bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive changes in the gut microbiome during standard-of-care chemoradiotherapy for gynecologic cancers
Authors: El Alam Molly B. , Sims Travis T. , Kouzy Ramez , Biegert Greyson W. G. , Abi Jaoude Joseph , Karpinets Tatiana V. , Yoshida-Court Kyoko , Wu Xiaogang , Delgado Medrano Andrea Y. , Mezzari Melissa P. , Ajami Nadim J. , Solley Travis , Ahmed-Kaddar Mustapha , Lin Lilie L. , Ramondetta Lois , Jazaeri Amir , Jhingran Anuja , Eifel Patricia J. , Schmeler Kathleen M. , Wargo Jennifer , Klopp Ann H. , Colbert Lauren E.
Published: April 2020

Background

A diverse and abundant gut microbiome can improve cancer patients’ treatment response; however, the effect of pelvic chemoradiotherapy (CRT) on gut diversity and composition is unclear. The purpose of this prospective study was to identify changes in the diversity and composition of the gut microbiome during and after pelvic CRT.

Materials and Methods

Rectal swabs from 58 women with cervical, vaginal, or vulvar cancer from two institutions were prospectively analyzed before CRT (baseline), during CRT (weeks 1, 3, and 5), and at first follow-up (week 12) using 16Sv4 rRNA gene sequencing of the V4 hypervariable region of the bacterial 16S rRNA marker gene. Observed operational taxonomic units (OTUs; representative of richness) and Shannon, Simpson, Inverse Simpson, and Fisher diversity indices were used to characterize alpha (within-sample) diversity. Changes over time were assessed using a paired t-test, repeated measures ANOVA, and linear mixed modeling. Compositional changes in specific bacteria over time were evaluated using linear discriminant analysis effect size.

Results

Gut microbiome richness and diversity levels continually decreased throughout CRT (mean Shannon diversity index, 2.52 vs. 2.91; allP<0.01), but were at or near baseline levels in 60% of patients by week 12. Patients with higher gut diversity at baseline had the steepest decline in gut microbiome diversity. Gut microbiome composition was significantly altered during CRT, with increases in Proteobacteria and decreases in Clostridiales, but adapted after CRT, with increases in Bacteroides species.

Conclusion

After CRT, the gut microbiome’s diversity tends to return to baseline levels, but its structure and composition remain significantly altered. These changes should be considered when designing studies to analyze the gut microbiome as a predictive or prognostic biomarker in patients who receive pelvic CRT for gynecologic cancers.
Sensitivity to Monoclonal Antibody 447-52D and an Open Env Trimer Conformation Correlate Poorly with Inhibition of HIV-1 Infectivity by SERINC5
Authors: Angerstein Aaron O. , Stoneham Charlotte A. , Ramirez Peter W. , Guatelli John C. , Vollbrecht Thomas
Published: April 2020

The host protein SERINC5 inhibits the infectivity of HIV-1 virions in an Env-dependent manner and is counteracted by Nef. The conformation of the Env trimer reportedly correlates with sensitivity to SERINC5. Here, we tested the hypothesis that the “open” conformation of the Env trimer revealed by sensitivity to the V3-loop specific antibody 447-52D directly correlates with sensitivity to SERINC5. Of five Envs tested, SF162 was the most sensitive to neutralization by 447-52D, but it was not the most sensitive to SERINC5; instead the Env of LAI was substantially more sensitive to SERINC5 than all the other Envs. Mutational opening of the trimer by substitution of two tyrosines that mediate interaction between the V2 and V3 loops sensitized the Envs of JRFL and LAI to 447-52D as previously reported, but only BaL was sensitized to SERINC5. These data suggest that trimer “openness” is not sufficient for sensitivity to SERINC5.
Python nidoviruses, more than respiratory pathogens
Authors: Dervas Eva , Hepojoki Jussi , Smura Teemu , Prähauser Barbara , Windbichler Katharina , Blümich Sandra , Ramis Antonio , Hetzel Udo , Kipar Anja
Published: April 2020

In recent years nidoviruses have emerged as an important respiratory pathogen of reptiles, affecting especially captive python populations. In pythons, nidovirus infection induces an inflammation of the upper respiratory and alimentary tract which can develop into a severe and often fatal proliferative pneumonia. We observed pyogranulomatous and fibrinonecrotic lesions in organ systems other than the respiratory tract during full post mortem examinations on 30 nidovirus RT-PCR positive pythons of varying species originating from Switzerland and Spain. The observations prompted us to study whether the atypical tissue tropism associates with previously unknown nidoviruses or changes in the nidovirus genome. RT-PCR and inoculation ofMorelia viridiscell cultures served to recruit the cases and to obtain virus isolates. Immunohistochemistry and immunofluorescence staining against nidovirus nucleoprotein demonstrated that the virus not only infects a broad spectrum of epithelial (respiratory and alimentary epithelium, hepatocytes, renal tubules, pancreatic ducts etc.), but also intravascular monocytes, intralesional macrophages and endothelial cells. By next-generation sequencing we obtained full length genome for a novel nidovirus species circulating in Switzerland. Analysis of viral genomes recovered from pythons showing nidovirus infection-associated respiratory or systemic disease did not explain the observed phenotypes. The results indicate that python nidoviruses have a broad cell and tissue tropism, further suggesting that the course of infection could vary and involve lesions in a broad spectrum of tissues and organ systems as a consequence of monocyte-mediated systemic spread of the virus.

