bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural variants at theBRCA1/2loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma
Authors: Ewing Ailith , Meynert Alison , Churchman Michael , Grimes Graeme R. , Hollis Robert L. , Herrington C. Simon , Rye Tzyvia , Bartos Clare , Croy Ian , Ferguson Michelle , Lennie Mairi , McGoldrick Trevor , McPhail Neil , Siddiqui Nadeem , Dowson Suzanne , Glasspool Rosalind , Mackean Melanie , Nussey Fiona , McDade Brian ,   The Scottish Genomes Partnership, McMahon Lynn , Matakidou Athena , Dougherty Brian , March Ruth , Barrett J. Carl , McNeish Iain A. , Biankin Andrew V. , Roxburgh Patricia , Gourley Charlie , Semple Colin A.
Published: May 2020

Around half of high grade serous ovarian carcinomas (HGSOC) show homologous recombination repair deficiency (HRD), often caused by germline or somatic single nucleotide variant (SNV) mutations or small indels disruptingBRCA1/2. We have uniformly processed the largest collection of whole genome sequencing (WGS) data from HGSOC samples to date (N=205), comprehensively characterising the somatic mutational landscape, and expression at theBRCA1/2loci. We discover that large structural variants (SV) are a frequent but unappreciated source ofBRCA1/2disruption in these tumours. Somatic structural variation at these loci is dominated by multi-megabase deletions that span the entirety ofBRCA1(median = 4.9Mb) orBRCA2(median = 6.2Mb), independently affecting a substantial proportion of patients (16%) in addition to those affected by damaging germline or somatic short variants, within theBRCA1/2coding sequences (24%). In common with previous studies, we show that the presence of damaging somatic SNVs or short indels inBRCA1(OR=10, 95% CI 1.8-103, p=0.002, adj p=0.027 andBRCA2(OR=17, 95% CI 2.1-816), p=0.002, adj.p=0.021) was found to influence HRD. For the first time we also study the compound effect of SV and SNV or short indel mutations at both loci, demonstrating that SVs often contribute to compound deficiencies involving SNVs or indels, with large somatic deletions contributing to these compound deficiencies in 15/205 (7%) of samples. Notably the strongest risk of HRD (OR=19 (2.4-896), p=6.6×10-3, adj P=8.5×10-3) is generated by combined large deletions atBRCA1andBRCA2in the absence of SNVs or indels, affecting 3% of patients. Overall, we show that HRD is a complex phenotype in HGSOC tumours, affected by the patterns of shorter variants such as SNVs and indels, SVs, methylation and expression seen at multiple loci, and we construct a successful (ROC AUC = 0.75) predictive model of HRD using such variables. In addition, HRD impacts patient survival when conferred by mechanisms other than through the well-understood short variants atBRCA1/2, currently exploited in the clinic. These results alter our understanding of the mutational landscape at theBRCA1/2loci in highly rearranged tumours, and increase the number of patients predicted to benefit from therapies exploiting HRD in tumours such as PARP inhibition.
Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals
Authors: Ducrot Charles , Bourque Marie-Josée , Delmas Constantin V. L. , Racine Anne-Sophie , Bello Dainelys Guadarrama , Delignat-Lavaud Benoît , Lycas Matthew Domenic , Fallon Aurélie , Michaud-Tardif Charlotte , Nanni Samuel Burke , Herborg Freja , Gether Ulrik , Nanci Antonio , Takahashi Hideto , Parent Martin , Trudeau Louis-Eric
Published: May 2020

Chemical neurotransmission in the brain typically occurs through synapses, which are structurally and functionally defined as sites of close apposition between an axon terminal and a postsynaptic domain. Ultrastructural examinations of axon terminals established by monoamine neurons in the brain often failed to identify a similar tight pre- and postsynaptic coupling, giving rise to the concept of “diffuse” or “volume” transmission. Whether this results from intrinsic properties of such modulatory neurons remains undefined. Using an efficient co-culture model, we find that dopaminergic neurons establish an axonal arbor that is distinctive compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. Furthermore, while most dopaminergic varicosities express key proteins involved in exocytosis such as synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in a subset of dopaminergic terminals that are in proximity to a target cell. Irrespective of their structure, a majority of dopaminergic terminals were found to be active. Finally, we found that the presynaptic protein Nrxn-1αSS4-and the postsynaptic protein NL-1AB, two major components involved in excitatory synapse formation, play a critical role in the formation of synapses by dopamine neurons. Taken together, our findings support the idea that dopamine neurons in the brain are endowed with a distinctive developmental program that leads them to adopt a fundamentally different mode of connectivity, compared to glutamatergic and GABAergic neurons involved in fast point-to-point signaling.

