE, 4 - 25°C). FE strains, which can be either phylogenetically basal or derived, have smaller genomes and higher transposon copy numbers. RE strains have larger genomes, and show genomic adaptations towards a psychrophilic lifestyle and are phylogenetically derived only. We then assessedPsychrobacterabundance in 86 mostly wild polar bear stools and tested persistence of select strains in germfree mice.Psychrobacter(both FE and RE) was enriched in stool of polar bears feeding on mammals, but only FE strains persisted in germfree mice. Together these results indicate growth at 37°C is ancestral inPsychrobacter, lost in many derived species, and likely necessary to colonize the mammalian gut.
A computational approach to evaluate the combined effect of SARS-CoV-2 RBD mutations and ACE2 receptor genetic variants on infectivity: The COVID-19 host-pathogen nexus
Authors: Ashoor Dana , Khalaf Noureddine Ben , Marzouq Maryam , Al Jarjanazi Hamdi , Chelif Sadok , Fathallah M. Dahmani
Published: October 2020

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.
H3k27ac-HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility
Authors: Giambartolomei Claudia , Seo Ji-Heui , Schwarz Tommer , Freund Malika Kumar , Johnson Ruth Dolly , Spisak Sandor , Baca Sylvan C. , Gusev Alexander , Mancuso Nicholas , Pasaniuc Bogdan , Freedman Matthew L.
Published: October 2020

Genome-wide association studies (GWAS) have identified more than 140 prostate cancer (PrCa) risk regions which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirms previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g.,MLPH). Interestingly, HiChIP identified links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g.,AR) that are not detected by eQTL-based methods. We validate these findings through CRISPR interference (CRISPRi) perturbation of the variant-containing regulatory elements forNKX3-1andARin the LNCaP cell line. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes.
Behavioural responses to chemical cues of predators differ between fire salamander larvae from two different habitats
Authors: Hahn Luca G. , Oswald Pia , Caspers Barbara A.
Published: October 2020

Predation is one of the strongest selection pressures, forcing prey organisms to detect predators and to display various antipredator behaviours, such as refuge-use or decreased activity. To recognise predators, chemosensory cues play a pivotal role, particularly in aquatic ecosystems. However, it is less known whether the ability to use these cues to respond with adequate antipredator behaviour varies between individuals occupying different habitats that are dissimilar in predation risk. Using field experiments, we examined antipredator behaviour of larval fire salamanders (Salamandra salamandra) from two different habitats, ponds and streams. Among other differences, ponds and streams are inhabited by habitat-specific predators, such as alpine newts (Ichthyosaura alpestris) occurring in ponds. We exposed larvae from both habitats to either chemical cues from alpine newts or a blank control (tap water) and investigated potential differences in their behavioural responses in two experiments. Pond larvae, but not stream larvae, became significantly less active when faced with chemical cues from newts compared to those faced with a control stimulus. Moreover, larvae from both habitats tested in water containing chemical cues spent significantly less time outside a shelter than those in control water. Our results demonstrate that larval fire salamanders recognise predatory newts through kairomones and alter their behaviour accordingly. However, experience with predatory newts may not be necessary to differentiate kairomones from control water, but may be beneficial for larvae to further develop their antipredator behaviour, thus representing conformance to a niche.
Assumptions about frequency-dependent architectures of complex traits bias measures of functional enrichment
Authors: Zabad Shadi , Ragsdale Aaron P. , Sun Rosie , Li Yue , Gravel Simon
Published: October 2020

Linkage-Disequilibrium Score Regression (LDSC) is a popular framework for analyzing GWAS summary statistics that allows for estimating SNP heritability, confounding, and functional enrichment of genetic variants with different annotations. Recent work has highlighted the influence of implicit and explicit assumptions of the model on the biological interpretation of the results. In this work, we explored a formulation of LDSC that replaces ther2measure of LD with a recently-proposed unbiased estimator of theD2statistic. In addition to modest statistical difference across estimators, this derivation highlighted implicit and unrealistic assumptions about the relationship between allele frequency, effect size, and annotation status. We carry out a systematic comparison of alternative LDSC formulations by applying them to summary statistics from 47 GWAS traits. Our results show that commonly used models likely underestimate functional enrichment. These results highlight the importance of calibrating the LDSC model to achieve a more robust understanding of polygenic traits.
Machine-learning predicts genomic determinants of meiosis-driven structural variation in a eukaryotic pathogen
Authors: Badet Thomas , Fouché Simone , Hartmann Fanny E. , Zala Marcello , Croll Daniel
Published: October 2020