IMPORTANCE

During the last years, python nidoviruses have become a primary cause of fatal disease in pythons. Nidoviruses represent a threat to captive snake collections, as they spread rapidly and can be associated with high morbidity and mortality. Our study indicates that, different from previously evidence, the viruses do not only affect the respiratory tract, but can spread in the entire body with blood monocytes, have a broad spectrum of target cells, and can induce a variety of lesions. Nidovirales is an order of animal and human viruses that compromise important zoonotic pathogens such as MERS-CoV and SARS-CoV, as well as the recently emerged SARS-CoV-2. Python nidoviruses belong to the same subfamily as the mentioned human viruses and show similar characteristics (rapid spread, respiratory and gastrointestinal tropism, etc.). The present study confirms the relevance of natural animal diseases to better understand the complexity of viruses of the order nidovirales.
Validating the use of bovine buccal sampling as a proxy for the rumen microbiota using a time course and random forest classification approach
Authors: Young Juliana , Skarlupka Joseph H. , Resende Rafael Tassinari , Fischer Amelie , Kalscheur Kenneth F. , McClure Jennifer C. , Cole John B. , Suen Garret , Bickhart Derek M.
Published: April 2020

Analysis of the cow microbiome, as well as host genetic influences on the establishment and colonization of the rumen microbiota, is critical for development of strategies to manipulate ruminal function toward more efficient and environmentally friendly milk production. To this end, the development and validation of noninvasive methods to sample the rumen microbiota at a large-scale is required. Here, we further optimized the analysis of buccal swab samples as a proxy for direct microbial samples of the rumen of dairy cows. To identify an optimal time for sampling, we collected buccal swab and rumen samples at six different time points relative to animal feeding. We then evaluated several biases in these samples using a machine learning classifier (random forest) to select taxa that discriminate between buccal swab and rumen samples. Differences in the Simpson’s diversity, Shannon’s evenness and Bray-Curtis dissimilarities between methods were significantly less apparent when sampling was performed prior to morning feeding (P<0.05), suggesting that this time point was optimal for representative sampling. In addition, the random forest classifier was able to accurately identify non-rumen taxa, including 10 oral and feed-associated taxa. Two highly prevalent (> 60%) taxa in buccal and rumen samples had significant variance in absolute abundance between sampling methods, but could be qualitatively assessed via regular buccal swab sampling. This work not only provides new insights into the oral community of ruminants, but further validates and refines buccal swabbing as a method to assess the rumen microbiota in large herds.

IMPORTANCE

The gastrointestinal tract of ruminants harbors a diverse microbial community that coevolved symbiotically with the host, influencing its nutrition, health and performance. While the influence of environmental factors on rumen microbes is well-documented, the process by which host genetics influences the establishment and colonization of the rumen microbiota still needs to be elucidated. This knowledge gap is due largely to our inability to easily sample the rumen microbiota. There are three common methods for rumen sampling but all of them present at least one disadvantage, including animal welfare, sample quality, labor, and scalability. The development and validation of non-invasive methods, such as buccal swabbing, for large-scale rumen sampling is needed to support studies that require large sample sizes to generate reliable results. The validation of buccal swabbing will also support the development of molecular tools for the early diagnosis of metabolic disorders associated with microbial changes in large herds.
Glucosamine-6P and glucosamine-1P, respectively an activator and a substrate of rhodococcal ADP-glucose pyrophosphorylases, show a hint to ascertain (actino)bacterial glucosamine metabolism
Authors: Cereijo AE , Alvarez HM , Iglesias AA , Asencion Diez MD
Published: April 2020

Rhodococcusspp. are important microorganisms for biotechnological purposes, such as bioremediation and biofuel production. The latter, founded on the oleaginous characteristic (high lipid accumulation) exhibited by manyRhodococcusspecies when grown in certain carbon sources under low nitrogen availability. These bacteria accumulate glycogen during exponential growth, and the glucan plays a role as an intermediary metabolite for temporary carbon storage related to lipid metabolism. The kinetic and regulatory properties of the ADP-glucose pyrophosphorylase (ADP-GlcPPase) fromRhodococcus jostiisupports this hypothesis. The enzyme was found able to use glucosamine-1P as an alternative substrate. Curiously, the activity with glucosamine-1P was sensitive to glucose-6P, the main activator of actinobacterial ADP-GlcPPases. Herein, we report the study of glucosamine-1P related to the activity and regulation of ADP-GlcPPases fromR. jostiiandR. fascians, with the finding that glucosamine-6P is also a significant activator. Glucosamine-6P, belonging to a node between carbon and nitrogen metabolism, was identified as a main regulator in Actinobacteria. Thus, its effect on rhodococcal ADP-GlcPPases reinforces the function proposed for glycogen as temporary carbon storage. Results indicate that the activity of the studied enzymes using glucosamine-1P as a substrate responds to the activation by several metabolites that improve their catalytic performance, which strongly suggest metabolic feasibility. Then, studying the allosteric regulation exerted on an alternative activity would open two scenarios for consideration: (i) the existence of new molecules/metabolites yet undescribed, and (ii) evolutionary mechanisms underlying enzyme promiscuity that give rise new metabolic features in bacteria.
Vegetation and Microbes Interact to Preserve Organic Matter in Wooded Peatlands
Authors: Wang Hongjun , Tian Jianqing , Chen Huai , Ho Mengchi , Vilgalys Rytas , Liu Xingzhong , Richardson Curtis J.
Published: April 2020

