bluuebunny/crossref_metadata_2025 huggingface dataset:
The performance of the SARS-CoV-2 RT-PCR test as a tool for detecting SARS-CoV-2 infection in the population: A survey of routine laboratory RT-PCR test results from the region of Münster, Germany
Authors: Stang Andreas , Robers Johannes , Schonert Birte , Jöckel Karl-Heinz , Spelsberg Angela , Keil Ulrich , Cullen Paul
Published: May 2021

Objectives

To evaluate the population-based performance of the SARS-CoV-2 RT-PCR test as a tool for detecting SARS-CoV-2 infection during the pandemic in 2020.

Methods

We analysed SARS-CoV-2 RT-PCR results of 162,457 people living in Münster, Germany screened at nursing homes, testing sites, at schools, regional hospitals, and by general practitioners. All PCRs were done with the same cobas SARS-CoV-2 RT-PCR system (Roche Diagnostics). We stratified positive RT-PCR results by cycle threshold (Ct) values, periods of the national test strategy, age, sex, and symptoms.

Results

Among 162,457 individuals, 4164 (2.6%) had a positive RT-PCR test result, defined as Ct<40. Depending on the national test strategy, higher positive rates were associated with testing predominantly symptomatic people. Children (0-9 years) and older adults (70+ years). Only 40.6% of test positives showed low Ct values < 25 (potentially infectious). The percentage of Ct values below 25 was lower among children (0-9), adolescents (10-19), and among the elderly (70+ years).

Conclusions

RT-PCR testing as a tool for mass screening should not be used alone as a base for pandemic decision making including measures such as quarantine, isolation, and lockdown.
multiSero: open multiplex-ELISA platform for analyzing antibody responses to SARS-CoV-2 infection
Authors: Byrum Janie R. , Waltari Eric , Janson Owen , Guo Syuan-Ming , Folkesson Jenny , Chhun Bryant B. , Vinden Joanna , Ivanov Ivan E. , Forst Marcus L. , Li Hongquan , Larson Adam G. , Wu Wesley , Tato Cristina M. , McCutcheon Krista M. , Peluso Michael J. , Henrich Timothy J. , Deeks Steven G. , Prakash Manu , Greenhouse Bryan , Pak John E. , Mehta Shalin B.
Published: May 2021

Serology has provided valuable diagnostic and epidemiological data on antibody responses to SARS-CoV-2 in diverse patient cohorts. Deployment of high content, multiplex serology platforms across the world, including in low and medium income countries, can accelerate longitudinal epidemiological surveys. Here we report multiSero, an open platform to enable multiplex serology with up to 48 antigens in a 96-well format. The platform consists of three components: ELISA-array of printed proteins, a commercial or home-built plate reader, and modular python software for automated analysis (pysero). We validate the platform by comparing antibody titers against the SARS-CoV-2 Spike, receptor binding domain (RBD), and nucleocapsid (N) in 114 sera from COVID-19 positive individuals and 87 pre-pandemic COVID-19 negative sera. We report data with both a commercial plate reader and an inexpensive, open plate reader (nautilus). Receiver operating characteristic (ROC) analysis of classification with single antigens shows that Spike and RBD classify positive and negative sera with the highest sensitivity at a given specificity. The platform distinguished positive sera from negative sera when the reactivity of the sera was equivalent to the binding of 1 ng mL−1 RBD-specific monoclonal antibody. We developed normalization and classification methods to pool antibody responses from multiple antigens and multiple experiments. Our results demonstrate a performant and accessible pipeline for multiplexed ELISA ready for multiple applications, including serosurveillance, identification of viral proteins that elicit antibody responses, differential diagnosis of circulating pathogens, and immune responses to vaccines.
Sunshine on KOL : a retrospective study about financial ties between medical key opinion leaders and pharmaceutical industry in France
Authors: Clinckemaillie Marie , Scanff Alexandre , Naudet Florian , Barbaroux Adriaan
Published: May 2021

Objective

To investigate the nature, extent and evolution of financial relationships between key opinion leaders (KOL) or non-KOL physicians and pharmaceutical and device companies in France.

Design

Retrospective and descriptive study

Setting

All doctors practicing in France, with a focus on 548 KOL defined as board members of all the professional medical associations having published clinical practice guidelines in 2018 or 2019. These 99 associations were identified by the cross-checking of 3 databases.

Main outcome measures

The number and the amount of gifts (year by year since 2014), remunerations and agreements (year by year since 2017).

Results

Physicians had 818m€ ($936m, £741m) of gifts declared from 2014 to 2019. 83% of KOL had such links of interest. The 548 identified KOL represented 0.24% of physicians in France but received 1.5% of the total amount of gifts, i.e. €12.3m ($14m, £11m or €3 700 per capita per year).

Physicians had 125m€ ($143m and 114m£) of agreements declared from 2017 to 2019. The 548 KOL received 0.72% of the agreements and 2.5% of the value of the agreements, i.e. 3.1m€ ($3.6m, £2.8m) or €1 900 per capita per year ($2200, £1700).