SIGNIFICANCE STATEMENT

Midbrain dopamine (DA) neurons regulate circuits controlling movement, motivation, and learning. The axonal connectivity of DA neurons is intriguing due to its hyperdense nature, with a particularly large number of release sites, most of which not adopting a classical synaptic structure. In this study, we provide new evidence highlighting the unique ability of DA neurons to establish a large and heterogeneous axonal arbor with terminals that, in striking contrast with glutamate and GABA neurons, actively avoid contact with the target cells. The majority of synaptic and non-synaptic terminals express proteins for exocytosis and are active. Finally, our finding suggests that, NL-1A+Band Nrxn-1αSS4-, play a critical role in the formation of synapses by DA neurons.
Arthropod IGF, Relaxin and Gonadulin, putative orthologs ofDrosophilainsulin-like peptides 6, 7 and 8, likely originated from an ancient gene triplication
Authors: Veenstra Jan A.
Published: May 2020

Background

Insects have several genes coding for insulin-like peptides and they have been particularly well studied inDrosophila. Some of these hormones function as growth hormones and are produced by the fat body and the brain. These act through a typical insulin receptor tyrosine kinase. Two otherDrosophilainsulin-like hormones are either known or suspected to act through a G-protein coupled receptor. Although insulin-related peptides are known from other insect species,Drosophilainsulin-like peptide 8, one that uses a G-protein coupled receptor, has so far only been identified fromDrosophilaand other flies. However, its receptor is widespread within arthropods and hence it should have orthologs. Such putative orthologs were recently identified in decapods and have been called gonadulins.

Methodology

In an effort to identify gonadulins in other arthropods public genome assemblies and short-read archives from insects and other arthropods were explored for the presence of genes and transcripts coding insulin-like peptides and their putative receptors.

Results

Gonadulins were detected in a number of arthropods. In those species for which transcriptome data from the gonads is available insect gonadulin genes are expressed in the ovaries and at least in some species also in the testes. In some insects differences in gonadulin expression in the ovary between actively reproducing and non-reproducing females differs more than 100-fold. Putative orthologs ofDrosophilailp 6 were also identified. In several non-Dipteran insects these peptides have C-terminally extensions that are alternatively spliced. The predicted peptides have been called arthropod insulin-like growth factors. In cockroaches, termites and stick insects genes coding for the arthropod insulin-like growth factors, gonadulin and relaxin, a third insulin-like peptide, are encoded by genes that are next to one another suggesting that they are the result of a local gene triplication. Such a close chromosomal association was also found for the arthropod insulin-like growth factor and gonadulin genes in spiders. Phylogenetic tree analysis of the typical insulin receptor tyrosine kinases from insects, decapods and chelicerates shows that the insulin signaling pathway evolved differently in these three groups. The G-protein coupled receptors that are related to theDrosophilailp 8 receptor similarly show significant differences between those groups.

Conclusion

A local gene triplication in an early ancestor likely yielded three genes coding gonadulin, arthropod insulin-like growth factor and relaxin. Orthologs of these genes are now commonly present in arthropods and almost certainly include theDrosophilainsulin-like peptides 6, 7 and 8.
Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse
Authors: Müller-Eigner Annika , Sanz-Moreno Adrián , de-Diego Irene , Venkatasubramani Anuroop Venkateswaran , Langhammer Martina , Gerlini Raffaele , Rathkolb Birgit , Aguilar-Pimentel Antonio , Klein-Rodewald Tanja , Calzada-Wack Julia , Becker Lore , Palma-Vera Sergio , Gille Benedikt , Forne Ignasi , Imhof Axel , Meng Chen , Ludwig Christina , Koch Franziska , Kuhla Angela , Caton Vanessa , Brenmoehl Julia , Schoen Jennifer , Fuchs Helmut , Gailus-Durner Valerie , Hoeflich Andreas , de Angelis Martin Hrabe , Peleg Shahaf
Published: May 2020

Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The outbred mouse line Titan (DU6) results from the world’s longest selection experiment for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study deeper characterized the geno- and phenotypes of this outbred mouse line and tested its suitability as an interventional obesity model. In contrast to previous findings, our data suggests that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice show modifications in the liver transcriptome, proteome and epigenome that are linked to metabolic (dys)regulations. However, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.
Gene expression and chromatin accessibility during progressive EMT and MET linked to dynamic CTCF engagement
Authors: Johnson Kelsey S. , Hussein Shaimaa , Song Shuxuan , Chakraborty Priyanka , Jolly Mohit Kumar , Toneff Michael J. , Lin Yin C. , Taube Joseph H.
Published: May 2020

Background

Epithelial-mesenchymal transition (EMT) facilitates cellular movements critical for proper development; however, in a carcinoma, EMT promotes metastatic dissemination. Stable intermediate states (partial-EMT) are increasingly implicated in metastatic dissemination while reversal of EMT, termed mesenchymal-epithelial transition (MET), is increasingly implicated in metastatic colonization. To understand the partial and reversible nature of EMT, we characterized chromatin accessibility dynamics, transcriptome changes, protein expression patterns, as well as E-cadherin expression, localization, and gene-level dynamics in mammary epithelial cells undergoing stepwise reversible EMT.

Results

While shorter EMT induction induced internalization of E-cadherin protein, surface expression was recovered upon MET without loss of transcript or bulk protein. Conversely, a longer EMT induced stable repression of E-cadherin indicated by loss of chromatin accessibility and induced global expansion of accessible sites across the genome, facilitated by increased engagement of multiple transcription factor families, including AP-1 and SMAD. We observe enrichment for binding sites for the insulator proteins CTCF and BORIS was significantly diminished in both stemness-enriched partial-EMT and partial-MET states and determined that CTCF repression imparts alterations in some histone covalent modifications concomitant with those observed during TGFβ-induced EMT.

Conclusions

These findings are indicative of a major role for chromatin looping and reorganization in plasticity, stemness, and partial EMT phenotypes.
MapA, a second large RTX adhesin, contributes to biofilm formation byPseudomonas fluorescens
Authors: Collins Alan J. , Pastora Alexander B. , Smith T. Jarrod , Dahlstrom Kurt , O’Toole George A.
Published: May 2020

Mechanisms by which cells attach to a surface and form a biofilm are diverse and differ greatly between organisms. The Gram-negative, GammaproteobacteriumPseudomonasfluorescens attaches to a surface through the localization of the large type 1-secreted RTX adhesin LapA to the outer surface of the cell. LapA localization to the cell surface is controlled by the activities of a periplasmic protease, LapG and an inner-membrane spanning cyclic di-GMP responsive effector protein, LapD. A previous study identified a second, LapA-like protein encoded in theP. fluorescensPf0-1 genome: Pfl01_1463. However, deletion of this gene had no discernible phenotype under our standard laboratory growth conditions. Here, we identified specific growth conditions wherein, Pfl01_1463, hereafter called MapA (MediumAdhesionProtein A) is a functional adhesin contributing to biofilm formation. This adhesin, like LapA, appears to be secreted through a Lap-related type 1 secretion machinery. We show MapA involvement in biofilm formation is also controlled by LapD and LapG, and that the differing roles of LapA and MapA in biofilm formation are achieved, at least in part, through the differences in the sequences of the two adhesins and their differential, cyclic di-GMP-dependent transcriptional regulation. This differential regulation appears to lead to different distributions of the expression oflapAandmapAwithin a biofilm. Our data indicate that the mechanisms by which a cell forms a biofilm and the components of a biofilm matrix can differ depending on growth conditions in the biofilm.