Peatlands have persisted as massive carbon sinks over millennia, even during past periods of climate change. The commonly accepted theory of abiotic controls (mainly anoxia and low temperature) over carbon decomposition cannot explain how vast low-latitude wooded peatlands consistently accrete peat under warm and seasonally unsaturated conditions. Similarly, that theory cannot accurately project the decomposition rate in boreal peatlands where warming and drought have decreasedSphagnumand increased shrub expansion. Here, by comparing composition and ecological traits of microbes betweenSphagnum- and shrub-dominated peatlands, we present a previously unrecognized natural course that curbs carbon loss against climate change. Slow-growing microbes decisively dominate the studied wooded peatlands, concomitant with plant-induced, high recalcitrant carbon and phenolics. The slow-growing microbes inherently metabolize organic matter slowly. However, the fast-growing microbes that dominate ourSphagnumsite (most boreal peatlands as well) decomposed labile carbon >30 times faster than the slow-growing microbes. We show that the high-phenolic shrub/tree induced shifts in microbial composition may compensate for positive effects of temperature and/or drought on metabolism over time in peatlands. This biotic self-sustaining process that modulates abiotic controls on carbon cycling may help better project long-term climate-carbon feedbacks in peatlands.
Involvement of thedoublesexgene in body color masculinization of the blue-tailed damselfly,Ischnura senegalensis
Authors: Takahashi Michihiko , Okude Genta , Futahashi Ryo , Takahashi Yuma , Kawata Masakado
Published: April 2020

Odonata (dragonflies and damselflies) display remarkable color pattern diversity including sexual dimorphism and intrasexual polymorphism. We previously found that expression of a sex-determining transcription factor, thedoublesex(dsx) gene, is associated with female color polymorphism (gynomorph for female-specific color and andromorph for male mimicking color) in the blue-tailed damselfly,Ischnura senegalensis. Here we investigate the function of dsx gene on thoracic coloration by electroporation-mediated RNA interference (RNAi). RNAi of thedsxcommon region changed color patterns of males and andromorphic females to patterns of gynomorphic females. Further, gynomorphic color pattern was not affected bydsxRNAi. The long isoform ofdsxRNAi produced no effects, suggesting that the short isoform ofdsxis important for body color masculinization in both males and andromorphic females. Expression pattern changes were also examined in five genes with different expression levels between sexes and female morphs. Among these genes are two melanin suppressing genes,blackandebony, that were upregulated in thedsx-RNAi region compared to a control region. Upregulation coincides with a gynomorphic orange color instead of the black stripe observed in males and andromorphic females.dsxmay regulate male color differentiation by suppressingblackandebonyin the thoracic region ofI. senegalensis.Results add to the understanding of molecular mechanisms underlying the evolution of female polymorphism in Odonata.
Complete Coding Genome Sequence for a Novel Multicomponent Kindia Tick Virus Detected from Ticks Collected in Guinea
Authors: Ternovoi Vladimir A. , Protopopova Elena V. , Shvalov Alexander N. , Kartashov Mikhail Yu. , Bayandin Roman B. , Tregubchak Tatyana V. , Yakovlev Sergey A. , Nikiforov Konstantin A. , Konovalova Svetlana N. , Loktev Valery B. , Agafonov Alexander P. , Maksyutov Rinat A. , Popova Anna Yu.
Published: April 2020

Kindia tick virus (KITV) is a novel multicomponent virus first detected by direct sequencing ofRhipicephalus geigyiticks in Guinea in 2017. Here, we present a complete coding genome sequence for all four segments of KITV/2017/1. This virus appears to be evolutionarily related to unclassified flaviviruses, such as Alongshan virus.
An Algorithm to Build aMulti-genomeReference
Authors: Rabbani Leily , Müller Jonas , Weigel Detlef
Published: April 2020

1

Motivation

New DNA sequencing technologies have enabled the rapid analysis of many thousands of genomes from a single species. At the same time, the conventional approach of mapping sequencing reads against a single reference genome sequence is no longer adequate. However, even where multiple high-quality reference genomes are available, the problem remains how one would integrate results from pairwise analyses.

Result

To overcome the limits imposed by mapping sequence reads against a single reference genome, or serially mapping them against multiple reference genomes, we have developed theMGRmethod that allows simultaneous comparison against multiple high-quality reference genomes, in order to remove the bias that comes from using only a single-genome reference and to simplify downstream analyses. To this end, we present theMGRalgorithm that creates a graph (MGRgraph) as amulti-genomereference. To reduce the size and complexity of themulti-genomereference, highly similar orthologous1and paralogous2regions are collapsed while more substantial differences are retained. To evaluate the performance of our model, we have developed a genome compression tool, which can be used to estimate the amount of shared information between genomes.