Physicians had 156m€ ($178m and 141m£) of remunerations declared from 2017 to 2019. The 548 identified KOL received 4.4% of the total value of remunerations to physicians, i.e. 6.8m€ ($7.8m, £6.2m) or 4 100€ per capita per year ($4 800, £3 700).

Almost every professional medical associations (99%) had in their board at least one KOL with a financial tie.

Conclusion

Financial relationships between KOL and the industry in France are extensive, KOL have much more financial ties than non-KOL practitioners. The main limit of this study arises from the quality of information provided on the French Transparency in Healthcare database.

Pre-registration: osf.io/m8syh

Strengths and limitations of this study

This is the first attempt to provide data on the extent of the links of interest between opinion leaders and pharmaceutical industry in France.

Author crossed the nationwide databases of financial ties with three databases of professional medical associations.

All medical doctors practicing in France were inclused, with a focus on 548 KOL defined as board members of all the professional medical associations having published clinical practice guidelines in 2018 or 2019.

These 99 associations were identified by the cross-checking of 3 different catalogs of French professional associations.

The major links between key opinion leaders and industry ask the question of the independence of the experts, and raises concern that guidelines can be influenced by industry.
Intra-host evolution provides for continuous emergence of SARS-CoV-2 variants
Authors: Landis Justin T. , Moorad Razia , Pluta Linda J. , Caro-Vegas Carolina , McNamara Ryan P , Eason Anthony B. , Bailey Aubrey , Villamor Femi Cleola S. , Juarez Angelica , Wong Jason P. , Yang Brian , Broussard Grant S. , Damania Blossom , Dittmer Dirk P.
Published: May 2021

Variants of concern (VOC) in SARS-CoV-2 refer to viral genomes that differ significantly from the ancestor virus and that show the potential for higher transmissibility and/or worse clinical progression. VOC have the potential to disrupt ongoing public health measures and vaccine efforts. Yet, little is known regarding how frequently different viral variants emerge and under what circumstances. We report a longitudinal study to determine the degree of SARS-CoV-2 sequence evolution in 94 COVID-19 cases and to estimate the frequency at which highly diverse variants emerge. 2 cases accumulated ≥9 single-nucleotide variants (SNVs) over a two-week period and 1 case accumulated 23 SNVs over a three-week period, including three non-synonymous mutations in the Spike protein (D138H, E554D, D614G). We estimate that in 2% of COVID cases, viral variants with multiple mutations, including in the Spike glycoprotein, can become the dominant strains in as little as one month of persistent in patient virus replication. This suggests the continued local emergence of VOC independent of travel patterns. Surveillance by sequencing for (i) viremic COVID-19 patients, (ii) patients suspected of re-infection, and (iii) patients with diminished immune function may offer broad public health benefits.
Pigment pattern morphospace ofDaniofishes: evolutionary diversification and mutational effects
Authors: McCluskey Braedan M. , Liang Yipeng , Lewis Victor M. , Patterson Larissa B. , Parichy David M.
Published: May 2021

Molecular and cellular mechanisms underlying differences in adult form remain largely unknown. Adult pigment patterns of fishes in the genusDanio, which includes zebrafish,D. rerio, include horizontal stripes, vertical bars, spots and uniform patterns, and provide an outstanding opportunity to identify causes of species level variation in a neural crest derived trait. Yet understanding such variation requires quantitative approaches to assess phenotypes, and such methods have been mostly lacking for pigment patterns. We introduce metrics derived from information theory that describe patterns and pattern variation inDaniofishes. We find that such metrics used singly and in multivariate combinations are suitable for distinguishing general pattern types, and can reveal even subtle phenotypic differences attributable to mutations. Our study provides new tools for analyzing pigment pattern inDanioand potentially other groups, and sets the stage for future analyses of pattern morphospace and its mechanistic underpinnings.

Summary statement

We provide quantitative metrics for studying pigment patterns of zebrafish and other species. These metrics are applicable to changes between species as well as impacts of laboratory induced mutations
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
Authors: Baca Sylvan C. , Singler Cassandra , Zacharia Soumya , Seo Ji-Heui , Morova Tunc , Hach Faraz , Ding Yi , Schwarz Tommer , Huang Chia-Chi Flora , Kalita Cynthia , Groha Stefan , Pomerantz Mark M. , Wang Victoria , Linder Simon , Sweeney Christopher J. , Zwart Wilbert , Lack Nathan A. , Pasaniuc Bogdan , Takeda David Y. , Gusev Alexander , Freedman Matthew L.
Published: May 2021

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.
Ribosome protein mutant cells rely on the GR64 cluster of gustatory receptors for survival and proteostasis in Drosophila
Authors: Baumgartner Michael E. , Kucinski Iwo , Piddini Eugenia
Published: May 2021

