bluuebunny/crossref_metadata_2025 huggingface dataset:
Signatures of Discriminative Copy Number Aberrations in 31 Cancer Subtypes
Authors: Gao Bo , Baudis Michael
Published: December 2020

Copy number aberrations (CNA) are one of the most important classes of genomic mutations related to oncogenetic effects. In the past three decades, a vast amount of CNA data has been generated by molecular-cytogenetic and genome sequencing based methods. While this data has been instrumental in the identification of cancer-related genes and promoted research into the relation between CNA and histo-pathologically defined cancer types, the heterogeneity of source data and derived CNV profiles pose great challenges for data integration and comparative analysis. Furthermore, a majority of existing studies have been focused on the association of CNA to pre-selected “driver” genes with limited application to rare drivers and other genomic elements.

In this study, we developed a bioinformatics pipeline to integrate a collection of 44,988 high-quality CNA profiles of high diversity. Using a hybrid model of neural networks and attention algorithm, we generated the CNA signatures of 31 cancer subtypes, depicting the uniqueness of their respective CNA landscapes. Finally, we constructed a multi-label classifier to identify the cancer type and the organ of origin from copy number profiling data. The investigation of the signatures suggested common patterns, not only of physiologically related cancer types but also of clinico-pathologically distant cancer types such as different cancers originating from the neural crest. Further experiments of classification models confirmed the effectiveness of the signatures in distinguishing different cancer types and demonstrated their potential in tumor classification.
Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
Authors: Yamazaki Chisato M. , Yamaguchi Aiko , Anami Yasuaki , Xiong Wei , Otani Yoshihiro , Lee Jangsoon , Ueno Naoto T. , Zhang Ningyan , An Zhiqiang , Tsuchikama Kyoji
Published: December 2020

Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal immunogenicity, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in a xenograft mouse model representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
Inferring brain-wide interactions using data-constrained recurrent neural network models
Authors: Perich Matthew G. , Arlt Charlotte , Soares Sofia , Young Megan E. , Mosher Clayton P. , Minxha Juri , Carter Eugene , Rutishauser Ueli , Rudebeck Peter H. , Harvey Christopher D. , Rajan Kanaka
Published: December 2020

Behavior arises from the coordinated activity of numerous anatomically and functionally distinct brain regions. Modern experimental tools allow unprecedented access to large neural populations spanning many interacting regions brain-wide. Yet, understanding such large-scale datasets necessitates both scalable computational models to extract meaningful features of inter-region communication and principled theories to interpret those features. Here, we introduce Current-Based Decomposition (CURBD), an approach for inferring brain-wide interactions using data-constrained recurrent neural network models that directly reproduce experimentally-obtained neural data. CURBD leverages the functional interactions inferred by such models to reveal directional currents between multiple brain regions. We first show that CURBD accurately isolates inter-region currents in simulated networks with known dynamics. We then apply CURBD to multi-region neural recordings obtained from mice during running, macaques during Pavlovian conditioning, and humans during memory retrieval to demonstrate the widespread applicability of CURBD to untangle brain-wide interactions underlying behavior from a variety of neural datasets.
Emergence and global spread ofListeria monocytogenesmain clinical clonal complex
Authors: Moura Alexandra , Lefrancq Noémie , Leclercq Alexandre , Wirth Thierry , Borges Vítor , Gilpin Brent , Dallman Timothy J. , Frey Joachim , Franz Eelco , Nielsen Eva M. , Thomas Juno , Pightling Arthur , Howden Benjamin P. , Tarr Cheryl L. , Gerner-Smidt Peter , Cauchemez Simon , Salje Henrik , Brisse Sylvain , Lecuit Marc ,   for the Listeria CC1 Study Group
Published: December 2020

Retracing microbial emergence and spread is essential to understanding the evolution and dynamics of pathogens. The bacterial foodborne pathogenListeria monocytogenesclonal complex 1 (Lm-CC1) is the most prevalent clonal group associated with listeriosis, and is strongly associated with cattle and dairy products. Here we analysed 2,021Lm-CC1 isolates collected from 40 countries, since the firstLmisolation to the present day, to define its evolutionary history and population dynamics. Our results suggest thatLm-CC1 spread worldwide from North America following the Industrial Revolution through two waves of expansion, coinciding with the transatlantic livestock trade in the second half of the 19thcentury and the rapid growth of cattle farming in the 20thcentury.Lm-CC1 then firmly established at a local level, with limited inter-country spread. This study provides an unprecedented insight intoLm-CC1 phylogeography and dynamics and can contribute to effective disease surveillance to reduce the burden of listeriosis.
Glycan remodeled erythrocytes facilitate antigenic characterization of recent A/H3N2 influenza viruses
Authors: Broszeit Frederik , van Beek Rosanne J. , Unione Luca , Bestebroer Theo M. , Chapla Digantkumar , Yang Jeong-Yeh , Moremen Kelley W. , Herfst Sander , Fouchier Ron A.M. , de Vries Robert P. , Boons Geert-Jan
Published: December 2020

During circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities. These viruses lost the ability to agglutinate erythrocytes critical for antigenic characterization and give low yields and acquire adaptive mutations when cultured in eggs and cells, contributing to recent vaccine challenges. We examined receptor specificities of A/H3N2 viruses, revealing that recent viruses compensated for decreased binding of the prototypic human receptor by recognizing 2,6-sialosides on extended LacNAc moieties. Erythrocyte glycomics showed an absence of extended glycans, providing a rationale for lack of agglutination by recent A/H3N2 viruses. A glycan remodeling approach installed functional receptors on erythrocytes, allowing antigenic characterization of recent A/H3N2 viruses and confirming the cocirculation of several antigenically different viruses in humans. Computational studies of HAs in complex with a sialoside having an extended LacNAc moiety revealed that mutations distal to the RBD reoriented the Y159 side chain, resulting in an extended receptor binding site.
Multi-color fluorescence fluctuation spectroscopy in living cells via spectral detection
Authors: Dunsing Valentin , Petrich Annett , Chiantia Salvatore
Published: December 2020

Signaling pathways in biological systems rely on specific interactions between multiple biomolecules. Fluorescence fluctuation spectroscopy provides a powerful toolbox to quantify such interactions directly in living cells. Cross-correlation analysis of spectrally separated fluctuations provides information about inter-molecular interactions but is usually limited to two fluorophore species. Here, we present scanning fluorescence spectral correlation spectroscopy (SFSCS), a versatile approach that can be implemented on commercial confocal microscopes, allowing the investigation of interactions between multiple protein species at the plasma membrane. We demonstrate that SFSCS enables cross-talk-free cross-correlation, diffusion and oligomerization analysis of up to four protein species labeled with strongly overlapping fluorophores. As an example, we investigate the interactions of influenza A virus (IAV) matrix protein 2 with two cellular host factors simultaneously. We furthermore apply raster spectral image correlation spectroscopy for the simultaneous analysis of up to four species and determine the stoichiometry of ternary IAV polymerase complexes in the cell nucleus.
Compressed sensing-based super-resolution ultrasound imaging for faster acquisition and high quality images
Authors: Kim Jihun , Wang Qingfei , Zhang Siyuan , Yoon Sangpil
Published: December 2020

Super-resolution ultrasound (SRUS) imaging technique has overcome the diffraction limit of conventional ultrasound imaging, resulting in an improved spatial resolution while preserving imaging depth. Typical SRUS images are reconstructed by localizing ultrasound microbubbles (MBs) injected in a vessel using normalized 2-dimensional cross-correlation (2DCC) between MBs signals and the point spread function of the system. However, current techniques require isolated MBs in a confined area due to inaccurate localization of densely populated MBs. To overcome this limitation, we developed the ℓ1-homotopy based compressed sensing (L1H-CS) based SRUS imaging technique which localizes densely populated MBs to visualize microvasculature in vivo. To evaluate the performance of L1H-CS, we compared the performance of 2DCC, interior-point method based compressed sensing (CVX-CS), and L1H-CS algorithms. Localization efficiency was compared using axially and laterally aligned point targets (PTs) with known distances and randomly distributed PTs generated by simulation. We developed post-processing techniques including clutter reduction, noise equalization, motion compensation, and spatiotemporal noise filtering for in vivo imaging. We then validated the capabilities of L1H-CS based SRUS imaging technique with high-density MBs in a mouse tumor model, kidney, and zebrafish dorsal trunk, and brain. Compared to 2DCC, and CVX-CS algorithm, L1H-CS algorithm, considerable improvement in SRUS image quality and data acquisition time was achieved. These results demonstrate that the L1H-CS based SRUS imaging technique has the potential to examine the microvasculature with reduced acquisition and reconstruction time of SRUS image with enhanced image quality, which may be necessary to translate it into the clinics.
SIRAH late harvest: coarse-grained models for protein glycosylation
Authors: Garay Pablo German , Machado Matias Rodrigo , Verli Hugo , Pantano Sergio
Published: December 2020

