bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole genome sequencing revealed genetic diversity and selection of Guangxi indigenous chickens
Authors: Sun Junli , Chen Tao , Zhu Min , Wang Ran , Huang Yingfei , Wei Qiang , Yang Manman , Liao Yuying 
Published: April 2021

AbstractGuangxi chickens play an important role in promoting the high-quality development of the broiler industry in China, but their value and potential are yet to be discovered. To determine the genetic diversity and population structure of Guangxi indigenous chicken, we analyzed the whole genomes of 185 chicken from 8 phenotypically and geographically representative Guangxi chicken breeds, together with 12 RJFt, 12 BRA and 12 WL genomes available from previous studies. Calculation of heterozygosity (Hp), nucleotide diversity (π), and LD level indicated that Guangxi populations were characterized by higher genetic diversity and lower differentiation than RJFt and commercial breeds except HGFC. Population structure analysis also confirmed the introgression from commercial broiler breeds. Each population clustered together while the overall differentiation was small, MA has the richest genetic diversity among all varieties. Selective sweep analysis revealedBCO2,EDN3and other candidate genes have received strong selection in local breeds, these also provided novel breeding visual and data basis for future breeding.
Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease
Authors: Canal Berta , McClure Allison W. , Curran Joseph F. , Wu Mary , Ulferts Rachel , Weissmann Florian , Zeng Jingkun , Bertolin Agustina P. , Milligan Jennifer C. , Basu Souradeep , Drury Lucy S. , Deegan Tom , Fujisawa Ryo , Roberts Emma L. , Basier Clovis , Labib Karim , Beale Rupert , Howell Michael , Diffley John F.X 
Published: April 2021

SummarySARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonucleasein vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.
Redetermination of the first unknown protein MicroED structure by high resolution X-ray diffraction
Authors: Xu Hongyi , Zou Xiaodong , Högbom Martin , Lebrette Hugo 
Published: April 2021

AbstractMicrocrystal electron diffraction (MicroED) has the potential to considerably impact the field of structural biology. Indeed, the method can solve atomic structures of a wide range of molecules, beyond the reach of single particle cryo-electron microscopy, exploiting crystals too small for X-ray diffraction (XRD) even using X-ray free-electron lasers. However, until the first unknown protein structure – a R2-like ligand-binding oxidase fromSulfolobus acidocaldarius(SaR2lox) – was recently solved at 3.0 Å resolution, MicroED had only been used to study known protein structures previously obtained by XRD. Here, after adapting sample preparation protocols, the structure of theSaR2lox protein originally solved by MicroED was redetermined by XRD at 2.1 Å resolution. In light of the higher resolution XRD data and taking into account experimental differences of the methods, the quality of the MicroED structure is examined. The analysis demonstrates that MicroED provided an overall accurate model, revealing biologically relevant information specific toSaR2lox, such as the absence of an ether cross-link, but did not allow to detect the presence of a ligand visible by XRD in the protein binding pocket. Furthermore, strengths and weaknesses of MicroED compared to XRD are discussed in the perspective of this real-life protein example. The study provides fundaments to help MicroED become a method of choice for solving novel protein structures.SynopsisThe first unknown protein structure solved by microcrystal electron diffraction (MicroED) was recently published. The redetermination by X-ray diffraction of this protein structure provides new insights into the strengths and weaknesses of the promising MicroED method.
Discovery of target genes and pathways of blood trait loci using pooled CRISPR screens and single cell RNA sequencing
Authors: Morris John A. , Daniloski Zharko , Domingo Júlia , Barry Timothy , Ziosi Marcello , Glinos Dafni A. , Hao Stephanie , Mimitou Eleni P. , Smibert Peter , Roeder Kathryn , Katsevich Eugene , Lappalainen Tuuli , Sanjana Neville E. 
Published: April 2021