Mutations in ribosome protein (Rp) genes and ribosome biogenesis factors result in debilitating diseases known as ribosomopathies. Recent studies in Drosophila have shown that cells heterozygous mutant for Rp genes (Rp/+) exhibit proteotoxic stress and aggregates, which drive stress pathway activation and apoptosis. Understanding how Rp/+ cells fend off proteotoxic stress could suggest mechanisms to ameliorate these and other conditions caused by proteotoxic stress. Here we find that Rp/+ epithelial cells express all six Gustatory Receptor 64 (Gr64) genes, a cluster of sugar receptors involved in taste sensation. We show that Rp/+ cells depend on Gr64 for survival and that loss of Gr64 autonomously exacerbates stress pathway activation and proteotoxic stress by negatively effecting autophagy and proteasome function in Rp/+ cells. This work identifies a non-canonical role in proteostasis maintenance for a family of gustatory receptors known for their function in neuronal sensation.
Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes
Authors: Sjödahl Gottfrid , Abrahamsson Johan , Holmsten Karin , Bernardo Carina , Chebil Gunilla , Eriksson Pontus , Johansson Iva , Kollberg Petter , Lindh Claes , Lövgren Kristina , Marzouka Nour-al-Dain , Olsson Hans , Höglund Mattias , Ullén Anders , Liedberg Fredrik
Published: May 2021

For muscle-invasive bladder cancer (MIBC), there are no tissue biomarkers in clinical use that identify patients sensitive or resistant to neoadjuvant chemotherapy. The present study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. Tumor classification was performed by transcriptomic profiling and by a 13-marker immunostaining panel. Furthermore, we explored differential gene expression and chemotherapy response beyond molecular subtypes. Tumors with Genomically Unstable (GU) and Urothelial-like (Uro) subtypes had higher proportions of pathological response and superior survival outcomes as compared to the Basal-Squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Based on our findings, we suggest that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy. We also found the gene coding for osteopontin (SPP1) to display a subtype-dependent effect on chemotherapy response, confirmed at the protein level by immunohistochemistry. Combined analyses of second-generation, subtype-specific biomarkers may be an additional way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.
Astrocytic Regulation of Basal Ganglia Dopamine/D2-Dependent Behaviors
Authors: Mastrogiacomo Rosa , Trigilio Gabriella , Dautan Daniel , Devroye Céline , Ferretti Valentina , Vitali Enrica , Orso Genny , Marotta Roberto , Maltese Federica , Piras Gessica , Forgiarini Alessia , Pacinelli Giada , Rothmond Debora A. , Waddington John L. , Drago Filippo , De Luca Maria Antonietta , Leggio Gian Marco , Weickert Cynthia S. , Managò Francesca , Papaleo Francesco
Published: May 2021

Astrocytic involvement in dopamine dynamics related to motivational and sensorimotor gating abilities is unknown. We found that dysbindin-1 (Dys1) hypofunction increases the activity of astrocytes, which express only the isoform Dys1A that is reduced in the caudate of patients with schizophrenia. Astrocytic Dys1A disruption resulted in avolition and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. Notably, astrocytic Dys1A hypofunction disrupted dopamine dynamics linked to reward expectancy and interconnected with astrocytes Ca2+responses mainly in the globus pallidus externus (GPe). Finally, we proved these phenotypes were mediated by D2 receptors in astrocytes as their selective deletion in astrocytes either in GPe or SNc/VTA enhanced motivation and sensorimotor gating abilities as well as dopaminergic release in the GPe. Therefore, astrocytes control motivational and sensorimotor gating processes through Dys1A/D2-dependent mechanisms within the basal ganglia.
Mitogen-activated protein kinases contribute to temperature induced cardiac remodelling in rainbow trout (Oncorhynchus mykiss) heart
Authors: Ding Y. , Johnston E.F. , Gillis T.E
Published: May 2021

Rainbow trout (Oncorhynchus mykiss) live in temperate environments and experience seasonal changes in temperature that range between 4°C and 20°C. Laboratory studies demonstrate that cold and warm acclimation of male trout can have oppositional effects on cardiac hypertrophy and the collagen content of the heart. The cellular mechanisms behind temperature induced cardiac remodelling are unclear, as is why this response differs between male and female fish. Recent work utilizing cultured trout cardiac fibroblasts suggests that collagen deposition is regulated, at least in part, by mitogen-activated protein kinase (MAPK) cell signalling pathways. We therefore hypothesized that temperature-dependent cardiac remodelling is regulated by these same cell signalling pathways. To test this, male and female trout were acclimated to 18°C (warm) in the summer and to 4°C (cold) in the winter and the activation of MAPK pathways in the hearts were characterized and compared to that of control fish maintained at 12°C. Animals, maintained under a natural photoperiod matched to time of year, were sampled throughout each acclimation. p38 MAPK phosphorylation increased in the hearts of female fish during the cold acclimation protocol and the phosphorylation of extracellular signal-regulated kinase (ERK) increased in the hearts of male fish with warm acclimation. These results indicate that thermal acclimation has transient and sex-specific effects on the phosphorylation of MAPKs.
Cortical ripples during NREM sleep and waking in humans
Authors: Dickey Charles W. , Verzhbinsky Ilya A. , Jiang Xi , Rosen Burke Q. , Kajfez Sophie , Eskandar Emad N. , Gonzalez-Martinez Jorge , Cash Sydney S. , Halgren Eric
Published: May 2021

Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in the cortex during non-rapid eye movement sleep (NREM). Recently, cortical ripples in humans have been shown to enfold the replay of neuron firing patterns during cued recall. Here, using intracranial recordings from 18 patients (12 female), we show that cortical ripples also occur during NREM in humans, with similar density, oscillation frequency (∼90 Hz), duration, and amplitude to waking. Ripples occurred in all cortical regions with similar characteristics, unrelated to putative hippocampal connectivity, and were less dense and robust in higher association areas. Putative pyramidal and interneuron spiking phase-locked to cortical ripples during NREM, with phase delays consistent with ripple generation through pyramidal-interneuron feedback. Cortical ripples were smaller in amplitude than hippocampal ripples, but were similar in density, frequency, and duration. Cortical ripples during NREM typically occurred just prior to the upstate peak, often during spindles. Upstates and spindles have previously been associated with memory consolidation, and we found that cortical ripples grouped co-firing between units within the window of spike-timing-dependent plasticity. Thus, human NREM cortical ripples are: ubiquitous and stereotyped with a tightly focused oscillation frequency; similar to hippocampal ripples; associated with upstates and spindles; and associated with unit co-firing. These properties are consistent with cortical ripples possibly contributing to memory consolidation and other functions during NREM in humans.

Significance Statement

In rodents, hippocampal ripples organize replay during sleep to promote memory consolidation in the cortex, where ripples also occur. However, evidence for cortical ripples in human sleep is limited, and their anatomical distribution and physiological properties are unexplored. Here, using human intracranial recordings, we demonstrate that ripples occur throughout the cortex during waking and sleep with highly stereotyped characteristics. During sleep, cortical ripples tend to occur during spindles on the down-to-upstate transition, and thus participate in a sequence of sleep waves that is important for consolidation. Furthermore, cortical ripples organize single unit spiking with timing optimal to facilitate plasticity. Therefore, cortical ripples in humans possess essential physiological properties to support memory and other cognitive functions.
A graphical, interactive and GPU-enabled workflow to process long-read sequencing data
Authors: Reddy Shishir , Hung Ling-Hong , Sala-Torra Olga , Radich Jerald , Yeung Cecilia CS , Yeung Ka Yee
Published: May 2021

We present a graphical cloud-enabled workflow for fast, interactive analysis of nanopore sequencing data using GPUs. Users customize parameters, monitor execution and visualize results through an accessible graphical interface. To facilitate reproducible deployment, we use Docker containers and provide an Amazon Machine Image (AMI) with all software and drivers pre-installed for GPU computing on the cloud. We observe a 34x speedup and a 109x reduction in costs for the rate-limiting basecalling step in the analysis of blood cancer cell line data. The graphical interface and greatly simplified deployment facilitate the adoption of GPUs for rapid, cost-effective analysis of long-read sequencing.
Research gaps and new insights in the intriguing evolution of Drosophila seminal proteins
Authors: Hurtado J , Almeida FC , Belliard SA , Revale S , Hasson E
Published: May 2021

While the striking effects that seminal fluid proteins (SFPs) exert on females are fairly conserved among Diptera, they exhibit remarkable evolutionary lability. Consequently, most SFPs lack detectable homologs among the repertoire of SFPs of phylogenetically distant species. How such a rapidly changing proteome “manages” to conserve functions across taxa is a fascinating question. However, this and other pivotal aspects of SFPs’ evolution remain elusive because discoveries on these proteins have been mainly restricted to the model D. melanogaster. Here, we provide an overview of the current knowledge on the inter-specific divergence of Drosophila SFPs and compile the increasing amount of relevant genomic information from multiple species. Capitalizing the accumulated knowledge in D. melanogaster, we present novel sets of high-confidence SFP candidates and transcription factors presumptively involved in regulating the expression of SFPs. We also address open questions by performing comparative genomic analyses that failed to support the existence of conserved SFPs shared by most dipterans and indicated that gene co-option is the most frequent mechanism accounting for the origin of Drosophila SFP-coding genes. We hope our update establishes a starting point to integrate, as more species are assayed for SFPs, further data and thus, to widen the understanding of the intricate evolution of these proteins.
Key Promoter Region of Wnt4 response to FSH and Genetic Effect on Several Production Traits of Its Mutations in Chicken
Authors: Zhong Conghao , Wang Yiya , Liu Cuiping , Jiang Yunliang , Kang Li
Published: May 2021