Glycans constitute one of the most complex families of biological molecules. Despite their crucial role in a plethora of biological processes, they remain uncharacterized because of their high complexity. Their intrinsic flexibility, along with the vast variability associated with the many combination possibilities and relatively loose structural character, has hampered their experimental determination. Although theoretical methods have proven a valid alternative to the study of glycans, the large size associated with polysaccharides, proteoglycans, and glycolipids poses significant challenges to a fully atomistic description of biologically relevant glycoconjugates. On the other hand, the exquisite dependence on Hydrogen bonds to determine glycans' structure makes the development of simplified or coarse-grained (CG) representations extremely challenging. This is particularly the case when glycan representations are expected to be compatible with CG models of, for instance, proteins. We introduce a CG representation able to represent a wide variety of polysaccharides and most glycosylation motifs in proteins, which is fully compatible with the CG SIRAH force field. Examples of application to N-glycosylated proteins, including antibody recognition and Calcium-mediated glycan-protein interactions, highlight the versatility of the enlarged set of CG molecules provided by SIRAH.
Studies overestimate the extent of circadian rhythm reprogramming in response to dietary and genetic changes
Authors: Pelikan Anne , Herzel Hanspeter , Kramer Achim , Ananthasubramaniam Bharath
Published: December 2020

The circadian clock modulates key physiological processes in many organisms. This widespread role of circadian rhythms is typically characterized at the molecular level by profiling the transcriptome at multiple time points. Subsequent analysis identifies transcripts with altered rhythms between control and perturbed conditions, i.e., are differentially rhythmic (DiffR). Commonly, Venn Diagram analysis (VDA) compares lists of rhythmic transcripts to catalog transcripts with rhythms in both conditions or have gained or lost rhythms. However, unavoidable errors in the rhythmicity detection propagate to the final DiffR classification resulting in overestimated DiffR. We show using artificial experiments constructed from biological data that VDA indeed produces excessive false DiffR hits both in the presence and absence of true DiffR transcripts. We present a hypothesis testing and a model selection approaches in an R-packagecompareRhythmsthat instead compare circadian amplitude and phase of transcripts between the two conditions. These methods identify transcripts with 'gain', 'loss', 'change' or have the 'same' rhythms; the third category is missed by VDA. We reanalyzed three studies on the interplay between metabolism and the clock in the mouse liver that used VDA. We found not only fewer DiffR transcripts than originally reported, but VDA overlooked many relevant DiffR transcripts. Our analyses confirmed some and contradicted other conclusions in the original studies and also generated novel hypotheses. Our insights also generalize easily to studies using other -omics technologies. We trust that avoiding Venn Diagrams and using our R-package will contribute to improved reproducibility in chronobiology.
assayM: a web application to monitor mutations in COVID-19 diagnostic assays
Authors: Naeem Raeece , Pain Arnab
Published: December 2020

Reverse Transcriptase – Polymerase Chain Reaction (RT-PCR) is the gold standard as diagnostic assays for the detection of COVID-19 and the specificity and sensitivity of these assays depend on the complementarity of the RT-PCR primers to the genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the virus mutates over time during replication cycles, there is an urgent need to continuously monitor the virus genome for appearances of mutations and mismatches in the PCR primers used in these assays. Here we present assayM, a web application to explore and monitor mutations introduced in the primer and probe sequences published by the World Health Organisation (WHO) or in any custom-designed assay primers for SARS-CoV-2 detection assays in globally available SARS-CoV-2 genome datasets.

Availability and implementation

assayM is available onhttps://grafnet.kaust.edu.sa/assayMas a web application and also as an open-source R shiny application, downloadable fromhttps://github.com/raeece/assayM

Contact

arnab.pain@kaust.edu.sa
Learning a non-neutral conditioned stimulus: place preference in the crabNeohelice granulata
Authors: Klappenbach Martín , Medina Candela , Freudenthal Ramiro
Published: December 2020

In the wild, being able to recognize and remember specific locations related to food sources and the associated attributes of landmarks is a cognitive trait important for survival. In the present work we show that the crab Neohelice granulata can be trained to associate a specific environment with an appetitive reward in a conditioned place preference task. After a single training trial, when the crabs were presented with a food pellet in the target quadrant of the training arena, they were able to form a long-term memory related to the event. This memory was evident at least 24 h after training and was protein-synthesis dependent. Importantly, the target area of the arena proved to be a non-neutral environment, given that animals initially avoided the target quadrant. In the present work we introduce for the first time an associative one-trial memory paradigm including a conditioned stimulus with a clear valence performed in a crustacean.
Experimental investigation of enzyme functional annotations reveals extensive annotation error
Authors: Rembeza Elzbieta , Engqvist Martin KM
Published: December 2020