Species harbor extensive structural variation underpinning recent adaptive evolution and major disease phenotypes. Most sequence rearrangements are generated non-randomly along the genome through non-allelic recombination and transposable element activity. However, the causality between genomic features and the induction of new rearrangements is poorly established. Here, we analyze a global set of telomere-to-telomere genome assemblies of a major fungal pathogen of wheat to establish a nucleotide-level map of structural variation. We show that the recent emergence of pesticide resistance has been disproportionally driven by rearrangements. We used machine-learning to train a model on structural variation events based on 30 chromosomal sequence features. We show that base composition and gene density are the major determinants of structural variation. Low-copy LINE and Gypsy retrotransposons explain most inversion, indel and duplication events. We retrain our model onArabidopsis thalianaand show that our modelling approach can be extended to more complex genomes. Finally, we analyzed complete genomes of haploid offspring in a four-generation pedigree. Meiotic crossover locations were enriched for newly generated structural variation consistent with crossovers being mutational hotspots. The model trained on species-wide structural variation predicted the position of >74% of the newly generated variants along the pedigree. The predictive power highlights causality between specific sequence features and the induction of chromosomal rearrangements. Our work demonstrates that training sequence-derived models can accurately identify regions of intrinsic DNA instability in eukaryotic genomes.
Responses of Neurons in the Medullary Lateral Tegmental Field and Nucleus Tractus Solitarius to Vestibular Stimuli in Conscious Felines
Authors: Bielanin John P. , Douglas Nerone O. , Shulgach Jonathan A. , McCall Andrew A. , Miller Derek M. , Amin Pooja R. , Murphey Charles P. , Barman Susan M. , Yates Bill J.
Published: October 2020

Considerable evidence shows that the vestibular system contributes to adjusting sympathetic nervous system activity to maintain adequate blood pressure during movement and changes in posture. However, only a few prior experiments entailed recordings in conscious animals from brainstem neurons presumed to convey baroreceptor and vestibular inputs to neurons in the rostral ventrolateral medulla (RVLM) that provide inputs to sympathetic preganglionic neurons in the spinal cord. In this study, recordings were made in conscious felines from neurons in the medullary lateral tegmental field (LTF) and nucleus tractus solitarius (NTS) identified as regulating sympathetic nervous system activity by exhibiting changes in firing rate related to the cardiac cycle, or cardiac-related activity (CRA). Approximately 38% of LTF and NTS neurons responded to static 40° head up tilts with a change in firing rate of~50%. However, few of these neurons responded to 10° sinusoidal rotations in the pitch plane, in contrast to prior findings in decerebrate animals that the firing rates of both NTS and LTF neurons are modulated by small-amplitude body rotations. Thus, as previously demonstrated for RVLM neurons, in conscious animals NTS and LTF neurons only respond to large rotations that lead to changes in sympathetic nervous system activity. The similar responses to head-up rotations of LTF and NTS neurons with those documented for RVLM neurons suggest that LTF and NTS neurons are components of the vestibulo-sympathetic reflex pathway. However, a difference between NTS/LTF neurons and RVLM was variability in CRA over time. This variability was significantly greater for RVLM neurons, raising the hypothesis that the responsiveness of these neurons to baroreceptor input is adjusted based on the animal’s vigilance and alertness.
Women show enhanced attractiveness ratings and neural processing of male faces associated with male chemosensory signals
Authors: Klinkenberg Isabelle A. G. , Dobel Christian , Bröckelmann Ann-Kathrin , Plessow Franziska , Kirschbaum Clemens , Zwitserlood Pienie , Junghöfer Markus
Published: October 2020