The signaling pathway of the wingless-type mouse mammary tumor virus integration site (Wnt) plays an important role in ovarian and follicular development. Wnt4 was shown in our previous study to be involved in the selection and development of chicken follicles by up-regulating the expression of follicle stimulating hormone receptors (FSHR), stimulating the proliferation of follicular granulosa cells and increasing the secretion of steroidal hormones. To further characterize cis-elements regulating chicken Wnt4 transcription, in this study we determined critical regulatory regions affecting chicken Wnt4 transcription, then identified a single nucleotide polymorphism (SNP) in this region, and finally analyzed the association of the SNP with chicken production traits. The results showed that the 5′ regulatory region from -3354 to -2689 of the chicken Wnt4 gene had the strongest activity and greatest response to FSH stimulation, and that one SNP site -3015 (G > C) in this segment was identified as affecting the binding of NFAT5 (nuclear factor of activated T cells 5). When G was replaced by C at this site, it eliminated the binding by NFAT5. Moreover, this locus was significantly associated with the keel length and comb length of hens. Individuals with the genotype CG had longer keels while those with genotype CC had longer combs. Collectively, these data suggested that the SNP-3015 (G > C) is (i) involved in the regulation of Wnt4 gene expression by affecting the binding of NFAT5, (ii) associated with chicken keel length and comb length, and (iii) is a potential DNA marker in the molecular breeding of chickens for egg laying.
Multiple ancestral and a plethora of recent gene duplications during the evolution of the green sensitive opsin genes (RH2) in teleost fishes
Authors: Musilova Zuzana , Cortesi Fabio
Published: May 2021

Vertebrates have four visual cone opsin classes that, together with a light-sensitive chromophore, provide sensitivity from the ultraviolet to the red wavelengths of light. The rhodopsin-like 2 (RH2) opsin is sensitive to the centre blue-green part of the spectrum, which is the most prevalent light underwater. While various vertebrate groups such as mammals and sharks have lost theRH2gene, in teleost fishes this opsin has continued to proliferate. By investigating the genomes of 115 teleost species, we find thatRH2shows an extremely dynamic evolutionary history with repeated gene duplications, gene losses and gene conversion affecting entire orders, families and species. At least four ancestral duplications provided the substrate for today’sRH2diversity with duplications occurring in the common ancestors of Clupeocephala, Neoteleostei, and Acanthopterygii. Following these events,RH2has continued to duplicate both in tandem and during lineage specific genome duplications. However, it has also been lost many times over so that in the genomes of extant teleosts, we find between zero to eightRH2copies. Using retinal transcriptomes in a phylogenetic representative dataset of 30 species, we show thatRH2is expressed as the dominant green-sensitive opsin in almost all fish lineages. The exceptions are the Osteoglossomorpha (bony tongues and mooneyes) and several characin species that have lostRH2, and tarpons, other characins and gobies which do not or only lowly express the gene. These fishes instead express a green-shifted long-wavelength-sensitiveLWSopsin. Our study highlights the strength of using modern genomic tools within a comparative framework to elucidate the detailed evolutionary history of gene families.
Social selection within aggregative multicellular development drives morphological evolution
Authors: Fortezza Marco La , Velicer Gregory J.
Published: May 2021

The evolution of developmental systems might be shaped by both historical differences in developmental features and social selection, among other factors. In aggregative multicellularity, development is itself a social process in which unicellular organisms cooperate in carrying out complex developmental programs. In some aggregative systems, development culminates in the construction of spore-packed fruiting bodies. Fruiting body development in myxobacteria often unfolds within genetically and behaviorally diverse conspecific cellular environments that can include social defection and warfare. Here we use the bacterium Myxococcus xanthus to test whether the character of the cellular environment during aggregative development shapes morphological evolution. We manipulated the cellular composition of Myxococcus development in an experiment in which evolving populations initiated from a single ancestor repeatedly co-developed with one of several non-evolving partners - a benign cooperator, one of three cheaters or one of three antagonists. Fruiting body morphology was found to diversify as a function of developmental partners, revealing adaptation specific to distinct cellular environments. Collectively, antagonistic partners selected for higher levels of robust fruiting body formation than did cheaters or the benign cooperator. Moreover, even small degrees of genetic divergence between the distinct cheater partners were sufficient to drive treatment-level morphological divergence. Co-developmental partners not only shaped mean trait evolution but also determined the magnitude and dynamics of stochastic morphological diversification and subsequent convergence. In sum, we find that even few genetic differences affecting developmental and social features can greatly impact the morphological evolution of multicellular bodies and experimentally demonstrate that microbial warfare can promote cooperation.
Spatiotemporal specificity of correlated DNA methylation and gene expression pairs across different human tissues and stages of brain development
Authors: Wang Kangli , Dai Rujia , Xia Yan , Tian Jianghua , Jiao Chuan , Mikhailova Tatiana , Zhang Chunling , Chen Chao , Liu Chunyu
Published: May 2021

DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs were identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs were tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlighted the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalog of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.
Probing DNA - transcription factor interactions using single-molecule fluorescence detection in nanofluidic devices
Authors: Fontana Mattia , Ivanovaitė Šarūnė , Lindhoud Simon , van den Berg Willy , Weijers Dolf , Hohlbein Johannes
Published: May 2021

Single-molecule fluorescence detection offers powerful ways to study biomolecules and their complex interactions. Here, we combine nanofluidic devices and camera-based, single-molecule Förster resonance energy transfer (smFRET) detection to study the interactions between plant transcription factors of the auxin response family (ARF) and DNA oligonucleotides that contain target DNA response elements. In particular, we show that the binding of the unlabelled ARF DNA binding domain (ARF-DBD) to donor and acceptor labelled DNA oligonucleotides can be detected by changes in the FRET efficiency and changes in the diffusion coefficient of the DNA. In addition, our data on fluorescently labelled ARF-DBDs suggest that, at nanomolar concentrations, ARF-DBDs are exclusively present as monomers. In general, the fluidic framework of freely diffusing molecules minimizes potential surface-induced artifacts, enables high-throughput measurements and proved to be instrumental in shedding more light on the interactions between ARF-DBDs monomers and between ARF-DBDs and their DNA response element.
Mycolactone enhances the Ca2+ leakage from endoplasmic reticulum by trapping Sec61 translocons in a Ca2+ permeable state
Authors: Bhadra Pratiti , Santos Scott Dos , Gamayun Igor , Pick Tillman , Ogbechi Joy , Hall Belinda S. , Zimmermann Richard , Helms Volkhard , Simmonds Rachel E. , Cavalié Adolfo
Published: May 2021

The Mycobacterium ulcerans exotoxin, mycolactone, is an inhibitor of co-translational translocation via the Sec61 complex. Mycolactone has previously been shown to bind to, and alter the structure of, the major translocon subunit Sec61α, and change its interaction with ribosome nascent chain complexes. In addition to its function in protein translocation into the ER, Sec61 also plays a key role in cellular Ca2+ homeostasis, acting as a leak channel between the endoplasmic reticulum (ER) and cytosol. Here, we have analysed the effect of mycolactone on cytosolic and ER Ca2+ levels using compartment-specific sensors. We also used molecular docking analysis to explore potential interaction sites for mycolactone on translocons in various states. These results show that mycolactone enhances the leak of Ca2+ ions via the Sec61 translocon, resulting in a slow but substantial depletion of ER Ca2+. This leak was dependent on mycolactone binding to Sec61α because resistance mutations in this protein completely ablated the increase. Molecular docking supports the existence of a mycolactone-binding transient inhibited state preceding translocation and suggests mycolactone may also bind Sec61α in its idle state. We propose that delayed ribosomal release after translation termination and/or translocon “breathing” during rapid transitions between the idle and intermediate-inhibited states allow for transient Ca2+ leak, and mycolactone’s stabilisation of the latter underpins the phenotype observed.
One Cell At a Time: A Unified Framework to Integrate and Analyze Single-cell RNA-seq Data
Authors: Wang Chloe X. , Zhang Lin , Wang Bo
Published: May 2021

1

The surge of single-cell RNA sequencing technologies gives rise to the abundance of large single-cell RNA-seq datasets at the scale of hundreds of thousands of single cells. Integrative analysis of large-scale scRNA-seq datasets has the potential of revealingde novocell types as well as aggregating biological information. However, most existing methods fail to integrate multiple large-scale scRNA-seq datasets in a computational and memory efficient way. We hereby propose OCAT,OneCellAt aTime, a graph-based method that sparsely encodes single-cell gene expressions to integrate data from multiple sources without most variable gene selection or explicit batch effect correction. We demonstrate that OCAT efficiently integrates multiple scRNA-seq datasets and achieves the state-of-the-art performance in cell type clustering, especially in challenging scenarios of non-overlapping cell types. In addition, OCAT efficaciously facilitates a variety of downstream analyses, such as differential gene analysis, trajectory inference, pseudotime inference and cell inference. OCAT is a unifying tool to simplify and expedite the analysis of large-scale scRNA-seq data from heterogeneous sources.
Lmo7 recruits myosin II heavy chain to induce apical constriction in Xenopus ectoderm
Authors: Matsuda Miho , Chu Chih-Wen , Sokol Sergei Y.
Published: May 2021

Apical constriction, or reduction of the apical domain, underlies many morphogenetic events during development, such as furrow or tube formation. Actomyosin complexes play an essential role in apical constriction, however the detailed analysis of molecular mechanisms is still pending. Here we show that Lim domain only protein 7 (Lmo7), a multidomain adaptor at apical junctions, promotes apical constriction in the Xenopus superficial ectoderm, whereas apical domain size increases in Lmo7-depleted cells. Lmo7 is localized to and promotes the formation of the circumferential actomyosin belt adjacent to apical junctions. We find that Lmo7-dependent apical constriction requires the RhoA-ROCK-Non-muscle myosin II (NMII) pathway. Strikingly, Lmo7 binds and recruits NMII heavy chains to apical junctions. Lmo7 overexpression altered the subcellular distribution of Wtip, a sensor of mechanical tension. Our findings suggest that Lmo7 serves as a scaffold organizing the actomyosin network to regulate contractility at apical junctions.
A spatially aware likelihood test to detect sweeps from haplotype distributions
Authors: DeGiorgio Michael , Szpiech Zachary A.
Published: May 2021