Only a small fraction of genes deposited to databases has been experimentally characterised. The majority of proteins have their function assigned automatically, which can result in erroneous annotations. The reliability of current annotations in public databases is largely unknown; experimental attempts to validate the accuracy of existing annotations are lacking. In this study we performed an overview of functional annotations to the BRENDA enzyme database. We first applied a high-throughput experimental platform to verify functional annotations to an enzyme class of S-2-hydroxyacid oxidases (EC 1.1.3.15). We chose 122 representative sequences of the class and screened them for their predicted function. Based on the experimental results, predicted domain architecture and similarity to previously characterised S-2-hydroxyacid oxidases, we inferred that at least 78% of sequences in the enzyme class are misannotated. We experimentally confirmed four alternative activities among the misannotated sequences and showed that misannotation in the enzyme class increased over time. Finally, we performed a computational analysis of annotations to all enzyme classes in BRENDA database, and showed that nearly 18% of all sequences are annotated to an enzyme class while sharing no similarity to experimentally characterised representatives. We showed that even well-studied enzyme classes of industrial relevance are affected by the problem of functional misannotation.
Analysis of PPI networks of transcriptomic expression identifies hub genes associated with Newcastle disease virus persistent infection in bladder cancer
Authors: Ahmad Umar , Chau De Ming , Chia Suet Lin , Yusoff Khatijah , Abdullah Syahril , Chan Soon Choy , Veerakumarasivam Abhi
Published: December 2020

Motivation

Bladder cancer cells acquire persistent infection associated with oncolytic Newcastle disease virus (NDV) in which its molecular events are still unclear. This poses a potential problem for oncolytic virus application for cancer therapy. To unravel the molecular mechanism underlying the development of NDV persistent infection in bladder cancer, we used mRNA expression profile of the persistently infected bladder cancer cells to construct PPI network.

Results

Based on path and module exploring in the PPI network, the bridges were found mainly from pathways of p53 signalling, ECM-receptor interaction, and TGF-beta signalling by the upregulated mRNAs, to the antigen processing and presentation, protein processing in endoplasmic reticulum, completement and coagulation cascades by the downregulated mRNAs in NDV persistent TCCSUPPi cells. In persistent EJ28Pi cells comparatively, connections were identified mainly from pathways of renal carcinoma, viral carcinogenesis, Ras signalling and cell cycle by the upregulated mRNAs, to the Wnt signalling, HTLV-I infection and pathways in cancer by the downregulated mRNAs. This connection was mainly dependent on ofRPL8- HSPA1A/HSPA4in TCCSUPPi cells andEP300, PTPN11, RAC1-TP53, SP1, CCND1andXPO1in EJ28Pi cells. Oncomine validation showed that the top hub genes identified in the network that includesRPL8, THBS1, F2from TCCSUPPi andTP53andRAC1from EJ28Pi are involved in the development and progression of bladder cancer. Protein-drug interaction network, have identified several drugs targets that could be used to disconnect the linkages between modules and prevent bladder cancer cells from acquiring NDV persistent infection. This is the first time reporting the PPI network analysis of differentially expressed mRNAs of the NDV persistently infected bladder cancer cell lines which provide an insight into screening drugs that could be used together with NDV to manage bladder cancer resistance to therapy and progression.
Evidence for distinct genetic and environmental influences on fear acquisition and extinction
Authors: Purves K. L. , Krebs G. , McGregor T. , Constantinou E. , Lester K.J. , Barry T.J. , Craske M.G. , Young K. S. , Breen G. , Eley T. C.
Published: December 2020

Background

Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction.

Methods

1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study (TEDS) took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app.

In the fear acquisition phase participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase.

Results

Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15%, 30% and 15% respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations .4-.5).

Conclusions

Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.
Pangenome analysis of the soil-borne fungal phytopathogenRhizoctonia solaniand development of a comprehensive web resource: RsolaniDB
Authors: Kaushik A. , Roberts D.P. , Ramaprasad A. , Mfarrej S. , Nair Mridul , Lakshman D.K. , Pain A.
Published: December 2020

Rhizoctonia solaniis a collective group of genetically and pathologically diverse basidiomycetous fungus that damages economically important crops. Its isolates are classified into 13 Anastomosis Groups (AGs) and subgroups having distinctive morphology and host range. The genetic factors driving the unique features ofR. solanipathology are not well characterized due to the limited availability of its annotated genomes. Therefore, we performed genome sequencing, assembly, annotation and functional analysis of 12R. solaniisolates covering 7 AGs and selected subgroups (AG1-IA, AG1-IB, AG1-IC, AG2-2IIIB, AG3-PT (isolates Rhs 1AP and the hypovirulent Rhs1A1), AG3-TB, AG4-HG-I (isolates Rs23 and R118-11), AG5, AG6, and AG8), in which six genomes are reported for the first time, wherein we discovered unique and shared secretomes, CAZymes, and effectors across the AGs. Using a pangenome comparative analysis of 12R. solaniisolates and 15 other basidiomycetes, we also elucidated the molecular factors potentially involved in determining the AG-specific host preference, and the attributes distinguishing them from other Basidiomycetes. Finally, we present the largest repertoire ofR. solanigenomes and their annotated components as a comprehensive database, viz. RsolaniDB, with tools for large-scale data mining, functional enrichment and sequence analysis not available with other state-of-the-art platforms, to assist mycologists in formulating new hypotheses.
Prochlorococcusextracellular vesicles: Molecular composition and adsorption to diverse microbes
Authors: Biller Steven J. , Lundeen Rachel A. , Hmelo Laura R. , Becker Kevin W. , Arellano Aldo A. , Dooley Keven , Heal Katherine R. , Carlson Laura T. , Van Mooy Benjamin A. S. , Ingalls Anitra E. , Chisholm Sallie W.
Published: December 2020