AbstractThe majority of variants associated with complex traits and common diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown regulatory effects incisandtrans. By leveraging biobank-scale GWAS data, massively parallel CRISPR screens and single cell transcriptome sequencing, we discovered target genes of noncoding variants for blood trait loci. The closest gene was often the target gene, but this was not always the case. We also identifiedtrans-effects networks of noncoding variants whencistarget genes encoded transcription factors, such asGFI1BandNFE2. We observed that GFI1Btrans-target genes were enriched for GFI1B binding sites and fine-mapped GWAS variants, and expressed in human bone marrow progenitor cells, suggesting that GFI1B acts as a master regulator of blood traits. This platform will enable massively parallel assays to catalog the target genes of human noncoding variants in bothcisandtrans.
The mitotic spindle mediates nuclear migration through an extremely narrow infection structure of the rice blast fungusMagnaporthe oryzae
Authors: Pfeifer Mariel A. , Khang Chang Hyun 
Published: April 2021

AbstractThe blast fungus,Magnaporthe oryzae, causes severe destruction to rice and other crops worldwide. As the fungus infects rice, it develops unique cellular structures, such as an appressorium and a narrow penetration peg, to permit successful invasion of host rice cells. Fundamental knowledge about these cellular structures and how organelles, such as the nucleus, are positioned within them is still emerging. Previous studies show that a single nucleus becomes highly stretched during movement through the narrow penetration peg in an extreme nuclear migration event. Yet, the mechanism permitting this nuclear migration event remains elusive. Here, we investigate the role of the mitotic spindle in mediating nuclear migration through the penetration peg. We find that disruption of spindle function during nuclear migration through the penetration peg prevents development of invasive hyphae and virulence on rice. Furthermore, regulated expression of conserved kinesin motor proteins, MoKin5 and MoKin14, is essential to form and maintain the spindle, as well as, properly nucleate the primary hypha. Overexpression of MoKin5 leads to formation of aberrant microtubule protrusions, which contributes to formation of nuclear fragments within the appressorium and primary hypha. Conversely, overexpression of MoKin14 causes the spindle to collapse leading to the formation of monopolar spindles. These results establish a mechanistic model towards understanding the intricate subcellular dynamics of extreme nuclear migration through the penetration peg, a critical step in the development of rice blast disease.ImportanceMagnaporthe oryzae, also known as the blast fungus, is a formidable hinderance to global food production, including rice. The destructive fungal pathogen develops highly-specialized cells and structures, such as appressoria and penetration pegs, to permit successful invasion of rice cells. Our understanding ofM. oryzae’sfundamental biology during host cell invasion and colonization is still developing. For instance, it is not yet known how organelles, such as the nucleus, migrate through the narrow penetration peg. Moreover, few previous studies examine the role of motor proteins inM. oryzae.In this study, we determined that the mitotic spindle propels a single nucleus through the penetration peg to permit successful development of fungal hyphae inside the first-invaded rice cell. We also identified two conserved kinesin motor proteins, MoKin5 and MoKin14. Our analyses suggested that MoKin5 and MoKin14 exhibit canonical functions inM. oryzaeduring rice infection. This study addressed long-standing questions in rice blast biology, and our results offer opportunities for future research.
CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition
Authors: Gallo David , Young Jordan T.F. , Fourtounis Jimmy , Martino Giovanni , Álvarez-Quilón Alejandro , Bernier Cynthia , Duffy Nicole M. , Papp Robert , Roulston Anne , Stocco Rino , Szychowski Janek , Veloso Artur , Alam Hunain , Baruah Prasamit S. , Fortin Alexanne Bonneau , Bowlan Julian , Chaudhary Natasha , Desjardins Jessica , Dietrich Evelyne , Fournier Sara , Fugère-Desjardins Chloe , de Rugy Theo Goullet , Leclaire Marie-Eve , Liu Bingcan , Melo Henrique , Nicolas Olivier , Singhania Akul , Szilard Rachel K. , Tkáč Ján , Yin Shou Yun , Morris Stephen J. , Zinda Michael , Gary Marshall C. , Durocher Daniel 
Published: April 2021

AbstractAmplification of the gene encoding cyclin E (CCNE1) is an oncogenic driver in several malignancies and is associated with chemoresistance and poor prognosis. To uncover therapeutic targets forCCNE1-amplified tumors, we undertook genome-scale CRISPR/Cas9-based synthetic lethality screens in cellular models ofCCNE1amplification. Here, we report that increasingCCNE1dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumor regressions when combined with gemcitabine in models ofCCNE1-amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively inCCNE1overexpressing-cells, promoting early mitosis in cells undergoing DNA synthesis.CCNE1overexpression disrupts CDK1 homeostasis at least in part through an early activation of the FOXM1/MYBL2/MuvB-dependent mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy forCCNE1-amplified cancers.
Modulation of endometrial E-Cadherin and N-Cadherin by ovarian steroids and embryonic stimuli
Authors: Tiwari Abhishek , Ashray Nancy , Singh Neha , Sharma Shipra , Modi Deepak 
Published: April 2021