The inference of positive selection in genomes is a problem of great interest in evolutionary genomics. By identifying putative regions of the genome that contain adaptive mutations, we are able to learn about the biology of organisms and their evolutionary history. Here we introduce a composite likelihood method that identifies recently completed or ongoing positive selection by searching for extreme distortions in the spatial distribution of the haplotype frequency spectrum along the genome relative to the genome-wide expectation taken as neutrality. Furthermore, the method simultaneously infers two parameters of the sweep: the number of sweeping haplotypes and the “width” of the sweep, which is related to the strength and timing of selection. We demonstrate that this method outperforms the leading haplotype-based selection statistics. As a positive control, we apply it to two well-studied human populations from the 1000 Genomes Project and examine haplotype frequency spectrum patterns at theLCTand MHC loci. We also apply it to a data set of brown rats sampled in NYC and identify genes related to olfactory perception. To facilitate use of this method, we have implemented it in user-friendly open source software.
Common clonal origin of chronic myelomonocytic leukemia and B-cell acute lymphoblastic leukemia in a patient with a germline CHEK2 variant
Authors: Bazinet Alexandre , Heath John , Chong Anne-Sophie , Simo-Cheyou Estelle R. , Worme Samantha , Rivera Polo Barbara , Foulkes William D. , Caplan Stephen , Johnson Nathalie A. , Orthwein Alexandre , Mercier François E.
Published: May 2021

Hematological malignancies are broadly divided into myeloid and lymphoid neoplasms, reflecting the two major cellular lineages of the hematopoietic system. It is generally rare for hematological malignancies to spontaneously progress with a switch from myeloid to lymphoid lineage. We describe the exceptional case of a patient who sequentially developed myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and B-cell acute lymphoblastic leukemia (B-ALL), as well as our investigation into the underlying pathogenesis. Using whole-exome sequencing (WES) performed on sorted CMML and B-ALL cell fractions, we identified both common and unique potential driver mutations, suggesting a branching clonal evolution giving rise to both diseases. Interestingly, we also identified a germline variant in the cancer susceptibility gene CHEK2. We validated that this variant (c.475T > C; p.Y159H), located in the forkhead-associated (FHA) domain, impairs its capacity to bind BRCA1 in cellulo. This unique case provides novel insight into the genetics of complex hematological diseases and highlights the possibility that such patients may carry inherited predispositions.
Structural effects of halogen bonding in iodochalcones
Authors: Hamilton Victoria , Harris Connah , Hall Charlie L. , Potticary Jason , Cremeens Matthew E. , D'Ambruoso Gemma D. , Matsumoto Masaomi , Warren Stephen D. , Pridmore Natalie E. , Sparkes Hazel A. , Hall Simon R.
Published: May 2021

The structures of three iodochalcones, functionalized with fluorine or a nitro group, have been investigated to explore the impact of different molecular electrostatic distributions on the halogen bonding within each crystal structure. The strongly withdrawing nitro group presented a switch of the halogen bond from a lateral to a linear motif. Surprisingly, this appears to be influenced by a net positive shift in charge distribution around the lateral edges of the σ-hole, making the lateral I...I bonding motif less preferable. A channel of amphoteric I...I type II halogen bonds is observed for a chalcone molecule, which was not previously reported in chalcones, alongside an example of the common synthon involving extended linear chains of I...O2N donor–acceptor halogen bonds. This work shows that halogenated chalcones may be an interesting target for developing halogen bonding as a significant tool within crystal engineering, a thus far underexplored area for this common structural motif.
Numerical study of external explosion characteristics induced by indoor natural gas vented explosion
Authors: Pang Lei , Hu Qianran , Yang Kai
Published: May 2021

Purpose

The purpose of this paper is to ascertain the harm to personnel and equipment caused by an external explosion during natural gas explosion venting. The external explosion characteristics induced by the indoor natural gas explosion are the focal points of the investigation.

Design/methodology/approach

Computational fluid dynamics technology was used to investigate the large-scale explosion venting process of natural gas in a 6 × 3 × 2.5 m room, and the characteristics of external explosion under different scaled vent size (Kv= Av/V2/3, 0.05, 0.08, 0.13, 0.18) were numerically analyzed.

Findings

When Kv = 0.08, the length and duration of the explosion fireball are 13.39 and 450 ms, respectively, which significantly expands the degree and range of high-temperature hazards. The suitable flow-field structure causes the external explosion overpressure to be more than twice that indoors, i.e. the natural gas explosion venting overpressure may be considerably more hazardous in an outdoor environment than inside a room. A specific range for the Kvcan promote the superposition of outdoor rupture waves and explosion shock waves, thereby creating a new overpressure hazard.