Extracellular vesicles are small (~50–200 nm diameter) membrane-bound structures released by cells from all domains of life. While vesicles are abundant in the oceans, our understanding of their functions, both for cells themselves and the emergent ecosystem, is in its infancy. To advance this understanding, we analyzed the lipid, protein, and metabolite content of vesicles produced by the marine cyanobacteriumProchlorococcus. We show thatProchlorococcusexports an enormous array of cellular compounds into the surrounding seawater within vesicles. Vesicles produced by two different strains contain some materials in common, but also display numerous strain-specific differences, reflecting functional complexity within natural vesicle populations.Prochlorococcusvesicles contain active enzymes, indicating that they can mediate extracellular biogeochemical reactions in the ocean. We demonstrate that vesicles fromProchlorococcusand other bacteria associate with diverse microbes including the most abundant marine bacterium,Pelagibacter. Our observations suggest that vesicles may play diverse functional roles in the oceans, including but not limited to mediating energy and nutrient transfers, catalyzing extracellular biochemical reactions, and mitigating toxicity of reactive oxygen species. These findings indicate that a portion of ‘dissolved’ compounds in the oceans are not truly dissolved, but are instead packaged within locally structured, particulate vesicles.
Decidual cell differentiation is evolutionarily derived from fibroblast activation
Authors: Wu Longjun , Stadtmauer Daniel J , Maziarz Jamie , Wagner Gunter
Published: December 2020

What the molecular mechanisms underlying the evolutionary origin of novel cell types are is a major unresolved question in biology. The uterine decidual cell is a novel cell type of placental mammals which serves as the interface between maternal and fetal tissues during pregnancy. In this paper, we investigate two models for the nature of the differentiation of decidual cells: first, that it represents a mesenchymal-epithelial transition (MET), and second, that it evolved from wound-induced fibroblast activation (WIFA). Immunocytochemistry and RNA-seq analysis of decidualizing human endometrial fibroblasts cast doubt on the MET hypothesis and instead demonstrate a similarity between decidualization and fibroblast activation, including a central role for TGFB1. Through single-cell RNA-seq, we found a transient myofibroblast-like cell population in the in vitro differentiation trajectory of human decidual cells and found that these cells represent a pre-decidual state approaching the inferred transcriptomic transition to decidual cells. We propose an evolutionary developmental model wherein the decidual cell is a novel cell type not equivalent to the myofibroblast, but the process of decidual differentiation itself evolved as an endometrial-specific modification to fibroblast activation in response to the wound caused by embryo implantation.
Quantifying shifts in natural selection on codon usage between protein regions: A population genetics approach
Authors: Cope Alexander L. , Gilchrist Michael A.
Published: December 2020

Background

Codon usage bias (CUB), the non-uniform usage of synonymous codons, occurs across all domains of life. Adaptive CUB is hypothesized to result from selection for efficient ribosome elongation, accurate translation, mRNA secondary structure, and/or protein folding. Given the critical link between protein folding and protein function, numerous studies have analyzed the relationship between codon usage and protein structure. The results from these studies have often been contradictory, likely reflecting the differing methods used for measuring codon usage and the failure to appropriately control for confounding factors, such as differences in amino acid usage between protein structures and changes in the frequency of different structures with gene expression.

Results

Here we take an explicit population genetics approach to quantify codon-specific shifts in natural selection related to protein structure. As a result, our approach avoids the problem of needing to choose a specific metric of codon usage, naturally takes amino acid usage of a region into account, and explicitly takes variation in gene expression into account. Our results reveal a weak relationship between codon usage and protein structure, indicating that differences in selection between structures are subtle and/or intermittent. While the magnitude of differences in selection are slight, our results indicate the relationship between codon usage and protein structure is more complex than previously believed.