Availability

https://github.com/LeilyR/Multi-genome-Reference.git

Contact

weigel@tue.mpg.de
Metabolite genome-wide association study (mGWAS) and gene-metabolite interaction network analysis reveal potential biomarkers for feed efficiency in pigs
Authors: Wang Xiao , Kadarmideen Haja N.
Published: April 2020

Metabolites represent the ultimate response of biological systems, so metabolomics is considered to link the genotypes and phenotypes. Feed efficiency is one of the most important phenotypes in sustainable pig production and is the main breeding goal trait. We utilized metabolic and genomic datasets from a total of 108 pigs from our own previously published studies that involved 59 Duroc and 49 Landrace pigs with data on feed efficiency (residual feed intake or RFI), genotype (PorcineSNP80 BeadChip) data and metabolomic data (45 final metabolite datasets derived from LC-MS system). Utilizing these datasets, our main aim was to identify genetic variants (single-nucleotide polymorphisms or SNPs) that affect 45 different metabolite concentrations in plasma collected at the start and end of the performance testing of pigs categorized as high or low in their feed efficiency (based on RFI values). Genome-wide significant genetic variants could be then used as potential genetic or biomarkers in breeding programs for feed efficiency. The other objective was to reveal the biochemical mechanisms underlying genetic variations for pigs’ feed efficiency. In order to achieve these objectives, we firstly conducted a metabolite genome-wide association study (mGWAS) based on mixed linear models and found 152 genome-wide significant SNPs (P-value < 1.06E-06) in association with 17 metabolites that included 90 significant SNPs annotated to 52 genes. On chromosome one alone, 51 significant SNPs associated with isovalerylcarnitine and propionylcarnitine were found to be in strong linkage disequilibrium (LD). SNPs in strong LD annotated toFBXL4andCCNCconsisted of two haplotype blocks where three SNPs (ALGA0004000, ALGA0004041 and ALGA0004042) were in the intron regions ofFBXL4andCCNC. The interaction network revealed thatCCNCandFBXL4were linked by the hub geneN6AMT1that was associated with isovalerylcarnitine and propionylcarnitine. Moreover, three metabolites (i.e., isovalerylcarnitine, propionylcarnitine and pyruvic acid) were clustered in one group based on the low-high RFI pigs.

This study performed a comprehensive metabolite-based GWAS analysis for pigs with differences in feed efficiency and provided significant metabolites for which there is a significant genetic variation as well as biological interaction networks. The identified metabolite genetic variants, genes and networks in high versus low feed efficient pigs could be considered as potential genetic or biomarkers for feed efficiency.
GeneDMRs: an R package for Gene-based Differentially Methylated Regions analysis
Authors: Wang Xiao , Hao Dan , Kadarmideen Haja N.
Published: April 2020

DNA methylation in gene or promoter or gene body could restrict/promote the gene transcription. Moreover, methylation in the gene regions along with CpG island regions could modulate the transcription to undetectable gene expression levels. Therefore, it is necessary to investigate the methylation levels within the gene, gene body, CpG island regions and their overlapped regions and then identify the gene-based differentially methylated regions (GeneDMRs). Here, R packageGeneDMRsaims to facilitate computing gene based methylation rate using next generation sequencing (NGS)-based methylome data. The user-friendly R packageGeneDMRsis presented to analyze the methylation levels in each gene/promoter/exon/intron/CpG island/CpG island shore or each overlapped region (e.g., gene-CpG island/promoter-CpG island/exon-CpG island/intron-CpG island/gene-CpG island shore/promoter-CpG island shore/exon-CpG island shore/intron-CpG island shore). Here, we used the public reduced representation bisulfite sequencing (RRBS) data of mouse (GSE62392) for evaluating software and found novel biologically significant results to supplement the previous research. The R packageGeneDMRscan facilitate computing gene based methylation rate to interpret complex interplay between methylation levels and gene expression differences or similarities across physiological conditions or disease states.
lncRNA Mediated Hijacking of T-cell Hypoxia Response Pathway byMycobacterium tuberculosisPredicts Latent to Active Progression in Humans
Authors: Mehra Jyotsana , Kumar Vikram , Srivastava Priyansh , Sethi Tavpritesh
Published: April 2020

Cytosolic functions of Long non-coding RNAs including mRNA translation masking and sponging are major regulators of biological pathways. Formation of T cell-bounded hypoxic granuloma is a host immune defence for containing infected Mtb-macrophages. Our study exploits the mechanistic pathway of Mtb-induced HIF1A silencing by the antisense lncRNA-HIF1A-AS2 in T cells. Computational analysis of in-vitro T-cell stimulation assays in progressors (n=119) versus non-progressor (n=221) tuberculosis patients revealed the role of lncRNA mediated disruption of hypoxia adaptation pathways in progressors. We found 291 upregulated and 227 downregulated DE lncRNAs that were correlated at mRNA level with HIF1A and HILPDA which are major players in hypoxia response. We also report novel lncRNA-AC010655 (AC010655.4 and AC010655.2) in cis with HILPDA, both of which contain binding sites for the BARX2 transcription factor, thus indicating a mechanistic role. Detailed comparison of infection with antigenic stimulation showed a non-random enrichment of lncRNAs in the cytoplasmic fraction of the cell in TB progressors. The lack of this pattern in non-progressors replicates indicates the hijacking of the lncRNA dynamics by Mtb. The in-vitro manifestation of this response in the absence of granuloma indicates pre-programmed host-pathogen interaction between T-cells and Mtb regulated through lncRNAs, thus tipping this balance towards progression or containment of Mtb. Finally, we trained multiple machine learning classifiers for reliable prediction of latent to the active progression of patients, yielding a model to guide aggressive treatment.
Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
Authors: Schierding William , Horsfield Julia , O’Sullivan Justin
Published: April 2020