Originality/value

Little attention has been devoted to investigating systematically the external explosion hazards. Based on the numerical simulation and the analysis, the external explosion characteristics induced by the indoor large-scale gas explosion were obtained. The research results are theoretically significant for mitigating the effects of external gas explosions on personnel and equipment.
MHD flow of MgO-Ag/water hybrid nanofluid past a moving slim needle considering dual solutions: an applicable model for hot-wire anemometer analysis
Authors: Dinarvand Saeed , Mousavi Seyed Mehdi , Yousefi Mohammad , Nademi Rostami Mohammadreza
Published: May 2021

Purpose

The purpose of this paper is to study the steady laminar magnetohydrodynamics (MHD) flow of a magnesium oxide-silver/water hybrid nanofluid along a horizontal slim needle with thermal radiation by considering dual solutions.

Design/methodology/approach

It is assumed that the needle can move in the same or opposite direction of the free stream. Also the solid phase and fluid phase are in thermal equilibrium. The basic partial differential equations become dimensionless using a similarity transformation method. Moreover, problem coding is accomplished using the finite difference method. The emerging parameters are nanoparticles mass (0–40 gr), base fluid mass (100 gr), needle’s size (0.001–0.2), magnetic field parameter, velocity ratio parameter, radiation parameter and Prandtl number (6.2).

Findings

With help of the stability analysis, it is shown that always the first solutions are physically stable. Results indicate that the magnetic parameter and the second nanoparticle’s mass limit the range of the velocity ratio parameter for which the solution exists. Besides, the magnetic parameter leads to decrease of quantities of engineering interest, i.e. skin friction coefficient and local Nusselt number.

Originality/value

To the best of the authors’ knowledge, no one has ever attempted to study the present problem through a mass-based model for hybrid nanofluid. Moreover, the dual solutions for the problem are new. Indeed, the results of this paper are purely original and the numerical achievements were never published up to now. Finally, the authors expect that the present investigation would be useful in hot-wire anemometer or shielded thermocouple for measuring the velocity of the wind, etc.
An empirical investigation on waqf governance practices in waqf institutions in Malaysia
Authors: Kamaruddin Muhammad Iqmal Hisham , Hanefah Mustafa Mohd
Published: May 2021

Purpose

This study aims to examine and compare the current waqf governance practices in waqf institutions in Malaysia.

Design/methodology/approach

This paper reviews professional documents and literature to propose a new and practical waqf governance measurement. Waqf governance measurements were used to examine and compare the current waqf governance practices among waqf institutions in Malaysia. The annual reports of all waqf institutions under the State Islamic Religious Councils (SIRCs) were analysed using content analysis on the current waqf governance practices using binomial logic.

Findings

Overall, the results indicate moderate waqf governance practices under three waqf governance categories, namely waqf governance policy, waqf governance board and waqf governance processes. This study also found a significant impact of corporatisation reformation of waqf institutions on waqf governance practices.

Research limitations/implications

The findings indicate the need for all waqf institutions in Malaysia, especially for non-corporate waqf institutions, to enhance their waqf governance practices by disclosing all relevant information to the public. This is because the success of waqf fund management can be portrayed through the management’s transparency in waqf governance practices on how they deliver and use their resources to attain socio-economic objectives.

Originality/value

To the best of the authors’ knowledge, this study is among the first studies that examined and evaluated the current waqf governance practices in several waqf institutions in Malaysia.
Open innovation antecedents and its consequences on commercialization performance in small and medium-sized enterprises
Authors: Asgari Mohammad Javad , Zakery Amir , Pishvaee Mir Saman
Published: May 2021

Purpose

This paper aims to investigate the impact of the factors affecting open innovation (OI) intensity, in terms of three components of cooperative innovation, resource search and external research and development (R&D), as well as the impact of OI intensity on commercialization performance in small and medium-sized enterprises.

Design/methodology/approach

The data obtained from the distributed questionnaire among small and medium-sized enterprises (SMEs) from Isfahan Science and Technology Town (ISTT) in Iran, was analyzed using inferential and parametric statistics to examine the research hypotheses. In this analysis, structural equation tests were used to confirm or reject the research hypotheses using Smart PLS software.

Findings

The results indicate that all three OI components influence commercialization in technology-based firms of ISTT, while the most important one is cooperative innovation. Among the factors affecting OI components, innovative incentives are the most effective one that increases both external R&D and cooperative innovation. Facilitators and limitations of open innovation are also affecting OI intensity, with lower priorities.

Practical implications

Science park managers and policymakers should lay the ground for enhancing the cooperation intensity among firms. Cooperation intensity is the most effective open innovation component to improve commercialization performance.

Originality/value

Open innovation antecedents and its consequence on commercialization performance have been investigated for the same time in SMEs of a science park.