Conclusions

While our results clearly indicate that selection on codon usage shifts between secondary structure, the overall impact of these shifts on codon usage are small. Nevertheless, our work demonstrates the statistical power and benefits of studying selective shifts on codon usage or other genomic features from an explicitly evolutionary approach. Limitations of this approach are discussed.
Body size affects immune cell proportions in birds and non-volant mammals, but not bats
Authors: Ruhs Emily Cornelius , Becker Daniel J. , Oakey Samantha J. , Ogunsina Ololade , Fenton M. Brock , Simmons Nancy B. , Martin Lynn B. , Downs Cynthia J.
Published: December 2020

Powered flight has evolved several times in vertebrates and constrains morphology and physiology in ways that likely have shaped how organisms cope with infections. Some of these constraints likely have impacts on aspects of immunology, such that larger fliers might prioritize risk reduction and safety. Addressing how the evolution of flight may have driven relationships between body size and immunity could be particularly informative for understanding the propensity of some taxa to harbor many virulent and sometimes zoonotic pathogens without showing clinical disease. Here, we used a scaling framework to quantify scaling relationships between body mass and the proportions of two types of white blood cells--lymphocytes, and granulocytes (neutr-/heterophils)--across 60 bat species, 414 bird species, and 256 non-volant mammal species. By using phylogenetically-informed statistical models on field-collected data from wild Neotropical bats, data gleaned from other wild bats available in the literature, and data from captive non-volant mammals and birds, we show that lymphocyte and neutrophil proportions do not vary systematically with body mass among bats. In contrast, larger birds and non-volant mammals have disproportionately higher granulocyte proportions than expected for their body size. Future comparative studies of wild bats, birds, and non-volant mammals of similar body mass should aim to further differentiate evolutionary effects and other aspects of life history on immune defense.

Summary statement

Powered flight might constrain morphology such that certain immunological features are prioritized. We show that bats largely have similar cell proportions across body mass compared to strong allometric scaling relationships in birds and non-flying mammals.
Amphipathic Bax core dimer forms part of apoptotic pore wall in the mitochondrial membrane
Authors: Lv Fujiao , Qi Fei , Zhang Zhi , Wen Maorong , Piai Alessandro , Du Lingyu , Zhou LiuJuan , Yang Yaqing , Wu Bin , Liu Zhijun , del Rosario Juan , Chou James J. , Andrews David W. , Lin Jialing , OuYang Bo
Published: December 2020

Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. They may embed in the cytosolic leaflet of the lipid bilayer generating tension to induce a lipid pore with radially arranged lipids forming the wall. Alternatively, they may comprise part of the pore wall. However, there is no unambiguous structural evidence for either hypothesis. Using NMR, we determine a high-resolution structure of the Bax core region that forms a dimer with the nonpolar surface covering the lipid bilayer edge and the polar surface exposed to water. The dimer tilts from the bilayer normal, not only maximizing nonpolar interactions with lipid tails but creating polar interactions between charged residues and lipid heads. Structure-guided mutations demonstrate the importance of both protein-lipid interactions in Bax pore assembly and core dimer configuration. Therefore, the Bax core dimer forms part of the proteolipid pore wall to permeabilize mitochondria.
Genetics of white color and iridophoroma in “Lemon Frost” leopard geckos
Authors: Guo Longhua , Bloom Joshua , Sykes Steve , Huang Elaine , Kashif Zain , Pham Elise , Ho Katarina , Alcaraz Ana , Xiao Xinshu Grace , Duarte-Vogel Sandra , Kruglyak Leonid
Published: December 2020

The squamates (lizards and snakes) are close relatives of birds and mammals, with more than 10,000 described species that display extensive variation in a number of important biological traits, including coloration, venom production, and regeneration. Due to a lack of genomic tools, few genetic studies in squamates have been carried out. The leopard gecko1,Eublepharis macularius,is a popular companion animal, and displays a variety of coloration patterns. We took advantage of a large breeding colony and used linkage analysis, synteny, and homozygosity mapping to investigate a spontaneous semi-dominant mutation, “Lemon Frost”, that produces white coloration and causes skin tumors (iridophoroma). We localized the mutation to a single locus which contains a strong candidate gene, SPINT12,3, a tumor suppressor implicated in human skin cutaneous melanoma (SKCM) and over-proliferation of epithelial cells in mice and zebrafish4–16. Our work establishes the leopard gecko as a tractable genetic system and suggests that a tumor suppressor in melanocytes in humans can also suppress tumor development in iridophores in lizards.
Persistence of ambigrammatic narnaviruses requires translation of the reverse open reading frame
Authors: Retallack Hanna , Popova Katerina D. , Laurie Matthew T. , Sunshine Sara , DeRisi Joseph L.
Published: December 2020