There is growing evidence that humans use olfactory chemosensory signals for social communication, but their role in affective associative learning is largely unknown. To examine this, women implicitly learned face-odor associations by pairing different neutral male faces with either a male chemosignal presumably involved in human mating behavior (dissolved Δ4,16-androstadien-3-one, “AND”), a pleasant smell (dissolved vanillin) or the neutral solvent alone. After learning, women rated faces previously paired with AND or vanillin as more attractive than faces paired with solvent, even though they were unable to identify the contingency of face-odor pairings above chance level. On a neurophysiological level, both AND- and vanillin-associated faces evoked stronger magnetoencephalographic correlates of enhanced emotional attention than solvent-associated faces at early (<120 ms) and mid-latency (140-270 ms) processing stages. This study stresses the role of AND as a human chemosignal in implicit social communication and demonstrates its effectiveness in modulating emotional learning.
Efficient storage and analysis of quantitative genomics data with the Dense Depth Data Dump (D4) format and d4tools
Authors: Hou Hao , Pedersen Brent , Quinlan Aaron
Published: October 2020

Modern DNA sequencing is used as a readout for diverse assays, with the count of aligned sequences, or “read depth”, serving as the quantitative signal for many underlying cellular phenomena. Despite wide use and thousands of datasets, existing formats used for the storage and analysis of read depths are limited with respect to both file size and analysis speed. For example, it is faster to recalculate sequencing depth from an alignment file than it is to analyze the text output from that calculation. We sought to improve on existing formats such as BigWig and compressed BED files by creating the Dense Depth Data Dump (D4) format and tool suite. The D4 format is adaptive in that it profiles a random sample of aligned sequence depth from the input BAM or CRAM file to determine an optimal encoding that often affords reductions in file size, while also enabling fast data access. We show that D4 uses less storage for both RNA-Seq and whole-genome sequencing and offers 3 to 440-fold speed improvements over existing formats for random access, aggregation and summarization. This performance enables scalable downstream analyses that would be otherwise difficult. The D4 tool suite (d4tools) is freely available under an MIT license at:https://github.com/38/d4-format.
Shortfalls and opportunities in terrestrial vertebrate species discovery
Authors: Moura Mario R. , Jetz Walter
Published: October 2020

Meter-resolution imagery of our world and myriad biodiversity records collected through citizen scientists and automated sensors belie the fact that much of the planet’s biodiversity remains undiscovered. Conservative estimates suggest only 13 to 18% of all living species may be known at this point1–4, although this number could be as low as 1.5%5. This biodiversity shortfall6,7strongly impedes the sustainable management of our planet’s resources, as the potential ecological and economic relevance of undiscovered species remains unrecognized8. Here we use model-based predictions of terrestrial vertebrate species discovery to estimate future taxonomic and geographic discovery opportunities. Our model identifies distinct taxonomic and geographic unevenness in future discovery potential, with greatest opportunities for amphibians and reptiles and for Neotropical and IndoMalayan forests. Brazil, Indonesia, Madagascar, and Colombia emerge as holding greatest discovery opportunities, with a quarter of future species descriptions expected there. These findings highlight the significance of international support for taxonomic initiatives and the potential of quantitative models to aid the discovery of species before their functions are lost in ignorance8. As nations draw up new policy goals under the post-2020 global biodiversity framework, a better understanding of the magnitude and geography of this known unknown is critical to inform goals and priorities9and to minimize future discoveries lost to extinction10.
Target lipidomics reveals associations between serum sphingolipids and insulin sensitivity by the glucose clamp
Authors: Ye Jingya , Ye Xuan , Jiang Wanzi , Lu Chenyan , Geng Xiaomei , Zhao Chenxi , Ma Yizhe , Yang Panpan , Lam Sin Man , Shui Guanghou , Yang Tao , Li John Zhong , Gong Yingyun , Fu Zhenzhen , Zhou Hongwen
Published: October 2020

Background

This study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes.

Methods

We conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity.

Results

Differential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria.

Conclusions

These results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.
Machine Learning Framework for Fully Automatic Quality Checking of Rigid and Affine Registrations in Big Data Brain MRI
Authors: Tummala Sudhakar , Focke Niels K.
Published: October 2020