Variants in DNA regulatory elements can alter the regulation of distant genes through spatial-regulatory connections. In humans, these spatial-regulatory connections are largely set during early development, when the cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components are often sufficient to produce a disease phenotype. The implication that genes encoding the cohesin complex and cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested. Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci, including linking their expression to that of other genes. Connections that centre on the cohesin ring subunits (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A and PDS5B), and CTCF provide evidence of coordinated regulation that has little tolerance for perturbation. We identified transcriptional changes across a set of genes co-regulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are co-regulated with cohesin loci are themselves intolerant to loss-of-function. The results highlight the importance of robust regulation of cohesin genes, indicating novel pathways that may be important in the human cohesinopathy disorders.
Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2
Authors: Banerjee Arinjay , Nasir Jalees A. , Budylowski Patrick , Yip Lily , Aftanas Patryk , Christie Natasha , Ghalami Ayoob , Baid Kaushal , Raphenya Amogelang R. , Hirota Jeremy A. , Miller Matthew S. , McGeer Allison J. , Ostrowski Mario , Kozak Robert A. , McArthur Andrew G. , Mossman Karen , Mubareka Samira
Published: April 2020

SARS-CoV-2 emerged in December 2019 in Wuhan, China and has since infected over 1.5 million people, of which over 107,000 have died. As SARS-CoV-2 spreads across the planet, speculations remain about the range of human cells that can be infected by SARS-CoV-2. In this study, we report the isolation of SARS-CoV-2 from two cases of COVID-19 in Toronto, Canada. We determined the genomic sequences of the two isolates and identified single nucleotide changes in representative populations of our virus stocks. More importantly, we tested a wide range of human immune cells for productive infection with SARS-CoV-2. Here we confirm that human primary peripheral blood mononuclear cells (PBMCs) are not permissive for SARS-CoV-2. As SARS-CoV-2 continues to spread globally, it is essential to monitor single nucleotide polymorphisms in the virus and to continue to isolate circulating viruses to determine viral genotype and phenotype usingin vitroandin vivoinfection models.
A general model to explain repeated turnovers of sex determination in the Salicaceae
Authors: Yang Wenlu , Zhang Zhiyang , Wang Deyan , Li Yiling , Tong Shaofei , Li Mengmeng , Zhang Xu , Zhang Lei , Ren Liwen , Ma Xinzhi , Zhou Ran , Sanderson Brian J. , Keefover-Ring Ken , Yin Tongming , Smart Lawrence B. , Liu Jianquan , DiFazio Stephen P. , Olson Matthew , Ma Tao
Published: April 2020

Dioecy, the presence of separate sexes on distinct individuals, has evolved repeatedly in multiple plant lineages. However, the specific mechanisms through which sex systems evolve and their commonalities among plant species remain poorly understood. With both XY and ZW sex systems, the family Salicaceae provides a system to uncover the evolutionary forces driving sex chromosome turnovers. In this study, we performed a genome-wide association study to characterize sex determination in twoPopulusspecies,P. euphraticaandP. alba. Our results reveal an XY system of sex determination on chromosome 14 ofP. euphratica, and a ZW system on chromosome 19 ofP. alba. We further assembled the corresponding sex determination regions, and found that their sex chromosome turnovers may be driven by the repeated translocations of aHelitron-like transposon. During the translocation, this factor may have captured partial or intact sequences that are orthologous to a type-A cytokinin response regulator gene. Based on results from this and other recently published studies, we hypothesize that this gene may act as a master regulator of sex determination for the entire family. We propose a general model to explain how the XY and ZW sex systems in this family can be determined by the sameRRgene. Our study provides new insights into the diversification of incipient sex chromosome in flowering plants by showing how transposition and rearrangement of a single gene can control sex in both XY and ZW systems.
Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria and produce parasite inhibitory IgM
Authors: Hopp Christine S. , Diouf Ababacar , Miura Kazutoyo , Boswell Kristin , Sekar Padmapriya , Skinner Jeff , Tipton Christopher M. , Chambers Michael , Andrews Sarah , Tan Joshua , Li Shanping , Doumbo Safiatou , Kayentao Kassoum , Ongoiba Aissata , Traore Boubacar , Portugal Silvia , Long Carole , Koup Richard A. , Long Eric , McDermott Adrian B. , Crompton Peter D.
Published: April 2020