Narnaviruses are RNA viruses detected in diverse fungi, plants, protists, arthropods and nematodes. Though initially described as simple single-gene non-segmented viruses encoding RNA-dependent RNA polymerase (RdRp), a subset of narnaviruses referred to as “ambigrammatic” harbor a unique genomic configuration consisting of overlapping open reading frames (ORFs) encoded on opposite strands. Phylogenetic analysis supports selection to maintain this unusual genome organization, but functional investigations are lacking. Here, we establish the mosquito-infecting Culex narnavirus 1 (CxNV1) as a model to investigate the functional role of overlapping ORFs in narnavirus replication. In CxNV1, a reverse ORF without homology to known proteins covers nearly the entire 3.2 kb segment encoding the RdRp. Additionally, two opposing and nearly completely overlapping novel ORFs are found on the second putative CxNV1 segment, the 0.8 kb “Robin” RNA. We developed a system to launch CxNV1 in a naïve mosquito cell line, then showed that functional RdRp is required for persistence of both segments, and an intact reverse ORF is required on the RdRp segment for persistence. Mass spectrometry of persistently CxNV1-infected cells provided evidence for translation of this reverse ORF. Finally, ribosome profiling yielded a striking pattern of footprints for all four CxNV1 RNA strands that was distinct from actively-translating ribosomes on host mRNA or co-infecting RNA viruses. Taken together, these data raise the possibility that the process of translation itself is important for persistence of ambigrammatic narnaviruses, potentially by protecting viral RNA with ribosomes, thus suggesting a heretofore undescribed viral tactic for replication and transmission.

IMPORTANCE

Fundamental to our understanding of RNA viruses is a description of which strand(s) of RNA are transmitted as the viral genome, relative to which encode the viral proteins. Ambigrammatic narnaviruses break the mold. These viruses, found broadly in fungi, plants, and insects, have the unique feature of two overlapping genes encoded on opposite strands, comprising nearly the full length of the viral genome. Such extensive overlap is not seen in other RNA viruses, and comes at the cost of reduced evolutionary flexibility in the sequence. The present study is motivated by investigating the benefits which balance that cost. We show for the first time a functional requirement for the ambigrammatic genome configuration in Culex narnavirus 1, which suggests a model for how translation of both strands might benefit this virus. Our work highlights a new blueprint for viral persistence, distinct from strategies defined by canonical definitions of the coding strand.
Auto-segmentation of the parotid glands on MR images of head and neck cancer patients with deep learning strategies
Authors: Kieselmann Jennifer P. , Fuller Clifton D. , Gurney-Champion Oliver J. , Oelfke Uwe
Published: December 2020

Adaptive online MRI-guided radiotherapy of head and neck cancer requires the reliable segmentation of the parotid glands as important organs at risk in clinically acceptable time frames. This can hardly be achieved by manual contouring. We therefore designed deep learning-based algorithms which automatically perform this task.

Imaging data comprised two datasets: 27 patient MR images (T1-weighted and T2-weighted) and eight healthy volunteer MR images (T2-weighted), together with manually drawn contours by an expert. We used four different convolutional neural network (CNN) designs that each processed the data differently, varying the dimensionality of the input. We assessed the segmentation accuracy calculating the Dice similarity coefficient (DSC), Hausdorff distance (HD) and mean surface distance (MSD) between manual and auto-generated contours. We benchmarked the developed methods by comparing to the inter-observer variability and to atlas-based segmentation. Additionally, we assessed the generalisability, strengths and limitations of deep learning-based compared to atlas-based methods in the independent volunteer test dataset.

With a mean DSC of 0.85± 0.11 and mean MSD of 1.82 ±1.94 mm, a 2D CNN could achieve an accuracy comparable to that of an atlas-based method (DSC: 0.85 ±0.05, MSD: 1.67 ±1.21 mm) and the inter-observer variability (DSC: 0.84 ±0.06, MSD: 1.50 ±0.77 mm) but considerably faster (<1s v.s. 45 min). Adding information (adjacent slices, fully 3D or multi-modality) did not further improve the accuracy. With additional preprocessing steps, the 2D CNN was able to generalise well for the fully independent volunteer dataset (DSC: 0.79 ±0.10, MSD: 1.72 ±0.96 mm)

We demonstrated the enormous potential for the application of CNNs to segment the parotid glands for online MRI-guided radiotherapy. The short computation times render deep learning-based methods suitable for online treatment planning workflows.
COVID-19 PANDEMICS: HOW FAR ARE WE FROM HERD IMMUNITY?
Authors: Hernandez-Suarez Carlos , Murillo-Zamora Efren , Gómez Francisco Espinoza
Published: December 2020

Objectives

to estimate the current number of total infections in a region in order to measure the progress of the epidemic with the purpose of reopening activities and planning the deployment of vaccines.

Study design

We recovered estimates of the basic reproductive number (R0) and the Infection Fatality Risk (IFR) as well as the number of confirmed cases and deaths in several countries.

Methods

this works presents an expression to estimate the number of remaining susceptible in a population using the observed number of SARS-CoV-2 related deaths and current estimates of R0and IFR.

Results

the epidemic will infect most of the population causing 2.5 deaths per thousand inhabitants on average, and herd immunity will be achieved when the number of deaths per thousand inhabitants is close to two. This work introduces an expression to provide estimates of the number of remaining susceptible in a region using the reported number of deaths.