Importance

Adhesins are critical for the formation and maturation of bacterial biofilms. We identify a second adhesin inP. fluorescens, called MapA, which appears to play a role in biofilm maturation and whose regulation is distinct from the previously reported LapA adhesin, which is critical for biofilm initiation. Analysis of bacterial adhesins show that LapA-like and MapA-like adhesins are found broadly in Pseudomonads and related organisms, indicating that the utilization of different suites of adhesins may be broadly important in the Gammaproteobacteria.
Evaluation of the EUROIMMUN Anti-SARS-CoV-2 ELISA Assay for detection of IgA and IgG antibodies
Authors: Matushek Scott M. , Beavis Kathleen G. , Abeleda Ana , Bethel Cindy , Hunt Carlissa , Gillen Stephanie , Moran Angelica , Tesic Vera
Published: May 2020

As the Coronavirus 2019 (COVID-19) pandemic evolves, the development of immunoassays to help determine exposure and potentially predict immunity has become a pressing priority. In this report we present the performance of the EUROIMMUN enzyme-linked immunosorbent assay (ELISA) for semi-quantitative detection of IgA and IgG antibodies in serum and plasma samples using recombinant S1 domain of the SARS-CoV-2 spike protein as antigen. Specimens from patients, with and without COVID-19 infection, were tested at the University of Chicago Clinical Microbiology and Immunology Laboratory. Of 57 samples from COVID-19 PCR-negative patients, including 28 samples positive for common human coronavirus strains, 53 tested negative and 4 tested positive for IgA (93.0% agreement) while 56 tested negative and 1 tested positive for IgG (98.2% agreement). For COVID-19 PCR-positive patients, 29 of 30 (96.7%) samples collected ≥3 days after positive PCR were positive for IgA, and 28 of 28 samples collected ≥4 days after positive PCR were positive for IgG.

The EUROIMMUN Anti-SARS-CoV-2 ELISA Assay demonstrates excellent sensitivity for detection of IgA and IgG antibodies from samples collected ≥3 days and ≥4 days, respectively, after COVID-19 diagnosis by PCR. This assay did not demonstrate cross reaction in any of the 28 samples from patients with common human coronaviruses, including types HKU1, NL63, CV229E, and OC43.
A Darwinian Selection Based Explanation of Peacock’s Tail
Authors: Wadhwa Dinkar
Published: May 2020

There is no satisfactory explanation for why peacock possesses a tail, presence and especially courtship display of which makes the organism vulnerable to predation. Here, I present a model according to which in a polygynous mating system a mechanism which increases vulnerability to predation, a Zahavian handicap, evolves when other two mechanisms to identify high-quality males are either absent or are not sufficiently strong. The two mechanisms are: 1) male resource acquisition ability, and 2) male-male competition for females. The three mechanisms are not necessarily mutually exclusive. Assuming the locus for the tail and choosiness to be sex-specific, it is shown through stochastic simulation that sexual selection, mediated by the tail (a Zahavian handicap), leads to higher rate of increase in the quality of the population of tailed peacocks and tailed-choosy peahens (which exclusively mate with tailed peacocks) as compared to the population of tailless peacocks and tailless-choosy peahens (which exclusively mate with tailless peacocks), through a positive feedback, as daughters of tailed-choosy peahens are of higher average quality and, by virtue of not carrying the tail’s handicap, also fitness than daughters of tailless-choosy peahens. Also, the fold-change in the population of tailed peacocks and tailless-choosy peahens are higher than the fold-change in the population of tailless peacocks and tailless-choosy peahens, for all combinations of the initial conditions. The same results were got, though in milder form, when tailless-choosy peahens were replaced by undiscriminating peahens (which mate with tailless and tailed peacocks in proportion to their frequencies in the population). Although sons of tailed-choosy peahens have lower average fitness than sons of undiscriminating peahens, this difference is inconsequential, because in a polygynous mating system a single male can potentially mate with every female. The work presented here reconciles Zahavi’s handicap principle with Darwin’s theories of natural and sexual selection. Further, it is hypothesized that a genotype responsible for producing in males a reliable indicator of high quality (a Zahavian handicap) or paternal care ability generates mating desirability in females towards males possessing the indicator. It is demonstrated through simulation that this cross-gender pleiotropy expedites the evolution of tailed peacocks and tailed-choosy peahens and leads to higher rate of increase in their quality.
Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability
Authors: Brouwer Philip J.M. , Caniels Tom G. , van der Straten Karlijn , Snitselaar Jonne L. , Aldon Yoann , Bangaru Sandhya , Torres Jonathan L. , Okba Nisreen M.A. , Claireaux Mathieu , Kerster Gius , Bentlage Arthur E.H. , van Haaren Marlies M. , Guerra Denise , Burger Judith A. , Schermer Edith E. , Verheul Kirsten D. , van der Velde Niels , van der Kooi Alex , van Schooten Jelle , van Breemen Mariëlle J. , Bijl Tom P. L. , Sliepen Kwinten , Aartse Aafke , Derking Ronald , Bontjer Ilja , Kootstra Neeltje A. , Wiersinga W. Joost , Vidarsson Gestur , Haagmans Bart L. , Ward Andrew B. , de Bree Godelieve J. , Sanders Rogier W. , van Gils Marit J.
Published: May 2020