AbstractThe endometrium is a dynamic tissue that undergoes extensive remodelling to attain a receptive state which is further modulated in presence of an embryo for successful initiation of pregnancy. Cadherins are the proteins of junctional complex of which E-cadherin (E-Cad) is crucial for maintaining epithelial cell state and integrity of the epithelial barrier; gain of N-cadherin (N-Cad) in epithelial cells leads to epithelial to mesenchymal transition (EMT). In the present study, we aimed to investigate the expression of E-Cad and N-Cad in the mouse endometrial luminal epithelium and its modulation by estrogen, progesterone and embryonic stimuli. We observed that E-Cad is diffusely expressed in the luminal epithelium of mouse endometrium during the estrus stage and upon estrogen treatment. It is apico-laterally and basolaterally sorted at the diestrus stage and in response to combined treatment of estrogen and progesterone. In 3D spheroids of human endometrial epithelial cells, combined treatment with estrogen and progesterone led to lateral sorting of E-Cad. In the mouse endometrium at the time of embryo implantation, there is loss of E-Cad which was associated with the gain of N-Cad suggestive of EMT in the luminal epithelium. This EMT is possibly driven by embryonic stimuli as treatment with estrogen and progesterone did not lead to gain of N-Cad expression. In conclusion, the present study demonstrates that steroid hormones directly affect E-Cad sorting in the endometrial epithelium.
Label-free tracking and mass measurement of single proteins on lipid bilayers
Authors: Foley Eric D. B. , Kushwah Manish S. , Young Gavin , Kukura Philipp 
Published: April 2021

AbstractWe introduce dynamic mass photometry, a method for label-free imaging, tracking and mass measurement of membrane-associated proteins. Our method enables quantitative studies of their mobility, membrane affinity and interactions at the single molecule level. Application to the membrane remodelling GTPase dynamin1 reveals heterogeneous mixtures of oligomers suggesting that the fundamental building block for oligomerisation is a dimer, challenging current tetramer-centric models. Dynamic mass photometry has the ability to transform our approach to studying biomolecular mechanisms in and on lipid bilayers.
Mass-sensitive particle tracking (MSPT) to elucidate the membrane-associated MinDE reaction cycle
Authors: Heermann Tamara , Steiert Frederik , Ramm Beatrice , Hundt Nikolas , Schwille Petra 
Published: April 2021

AbstractIn spite of their great importance in biology, methods providing access to spontaneous molecular interactions with and on biological membranes have been sparse. So far, it has been consensus that their observation with sufficient sensitivity and time resolution requires the introduction of - predominantly fluorescent-labels to the system. However, the recent advent of mass photometry to quantify mass distributions of unlabelled biomolecules landing on surfaces raised hopes that this approach could be transferred to membranes. Here, we introduce mass-sensitive particle tracking (MSPT), enabling simultaneous label-free tracking and monitoring of molecular masses of single biomolecules diffusing on lipid membranes. We applied this approach to the highly non-linear reaction cycles underlying MinDE protein self-organisation. MSPT allowed us to determine the stoichiometry and turnover of individual membrane-bound MinD/MinDE protein complexes and to quantify their size-dependent diffusion. We found that MinD assembles into complexes larger than the commonly postulated dimer, through lateral interactions of membrane-bound complexes and subunit recruitment from solution. Furthermore, the ATPase-activating protein MinE interconnects MinD into high-molecular-weight heteromeric complexes and affects their subunit turnover and concerted membrane release. This study demonstrates the potential of MSPT to enhance our quantitative understanding of both prokaryotic and eukaryotic membrane-associated biological systems.
Structure-based design of selective salt-inducible kinase (SIK) inhibitors
Authors: Tesch Roberta , Rak Marcel , Raab Monika , Berger Lena M. , Kronenberger Thales , Joerger Andreas C. , Berger Benedict-Tilman , Abdi Ismahan , Hanke Thomas , Poso Antti , Strebhardt Klaus , Sanhaji Mourad , Knapp Stefan 
Published: April 2021