IgG antibodies are known to play a central role in naturally acquired immunity to blood-stage malaria in humans, but little is known about the IgM response to blood-stage malaria, the mechanisms by which IgM may protect, or the underlying biology ofPlasmodium falciparum(Pf)-specific IgM B cells. In a Mali cohort spanning infants to adults we conducted a longitudinal analysis of B cells specific for thePfblood-stage antigens AMA1 and MSP1, as well as the comparator antigen influenza hemagglutinin (HA). At the uninfected baseline, before the malaria season,Pf-specific memory B cells (MBCs) in children are disproportionally IgM+and only gradually shift to IgG+with age, in contrast to HA-specific MBCs that are predominantly IgG+from infancy to adulthood. In response to acute febrile malaria,Pf-specific IgM B cells increase in frequency and upregulate activation and co-stimulatory markers. B cell receptor (BCR) analysis showed thatPf-specific IgM B cells are somatically hypermutated at levels comparable to HA-specific IgG B cells. Finally, IgM antibodies from the plasma of malaria-exposed individuals were comparable to IgG in inhibitingPfblood-stage growthin vitro, and significantly better at enhancing phagocytosis ofPfmerozoites, suggesting that IgM may protect through both direct neutralization and opsonization. Thus, somatically hypermutatedPf-specific IgM MBCs dominate in early life, are activated and expand during acute malaria and are associated with plasma IgM that inhibits parasite growthin vitro.
ASpediaFI: Functional interaction analysis of alternative splicing events
Authors: Yu Doyeong , Lee Kyubin , Hyung Daejin , Cho Soo Young , Park Charny
Published: April 2020

Alternative splicing (AS) regulates biological process governing phenotype or disease. However, it is challenging to systemically analyze global regulation of AS events, their gene interactions, and functions. Here, we introduce a novel application, ASpediaFI for identifying AS events and co-regulated gene interactions implicated in pathways. Our method establishes an interaction network including AS events, performs random walk with restart, and finally identifies a functional subnetwork containing the AS event. We validated the capability of ASpediaFI to interpret biological relevance based on three case studies. Using simulation data, we achieved higher accuracy than with other methods and detected pathway-associated AS events.
Alternative MyD88 -Cyclin D1 signaling in breast cancer cells regulates TLR3 mediated cell proliferation
Authors: Singh Aradhana , Devkar Ranjitsinh , Basu Anupam
Published: April 2020

TLR3 mediated apoptotic changes in cancer cells are well documented and hence several synthetic ligands of TLR3 are being used for adjuvant therapy. But there are reports showing contradictory effect of TLR3 signaling which includes our previous report that had shown cell proliferation following surface localization of TLR 3. However, the underlying mechanism of cell surface localization of TLR3 and subsequent cell proliferation lacks clarity. This study addresses TLR3 ligand mediated signaling cascade that regulates a proliferative effect in breast cancer cells (MDA MB 231 and T47D) challenged with TLR3 ligand in the presence of MyD88 inhibitor. Evidences were obtained using immunoblotting, co-immunoprecipitation, confocal microscopy, Immunocytochemistry, ELISA, and flowcytometry. Results had revealed that TLR3 ligand treatment significantly enhanced breast cancer cell proliferation marked by an upregulated expression of cyclinD1 but the same were suppressed by addition of MyD88 inhibitor. Also, expression of IRAK1-TRAF6-TAK1 were altered in the given TLR3-signaling pathway. Inhibition of MyD88 disrupted the downstream adaptor complex and mediated signaling through TLR3-MyD88-NF-κB (p65)-IL6-Cyclin D1 pathway. TLR3 mediated alternative signaling of the TLR3-MyD88-IRAK1-TRAF6-TAK1-TAB1-NF-κB axis leads to upregulation of IL6 and cyclinD1. This response is hypothesized to be via the MyD88 gateway that culminates in proliferation of breast cancer cells. Overall, this study provides first comprehensive evidence on involvement of canonical signaling of TLR3 using MyD88 - Cyclin D1 mediated breast cancer cell proliferation. The findings elucidated herein will provide valuable insights into understand the TLR3 mediated adjuvant therapy in cancer.
Genomic Architecture of Cells in Tissues (GeACT): Study of Human Mid-gestation Fetus
Authors: Tian Feng , Zhou Fan , Li Xiang , Ma Wenping , Wu Honggui , Yang Ming , Chapman Alec R. , Lee David F. , Tan Longzhi , Xing Dong , Yin Guangjun , Semayel Ayjan , Wang Jing , Wang Jia , Sun Wenjie , He Runsheng , Zhang Siwei , Cao Zhijie , Wei Lin , Lu Shen , Yang Dechang , Mao Yunuo , Gao Yuan , Chen Kexuan , Zhang Yu , Liu Xixi , Yong Jun , Yan Liying , Huang Yanyi , Qiao Jie , Tang Fuchou , Gao Ge , Xie X. Sunney
Published: April 2020

By circumventing cellular heterogeneity, single cell omics have now been widely utilized for cell typing in human tissues, culminating with the undertaking of human cell atlas aimed at characterizing all human cell types. However, more important are the probing of gene regulatory networks, underlying chromatin architecture and critical transcription factors for each cell type. Here we report the Genomic Architecture of Cells in Tissues (GeACT), a comprehensive genomic data base that collectively address the above needs with the goal of understanding the functional genome in action. GeACT was made possible by our novel single-cell RNA-seq (MALBAC-DT) and ATAC-seq (METATAC) methods of high detectability and precision. We exemplified GeACT by first studying representative organs in human mid-gestation fetus. In particular, correlated gene modules (CGMs) are observed and found to be cell-type-dependent. We linked gene expression profiles to the underlying chromatin states, and found the key transcription factors for representative CGMs.