The rapid spread of SARS-CoV-2 has a significant impact on global health, travel and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated neutralizing antibodies from convalescent COVID-19 patients using a SARS-CoV-2 stabilized prefusion spike protein. Several of these antibodies were able to potently inhibit live SARS-CoV-2 infection at concentrations as low as 0.007 µg/mL, making them the most potent human SARS-CoV-2 antibodies described to date. Mapping studies revealed that the SARS-CoV-2 spike protein contained multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as previously undefined non-RBD epitopes. In addition to providing guidance for vaccine design, these mAbs are promising candidates for treatment and prevention of COVID-19.
Visualizing the dynamics of exported bacterial proteins with the chemogenetic fluorescent reporter FAST
Authors: Chekli Yankel , Peron-Cane Caroline , Dell’Arciprete Dario , Allemand Jean-François , Li Chenge , Ghigo Jean-Marc , Gautier Arnaud , Lebreton Alice , Desprat Nicolas , Beloin Christophe
Published: May 2020

Bacterial proteins exported to the cell surface play key cellular functions. However, despite the interest to study the localization of surface proteins such as adhesins, transporters or hydrolases, monitoring their dynamics in live imaging remains challenging, due to the limited availability of fluorescent probes remaining functional after secretion. In this work, we used theEscherichia coliintimin and theListeria monocytogenesInlB invasin as surface exposed scaffolds fused with the recently developed chemogenetic fluorescent reporter protein FAST. Using both membrane permeant (HBR-3,5DM) and non-permeant (HBRAA-3E) fluorogens that fluoresce upon binding to FAST, we demonstrated that fully functional FAST can be exposed at the cell surface and specifically tagged on the external side of the bacterial envelop in both diderm and monoderm bacteria. Our work opens new avenues to study of the organization and dynamics of the bacterial cell surface proteins.
Population genomic molecular epidemiological study of macrolide resistantStreptococcus pyogenesin Iceland, 1995-2016: Identification of a large clonal population with apbp2xmutation conferring reducedin vitroβ-lactam susceptibility
Authors: Southon Sara B. , Beres Stephen B. , Kachroo Priyanka , Saavedra Matthew Ojeda , Erlendsdóttir Helga , Haraldsson Gunnsteinn , Yerramilli Prasanti , Pruitt Layne , Zhu Luchang , Musser James M. , Kristinsson Karl G.
Published: May 2020

Resistance to macrolide antibiotics is a global concern in the treatment ofStreptococcus pyogenes(Group A Streptococcus, GAS) infections. In Iceland, since the detection of the first macrolide-resistant isolate in 1998, three epidemic waves of macrolide-resistant GAS infections have occurred with peaks in 1999, 2004, and 2008. We conducted whole genome sequencing of all 1,575 available GAS macrolide-resistant clinical isolates of all infection types collected at the national reference laboratory in Reykjavik from 1998 to 2016. Among 1,515 erythromycin-resistant isolates, 90.3% were of only threeemmtypes:emm4(n= 713),emm6(n= 324), andemm12(n= 332), with each being predominant in a distinct epidemic peak. The antibiotic efflux pump genes,mef(A) andmsr(D), were present on chimeric mobile genetic elements in 99.3% of the macrolide-resistant isolates of theseemmtypes. Of note, in addition to macrolide resistance, virtually allemm12isolates had a single amino acid substitution in penicillin-binding protein PBP2X that conferred a two-fold increased penicillin G and ampicillin MIC among isolates tested. We conclude that each of the three large epidemic peaks of macrolide-resistant GAS infections occurring in Iceland since 1998 was caused by the emergence and clonal expansion of progenitor strains, with macrolide resistance being conferred predominantly by inducible Mef(A)-Msr(D) drug efflux pumps. The occurrence ofemm12strains with macrolide resistance and decreased beta-lactam susceptibility was unexpected and is of public health concern.