Rigid and affine registrations to a common template are the essential steps during pre-processing of brain structural magnetic resonance imaging (MRI) data. Manual quality check (QC) of these registrations is quite tedious if the data contains several thousands of images. Therefore, we propose a machine learning (ML) framework for fully automatic QC of these registrations via local computation of the similarity functions such as normalized cross-correlation, normalized mutual-information, and correlation ratio, and using these as features for training of different ML classifiers. To facilitate supervised learning, misaligned images are generated. A structural MRI dataset consisting of 215 subjects from autism brain imaging data exchange is used for 5-fold cross-validation and testing. Few classifiers such askNN,AdaBoost, andrandom forestreached testing F1-scores of 0.98 for QC of both rigid and affine registrations. These tested ML models could be deployed for practical use.
Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model
Authors: Errecalde J. , Lifschitz A. , Vecchioli G. , Ceballos L. , Errecalde F. , Ballent M. , Marín G. , Daniele M. , Turic E. , Spitzer E. , Toneguzzo F. , Gold S. , Krolewiecki A. , Alvarez L. , Lanusse C.
Published: October 2020

High ivermectin (IVM) concentrations suppressin vitroSARS-CoV-2 replication. Nasal IVM spray (N-IVM-spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new N-IVM spray formulation in a piglet model were assessed. Crossbred piglets (10–12 kg) were treated with either one or two (12 h apart) doses of N-IVM-spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of N-IVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel N–IVM-spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NP-tissue and lungs were observed after the 2-dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h post-dose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19.
Robust Cortical Criticality and Diverse Neural Network Dynamics Resulting from Functional Specification
Authors: Gu Lei , Wu Ruqian
Published: October 2020

Despite recognized layered structure and increasing evidence for criticality in the cortex, how the specification of input, output and computational layers affects the self-organized criticality has been surprisingly neglected. By constructing heterogeneous structures with a well-accepted model of leaky neurons, we found that the specification can lead to robust criticality almost insensitive to the strength of external stimuli. This naturally unifies the adaptation to strong inputs without extra synaptic plasticity mechanisms. Presence of output neurons constitutes an alternative explanation to subcriticality other than the high frequency inputs.Degree of recurrenceis proposed as a network metric to account for the signal termination due to output neurons. Unlike fully recurrent networks where external stimuli always render subcriticality, the dynamics of networks with sufficient feed-forward connections can be driven to criticality and supercriticality. These findings indicate that functional and structural specification and their interplay with external stimuli are of crucial importance for the network dynamics. The robust criticality puts forward networks of the leaky neurons as a promising platform for realizing artificial neural networks that work in the vicinity of critical points.
Coordination of gene expression noise with cell size: analytical results for agent-based models of growing cell populations
Authors: Thomas Philipp , Shahrezaei Vahid
Published: October 2020

The chemical master equation and the Gillespie algorithm are widely used to model the reaction kinetics inside living cells. It is thereby assumed that cell growth and division can be modelled through effective dilution reactions and extrinsic noise sources. We here re-examine these paradigms through developing an analytical agent-based framework of growing and dividing cells accompanied by an exact simulation algorithm, which allows us to quantify the dynamics of virtually any intracellular reaction network affected by stochastic cell size control and division noise. We find that the solution of the chemical master equation – including static extrinsic noise – exactly agrees with the agent-based formulation when the network under study exhibitsstochastic concentration homeostasis, a novel condition that generalises concentration homeostasis in deterministic systems to higher order moments and distributions. We illustrate stochastic concentration homeostasis for a range of common gene expression networks. When this condition is not met, we demonstrate by extending the linear noise approximation to agent-based models that the dependence of gene expression noise on cell size can qualitatively deviate from the chemical master equation. Surprisingly, the total noise of the agent-based approach can still be well approximated by extrinsic noise models.
Cortical Responses to the Amplitude Envelopes of Sounds Change with Age
Authors: Irsik Vanessa C. , Almanaseer Ala , Johnsrude Ingrid S. , Herrmann Björn
Published: October 2020

Many older listeners have difficulty understanding speech in noise, when cues to speech-sound identity are less redundant. The amplitude envelope of speech fluctuates dramatically over time, and features such as the rate of amplitude change at onsets (attack) and offsets (decay) signal critical information about the identity of speech sounds. Aging is also thought to be accompanied by increases in cortical excitability, which may differentially alter sensitivity to envelope dynamics. Here, we recorded electroencephalography in younger and older human adults (of both sexes) to investigate how aging affects neural synchronization to 4-Hz amplitude-modulated noises with different envelope shapes(ramped:slow attack & sharp decay;damped:sharp attack & slow decay). We observed that subcortical responses did not differ between age groups, whereas older compared to younger adults exhibited larger cortical responses to sound onsets, consistent with an increase in auditory cortical excitability. Neural activity in older adults synchronized more strongly with rapid-onset, slow-offset (damped) envelopes, was less sinusoidal, and more peaked. Younger adults demonstrated the opposite pattern, showing stronger synchronization with slow-onset, rapid-offset (ramped) envelopes, as well as a more sinusoidal neural response shape. The current results suggest that age-related changes in the excitability of auditory cortex alter responses to envelope dynamics. This may be part of the reason why older adults experience difficulty understanding speech in noise.