Highlights

Genomic Architecture of Cells in Tissues (GeACT) data for human mid-gestation fetus

Determining correlated gene modules (CGMs) in different cell types by MALBAC-DT

Measuring chromatin open regions in single cells with high detectability by METATAC

Integrating transcriptomics and chromatin accessibility to reveal key TFs for a CGM
Scalable hierarchical clustering by composition rank vector encoding and tree structure
Authors: Lai Xiao , Tian Pu
Published: April 2020

Supervised machine learning, especially deep learning based on a wide variety of neural network architectures, have contributed tremendously to fields such as marketing, computer vision and natural language processing. However, development of un-supervised machine learning algorithms has been a bottleneck of artificial intelligence. Clustering is a fundamental unsupervised task in many different subjects. Unfortunately, no present algorithm is satisfactory for clustering of high dimensional data with strong nonlinear correlations. In this work, we propose a simple and highly efficient hierarchical clustering algorithm based on encoding by composition rank vectors and tree structure, and demonstrate its utility with clustering of protein structural domains. No record comparison, which is an expensive and essential common step to all present clustering algorithms, is involved. Consequently, it achieves linear time and space computational complexity hierarchical clustering, thus applicable to arbitrarily large datasets. The key factor in this algorithm is definition of composition, which is dependent upon physical nature of target data and therefore need to be constructed case by case. Nonetheless, the algorithm is general and applicable to any high dimensional data with strong nonlinear correlations. We hope this algorithm to inspire a rich research field of encoding based clustering well beyond composition rank vector trees.
The rates of introgression and barriers to genetic exchange between hybridizing species: sex chromosomes vs. autosomes
Authors: Fraïsse Christelle , Sachdeva Himani
Published: April 2020

Interspecific crossing experiments have shown that sex chromosomes play a major role in reproductive isolation between many pairs of species. However, their ability to act as reproductive barriers, which hamper interspecific genetic exchange, has rarely been evaluated quantitatively compared to Autosomes. This genome-wide limitation of gene flow is essential for understanding the complete separation of species, and thus speciation. Here, we develop a mainland-island model of secondary contact between hybridizing species of an XY (or ZW) sexual system. We obtain theoretical predictions for the frequency of introgressed alleles, and the strength of the barrier to neutral gene flow for the two types of chromosomes carrying multiple interspecific barrier loci. Theoretical predictions are obtained for scenarios where introgressed alleles are rare. We show that the same analytical expressions apply for sex chromosomes and autosomes, but with different sex-averaged effective parameters. The specific features of sex chromosomes (hemizygosity and absence of recombination in the heterogametic sex) lead to reduced levels of introgression on the X (or Z) compared to autosomes. This effect can be enhanced by certain types of sex-biased forces, but it remains overall small (except when alleles causing incompatibilities are recessive). We discuss these predictions in the light of empirical data comprising model-based tests of introgression and cline surveys in various biological systems.
Clustering and reverse transcription of HIV-1 genomes in nuclear niches of macrophages
Authors: Rensen Elena , Mueller Florian , Scoca Viviana , Parmar Jyotsana J. , Souque Philippe , Zimmer Christophe , Di Nunzio Francesca
Published: April 2020

In order to replicate, the Human Immunodeficiency Virus (HIV-1) reverse transcribes its RNA genome into DNA, which subsequently integrates into host cell chromosomes. These two key events of the viral life cycle are commonly viewed as separate not only in time but also in cellular space, since reverse transcription (RT) is thought to be completed in the cytoplasm before nuclear import and integration. However, the spatiotemporal organization of the early replication cycle in macrophages, natural non-dividing target cells that constitute reservoirs of HIV-1 and an obstacle to curing AIDS, remains unclear. Here, we demonstrate that infected macrophages display large nuclear foci of viral DNA and viral RNA, in which multiple genomes cluster together. These clusters form in the absence of chromosomal integration, sequester the paraspeckle protein CPSF6 and localize to nuclear speckles. Strikingly, we show that viral RNA clusters consist mostly of genomic, incoming RNA, both in cells where RT is pharmacologically suppressed and in untreated cells. We demonstrate that, after temporary inhibition, RT can resume in the nucleus and lead to vDNA accumulation in these clusters. We further show that nuclear RT can result in transcription competent viral DNA. These findings change our understanding of the early HIV-1 replication cycle, and may have implications for understanding HIV-1 persistence.
Precise triggering and chemical control of single-virus fusion within endosomes
Authors: Haldar Sourav , Okamoto Kenta , Kasson Peter M.
Published: April 2020