Conclusions

any region with fewer than 2.5 deaths per thousand individuals will continue accumulating deaths until this average is achieved, and the infection rate will exceed the removal rate until the number of deaths is about two deaths per thousand, when herd immunity is reached. Waves may occur in any region where the number of deaths is below the herd immunity level.
Modelling population-wide screening of SARS-CoV-2 infection for containing COVID-19 pandemic in Okinawa, Japan
Authors: Shimizu Kazuki , Kuniya Toshikazu , Tokuda Yasuharu
Published: December 2020

Background

To break the chains of SARS-CoV-2 transmission and contain the coronavirus disease 2019 (COVID-19) pandemic, population-wide testing is practiced in various countries. However, scant research has addressed this topic in Japan.

Materials and Methods

In this modelling exercise, we extracted the number of daily reported cases of COVID-19 in Okinawa from October 1 to November 30, 2020 and explored possible scenarios for decreasing COVID-19 incidence by combining population-wide screening and/or social distancing policy.

Results

We reveal that permanent lockdown can be replaced by mass testing that mobilizes sufficient target population at an adequate frequency. In addition, solely imposing a circuit breaker will not bring a favorable outcome in the long-term, and mass testing presents implications for minimizing a period of lockdown.

Discussion

Our results highlight the importance of incentivizing citizens to join the frequent testing and ensure their appropriate isolation. To contain the COVID-19 pandemic, rigorous investment in public health is manifestly vital.
Free recall scaling laws and short-term memory effects in a latching attractor network
Authors: Boboeva Vezha , Pezzotta Alberto , Clopath Claudia
Published: December 2020

Despite the complexity of human memory, paradigms like free recall have revealed robust qualitative and quantitative characteristics, such as power laws governing recall capacity. Although abstract random matrix models could explain such laws, the possibility of their implementation in large networks of interacting neurons has so far remained unexplored. We study an attractor network model of long-term memory endowed with firing rate adaptation and global inhibition. Under appropriate conditions, the transitioning behaviour of the network from memory to memory is constrained by limit cycles that prevent the network from recalling all memories, with scaling similar to what has been found in experiments. When the model is supplemented with a heteroassociative learning rule, complementing the standard autoassociative learning rule, as well as short-term synaptic facilitation, our model reproduces other key findings in the free recall literature, namely serial position effects, contiguity and forward asymmetry effects, as well as the semantic effects found to guide memory recall. The model is consistent with a broad series of manipulations aimed at gaining a better understanding of the variables that affect recall, such as the role of rehearsal, presentation rates and (continuous/end-of-list) distractor conditions. We predict that recall capacity may be increased with the addition of small amounts of noise, for example in the form of weak random stimuli during recall. Moreover, we predict that although the statistics of the encoded memories has a strong effect on the recall capacity, the power laws governing recall capacity may still be expected to hold.
Genome evolution in bacteria isolated from million-year-old subseafloor sediment
Authors: Orsi William D. , Magritsch Tobias , Vargas Sergio , Coskun Ömer K. , Vuillemin Aurele , Höhna Sebastian , Wörheide Gert , D’Hondt Steven , Shapiro B. Jesse , Carini Paul
Published: December 2020

Beneath the seafloor, microbial life subsists in isolation from the surface world under persistent energy limitation. The nature and extent of genomic evolution in subseafloor microbes has been unknown. Here we show that the genomes ofThalassospirabacterial populations cultured from million-year-old subseafloor sediments evolve by point mutation, with a relatively low rate of homologous recombination and a high frequency of pseudogenes. Ratios of synonymous to non-synonymous mutation rates correlate with the accumulation of pseudogenes, consistent with a dominant role for genetic drift in the subseafloor strains, but not in type strains ofThalassospiraisolated from the surface world. Our findings demonstrate that the long term physical isolation of these bacteria, in the absence of recombination, has resulted in clonal populations that evolve consistent with ‘Mullers Ratchet’, whereby reduced access to novel genetic material from neighbors has resulted in fixation of new mutations that accumulate in genomes over millions of years.

Significance statement

The nature and extent of genomic evolution in subseafloor microbial populations subsisting for millions of years below the seafloor is unknown. Subseafloor populations have ultra-slow metabolic rates that are hypothesized to restrict reproduction and, consequently, the spread of new traits. Our findings demonstrate that genomes of cultivated bacterial strains from the genusThalassospiraisolated from million-year-old abyssal sediment exhibit greatly reduced levels of homologous recombination, elevated numbers of pseudogenes, and genome-wide evidence of relaxed purifying selection. These substitutions and pseudogenes are fixed into the population, suggesting the genome evolution of these bacteria has been dominated by genetic drift, whereby under long-term physical isolation in small population sizes, and in the absence of homologous recombination, newly acquired mutations accumulate in the genomes of clonal populations over millions of years.