Significance Statement

Many middle aged and older adults report difficulty understanding speech when there is background noise, which can trigger social withdrawal and negative psychosocial health outcomes. The difficulty may be related to age-related changes in how the brain processes temporal sound features. We tested younger and older people on their sensitivity to different envelope shapes, using EEG. Our results demonstrate that aging is associated with heightened sensitivity to sounds with a sharp attack and gradual decay, and sharper neural responses that deviate from the sinusoidal features of the stimulus, perhaps reflecting increased excitability in the aged auditory cortex. Altered responses to temporal sound features may be part of the reason why older adults often experience difficulty understanding speech in social situations.
N-myristoyltransferase: Tracing Steps Backwards to Find a Way Forward
Authors: Reddick Dean , Udenwobele Daniel I , Datzkiw David , Mukherjee Revanti , Shrivastav Shailly Varma , Good Sara , Shrivastav Anuraag
Published: October 2020

N-myristoylation refers to the attachment of a 14-carbon fatty acid onto the N-terminal glycine residue of a target protein. The myristoylation reaction, catalyzed by N-myristoyltrasnferase (NMT), is essential for regulating cellular activities such as signal transduction, proliferation, migration, differentiation, and transformation. Although a considerable amount of research is performed on the overexpression of NMT in pathogenic conditions, a fundamental knowledge gap exists on the evolution of NMT and the functional impact of myristoylation for normal cellular development and functions. We performed evolutionary analyses of the NMT gene and found that most non-vertebrates harbor a single nmt gene and all vertebrates examined harbor two genes; nmt1 and nmt2. For the first time, we report that teleosts harbor two copies of nmt1, named nmt1a and nmt1b. We traced the evolutionary history of the chromosomal fragments hosting NMT1 and NMT2 in humans and found that NMT1 and NMT2 trace back to a single vertebrate ancestral chromosome. We also report the presence of putative nuclear localization sequence (NLS) and amino acid residues flanking NLS. The presence of phosphorylatable amino acid residues flanking the NLS suggests that nuclear localization of NMT is regulated by phosphorylation. The nuclear localization of NMT suggest its potential role in gene transcription.
Life history tradeoffs, division of labor and evolutionary transitions in individuality
Authors: Doulcier Guilhem , Hammerschmidt Katrin , Bourrat Pierrick
Published: October 2020

Reproductive division of labor has been proposed to play a key role for evolutionary transitions in individuality (ETIs). This chapter provides a guide to a theoretical model that addresses the role of a tradeoff between life-history traits in selecting for a reproductive division of labor during the transition from unicellular to multicellular organisms. In particular, it focuses on the five key assumptions of the model, namely (1) fitness is viability times fecundity; (2) collective traits are linear functions of their cellular counterparts; (3) there is a tradeoff between cell viability and fecundity; (4) cell contribution to the collective is optimal; and (5) there is an initial reproductive cost in large collectives. Thereafter the chapter contrasts two interpretations of the model in the context of ETIs. Originally, the model was interpreted as showing that during the transition to multicellularity the fitness of the lower-level (the cells) is “transferred” to the higher level (the collective). Despite its apparent intuitiveness, fitness transfer may obscure actual mechanisms in metaphorical language. Thus, an alternative and more conservative interpretation of the model that focuses on cell traits and the evolutionary constraints that link them is advocated. In addition, it allows for pursuing subsequent questions, such as the evolution of development.
Fast and exact single and double mutation-response scanning of proteins
Authors: Echave Julian
Published: October 2020