Many enveloped viruses infect cells within endocytic compartments. The drop in pH that accompanies endosomal maturation, often in conjunction with proteolytic factors, serves as a trigger for viral fusion proteins to insert into the endosomal membrane and drive fusion. The dynamics of this process has been studied by tracking viruses within living cells, which limits the precision with which fusion can be synchronized and controlled, and by reconstituting viral fusion to synthetic membranes, which introduces non-physiological membrane curvature and composition. To overcome these limitations, we have engineered the chemically controllable triggering of single-virus fusion within endosomes. We isolate influenza virus:endosome conjugates from cells prior to fusion, immobilize them in a microfluidic flow cell, and then rapidly and controllably trigger fusion. This platform demonstrates lipid-mixing kinetics that are grossly similar to influenza fusion with model membranes but display some subtle differences. Because it preserves endosomal membrane asymmetry and protein composition, it also provides a means to test how perturbations to endosomal trafficking and cellular restriction factors affect viral membrane fusion.
Modern Hopfield Networks and Attention for Immune Repertoire Classification
Authors: Widrich Michael , Schäfl Bernhard , Pavlović Milena , Ramsauer Hubert , Gruber Lukas , Holzleitner Markus , Brandstetter Johannes , Sandve Geir Kjetil , Greiff Victor , Hochreiter Sepp , Klambauer Günter
Published: April 2020

A central mechanism in machine learning is to identify, store, and recognize patterns. How to learn, access, and retrieve such patterns is crucial in Hopfield networks and the more recent transformer architectures. We show that the attention mechanism of transformer architectures is actually the update rule of modern Hop-field networks that can store exponentially many patterns. We exploit this high storage capacity of modern Hopfield networks to solve a challenging multiple instance learning (MIL) problem in computational biology: immune repertoire classification. Accurate and interpretable machine learning methods solving this problem could pave the way towards new vaccines and therapies, which is currently a very relevant research topic intensified by the COVID-19 crisis. Immune repertoire classification based on the vast number of immunosequences of an individual is a MIL problem with an unprecedentedly massive number of instances, two orders of magnitude larger than currently considered problems, and with an extremely low witness rate. In this work, we present our novel method DeepRC that integrates transformer-like attention, or equivalently modern Hopfield networks, into deep learning architectures for massive MIL such as immune repertoire classification. We demonstrate that DeepRC outperforms all other methods with respect to predictive performance on large-scale experiments, including simulated and real-world virus infection data, and enables the extraction of sequence motifs that are connected to a given disease class. Source code and datasets:https://github.com/ml-jku/DeepRC
Crosstalk between microRNA expression and DNA methylation drive the hormone-dependent phenotype of breast cancer
Authors: Aure Miriam Ragle , Fleischer Thomas , Bjørklund Sunniva , Ankill Jørgen , Castro-Mondragon Jaime A. ,   OSBREAC, Børresen-Dale Anne-Lise , Sahlberg Kristine K. , Mathelier Anthony , Tekpli Xavier , Kristensen Vessela N.
Published: April 2020

Background

Abnormal DNA methylation is observed as an early event in breast carcinogenesis. However, how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and have been shown to play key roles in various biological processes. Here, we integrate miRNA expression and DNA methylation at CpGs to study how miRNAs may affect the breast cancer methylome and how DNA methylation may regulate miRNA expression.

Results

miRNA expression and DNA methylation data from two breast cancer cohorts were subjected to genome-wide correlation analysis. Clustering of the miRNA expression-DNA methylation association pairs significant in both cohorts identified distinct clusters of miRNAs and CpGs. These clusters recapitulated important biological processes associated with breast cancer pathogenesis. Notably, two major clusters were related to immune or fibroblast infiltration, hence identifying miRNAs associated with cells of the tumor microenvironment, while another large cluster was related to estrogen receptor (ER) signaling. Studying the chromatin landscape surrounding the CpGs associated with the estrogen-signaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2 and ER-alpha. Further, at the hub of the estrogen-cluster, we identified hsa-miR-29c-5p as negatively correlated with the mRNA and protein expression of the DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already in pre-invasive breast lesions and postulate that hsa-miR-29c-5p may trigger early event abnormal DNA methylation in ER positive breast cancer.

Conclusions

We describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes.
Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability
Authors: Barbosa RR , Xu AQ , D’Andrea D , Copley F , Patel H , Chakravarty P , Clear A , Calaminici M , Janz M , Zhang B , Schmidt-Supprian M , Wang J , Gribben JG , Tooze R , Fitzgibbon J , Franzoso G , Rajewsky K , Calado DP
Published: April 2020

NF-κB and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-κB is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-κB/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace cell lineage and oncogene activation we found that NF-κB/MYC co-deregulation originated cancers with a plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-IGH] multiple myeloma. Notably, in contrast to NF-κB or MYC activation alone, co-deregulation rendered cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven differentiation pressures can be accommodated at a cost in poorly-differentiated cancers.

Significance

Our studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-κB and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. Notably, we found that NF-κB and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat diseases.

Highlights

NF-κB and MYC co-activation originates (pre)plasmablast-like cancer

NF-κB/MYC+renders cancer cells addicted to IL6 for survival and phenotypic stability

NF-κB/MYC+cancers are alike a fraction of human plasmablastic lymphoma

t(8;14)[MYC-IGH] multiple myeloma is linked to a NF-κB/MYC co-activation signature