ABSTRACTSalt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.
Snazarus and its human ortholog SNX25 regulate autophagic flux by affecting VAMP8 endocytosis
Authors: Lauzier Annie , Bossanyi Marie-France , Ugrankar Rupali , Mike Henne W. , Jean Steve 
Published: April 2021

AbstractAutophagy, the degradation and recycling of cytosolic components in the lysosome, is an essential cellular mechanism. It is a membrane-mediated process that is linked to vesicular trafficking events. The sorting nexin (SNX) protein family controls the sorting of a large array of cargoes, and various SNXs can impact autophagy. To gain a better understanding of their functionsin vivounder nutrient starvation, we screened allDrosophilaSNXs by RNAi in the fat body. Significantly, depletion ofsnazarus(snz) strongly impacted autolysosome formation and led to decreased autophagic flux. Interestingly, we observed altered distribution of Vamp7-positive vesicles with snz depletion andsnzroles were conserved in human cells.SNX25is the closest ortholog tosnz, and we demonstrate a role for it in VAMP8 trafficking. We found that this activity was dependent on theSNX25PX domain, and independent ofSNX25anchoring at the ER. We also demonstrate that differentially spliced forms ofSNX14andSNX25are present in cancer cells. This work identifies a conserved role forsnz/SNX25as regulators of autophagic flux, and show differential isoform expression between orthologs.
Not a stranger to the dark: discrimination against autistic students and employees
Authors: Lorenz Timo , Brüning Chelsea Rebecca , Waltz Mitzi , Fabri Marc 
Published: April 2021

Purpose
The purpose of this paper is to reveal barriers and their coherences between discrimination and self-perceived employability which students and employees on the autism spectrum often face and need to overcome. These include discrimination based on disability, when applying for a job or retaining employment. This research located barriers in three different categories: formality – problems that focus on organizational structures in the application process; social – communication and interaction problems; and job demand barriers – obstacles that epitomize work-related strains.

Design/methodology/approach
Barriers and discrimination can prevent individuals from accessing the labor market which can lead to severe consequences for an individual on the autism spectrum, such as poverty, social deprivation or lack of health promotion and equal treatment. Self-perceived employability can be regarded as an additional strength, as it describes the perception of an individual’s own skills and versatility to acquire and keep a job. In total, 53 German-speaking individuals on the autism spectrum participated in an online survey.

Findings
Results showed statistically significant coherences between both, formality and social barriers with discrimination. Formality barriers also indicated statistically significant coherences with self-perceived employability. A mediation model with discrimination as mediator between each category of barriers and self-perceived employability was examined. The non-significant results suggest that discrimination does not work as a superior construct but as a sole influence next to barriers and self-perceived employability.

Originality/value
Individuals on the autism spectrum epitomize a less common research approach. Moreover, diversity policies and practices in the workplace often do not focus on including individuals on the autism spectrum even though the employment rates for this specific group of potential highly qualified employees were reported to be consistently lower when compared to any other group of disabled people. Findings suggest possible starting points for future research, which are discussed alongside practical strategies to overcome barriers and change discriminatory attitudes toward skilled individuals on the autism spectrum.
How far are we from understanding corruption? The effect of cultural distance on corruption perception
Authors: Szymanski Mike , Valdovinos Ivan , Kaltenecker Evodio 
Published: April 2021

Purpose
This study aims to examine the relationship between cultural distances between countries and their scores in the Corruption Perception Index (CPI), which is the most commonly used measure of corruption in international business (IB) research.

Design/methodology/approach
The authors applied fixed-effect (generalized least squares) statistical modeling technique to analyze 1,580 year-country observations.

Findings
The authors found that the CPI score is determined to a large extent by cultural distances between countries, specifically the distance to the USA and to Denmark.

Research limitations/implications
CPI is often used as a sole measure of state-level corruption in IB research. The results show that the measure is significantly influenced by cultural differences and hence it should be applied with great caution, preferably augmented with other measures.

Originality/value
To the best of the authors’ knowledge, this is the first study to look at cultural distances as determinants of CPI score. The authors empirically test whether the CPI is culturally biased.