Studying the effect of perturbations on protein structure is a basic approach in protein research. Important problems, such as predicting pathological mutations and understanding patterns structural evolution, have been addressed by computational simulations based on modelling mutations as forces and predicting deformations using the Linear Response Approximation. In single mutation-response scanning simulations, a sensitivity matrix is obtained by averaging deformations over point mutations. In double mutation-response scanning simulations, a compensation matrix is obtained by minimizing deformations over pairs of mutations. These very useful simulation-based methods may be too slow to deal with large supra-molecular complexes, such as a ribosome or a virus capsid, or large number of proteins, such as the human proteome, which limits their applicability. To address this issue, I derived analytical closed formulas to calculate the sensitivity and compensation matrices directly, without simulations. Here, I present these derivations and show that the resulting analytical methods are much faster than their simulation counterparts, and that where the simulation methods are approximate, the analytical methods are exact by design.
Exceptional Late Devonian arthropods document the origin of decapod crustaceans
Authors: Gueriau Pierre , Rak Štěpán , Broda Krzysztof , Kumpan Tomáš , Viktorýn Tomáš , Valach Petr , Zatoń Michał , Charbonnier Sylvain , Luque Javier
Published: October 2020

With over 15,000 extant species, Decapoda—or ten-legged crustaceans such as crabs, shrimp, lobsters, and relatives— are among the most speciose and economically important group of crustaceans. Despite of their diversity, anatomical disparity, and remarkable fossil record extending back to the Late Paleozoic, the origins of Decapoda and their phylogenetic relationships with eumalacostracans remains elusive and inconclusive. Molecular dating suggests that decapods originated in the Late Ordovician (~450 Mya), but no reliable fossil crown groups are found until the Late Devonian. Moreover, there is no consensus on which lineages belong to stem groups, obscuring our understanding of the roots of the ten-legged decapod body plans as a whole, and how they relate to other non-decapod crustaceans. We present new, exceptional fossils from the Late Devonian of Czech Republic and Poland that belong to †Angustidontida, an odd shrimp-looking crustacean with a combination of anatomical features unlike those of any crown eumalacostracan known—extinct or extant. Our phylogenetic analyses, including representatives of all major lineages of crown eumalacostracans plus †Angustidontida, identify angustidontids as the only known stem-group decapod, and give hints about the transformation series, polarity of change, and evolutionary pathways leading to the modern decapod body plans seen today.
Phylogenomic systematics of the spotted skunks (Carnivora, Mephitidae,Spilogale): Additional species diversity and Pleistocene climate change as a major driver of diversification
Authors: McDonough Molly M. , Ferguson Adam W. , Dowler Robert C. , Gompper Matthew E. , Maldonado Jesús E.
Published: October 2020

Four species of spotted skunks (Carnivora, Mephitidae,Spilogale) are currently recognized:Spilogale angustifrons,S. gracilis,S. putorius, andS. pygmaea. Understanding species boundaries within this group is critical for effective conservation given that regional populations or subspecies (e.g.,S. p. interrupta) have experienced significant population declines. Further, there may be currently unrecognized diversity within this genus as some taxa (e.g.,S. angustifrons) and geographic regions (e.g., Central America) never have been assessed using DNA sequence data. We analyzed species limits and diversification patterns in spotted skunks using multilocus nuclear (ultraconserved elements) and mitochondrial (whole mitogenomes and single gene analysis) data sets from broad geographic sampling representing all currently recognized species and subspecies. We found a high degree of genetic divergence amongSpilogalethat reflects seven distinct species and eight unique mitochondrial lineages. Initial divergence betweenS. pygmaeaand all otherSpilogaleoccurred 29 in the Early Pliocene (~ 5.0 million years ago) which was followed by subsequent diversification of the remainingSpilogaleinto an “eastern” and “western” lineage during the Early Pleistocene (~1.5 million years ago). These two lineages experienced temporally coincident patterns of diversification at ~0.66 and ~0.35 million years ago into two and ultimately three distinct evolutionary units, respectively. Diversification was confined almost entirely within the Pleistocene during a timeframe characterized by alternating glacial-interglacial cycles, with the origin of this diversity occurring in northeastern Mexico and the southwestern United States of America. Mitochondrial-nuclear discordance was recovered across three lineages in geographic regions consistent with secondary contact, including a distinct mitochondrial lineage confined to the Sonoran Desert. Our results have direct consequences for conservation of threatened populations, or species, as well as for our understanding of the evolution of delayed implantation in this enigmatic group of small carnivores.