Repositories

Genomic sequencing data for all 1,515 macrolide/erythromycin-resistant isolates were deposited into the National Center for Biotechnology Information Sequence Read Archive under bioproject accession PRJNA614628 and assembled sequences for composite elements Φ29854, Φ29862 and Φ29661 were deposited in Genbank under accessions ###, ### and ### respectively.
Inhibition of TRPV1 and TRPA1 by mosquito and mouse saliva
Authors: Li Tianbang , Derouiche Sandra , Sakai Yuya , Uta Daisuke , Aoyagi Seiji , Tominaga Makoto
Published: May 2020

Arthropods are the largest group of living organisms and among them, mosquitoes spread parasites and viruses causing deathly diseases. Mosquito’s painless piercing is due to the thinness of their fascicle, but mosquito saliva might also contribute to it. We found that mosquito and mouse saliva inhibit TRPV1 and TRPA1 channels, either heterologously expressed in HEK293T cells or endogenously expressed in native mouse sensory neurons. We have also identified sialorphin as a candidate antinociceptive peptide as it showed similar effects on TRPV1 and TRPA1. Finally, we confirmed the antinociceptive effects of saliva and sialorphinin vivoby observing decreased pain-related behaviors in mice coinjected with these substances. Similar inhibitory effects of mosquito and mouse saliva suggest that the antinociceptive effects of saliva are universal, which could explain why many animals including humans often lick their wounds. These findings would lead to the development of novel anti-nociceptive agents.
Phenoxyalkylimidazoles with an oxadiazole moiety are subject to efflux inMycobacterium tuberculosis
Authors: Thayer Mai B. , Parish Tanya
Published: May 2020

The phenoxyalkylimidazoles (PAI) are an attractive chemical series with potent anti-tubercular activity targetingMycobacterium tuberculosisrespiration. We determined if PAI compounds are subject to efflux. Two analogs containing an oxadiazole had improved potency in the presence of the efflux inhibitors reserpine and carbonyl cyanide m-chlorophenylhydrazine, whereas the potency of an analog with a diazole was not affected. Verapamil was unable to boost compound potency.
Characterization of neutralizing antibodies from a SARS-CoV-2 infected individual
Authors: Seydoux Emilie , Homad Leah J. , MacCamy Anna J. , Parks K. Rachael , Hurlburt Nicholas K. , Jennewein Madeleine F. , Akins Nicholas R. , Stuart Andrew B. , Wan Yu-Hsin , Feng Junli , Nelson Rachael E. , Singh Suruchi , Cohen Kristen W. , McElrath M. Juliana , Englund Janet A. , Chu Helen Y. , Pancera Marie , McGuire Andrew T. , Stamatatos Leonidas
Published: May 2020

B cells specific for the SARS-CoV-2 S envelope glycoprotein spike were isolated from a COVID-19-infected subject using a stabilized spike-derived ectodomain (S2P) twenty-one days post-infection. Forty-four S2P-specific monoclonal antibodies were generated, three of which bound to the receptor binding domain (RBD). The antibodies were minimally mutated from germline and were derived from different B cell lineages. Only two antibodies displayed neutralizing activity against SARS-CoV-2 pseudo-virus. The most potent antibody bound the RBD in a manner that prevented binding to the ACE2 receptor, while the other bound outside the RBD. Our study indicates that the majority of antibodies against the viral envelope spike that were generated during the first weeks of COVID-19 infection are non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 spike-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive/therapeutic potential and can serve as templates for vaccine-design.

IN BRIEF

SARS-CoV-2 infection leads to expansion of diverse B cells clones against the viral spike glycoprotein (S). The antibodies bind S with high affinity despite being minimally mutated. Thus, the development of neutralizing antibody responses by vaccination will require the activation of certain naïve B cells without requiring extensive somatic mutation.

Highlights

Analysis of early B cell response to SARS-CoV-2 spike protein

Most antibodies target non-neutralizing epitopes

Potent neutralizing mAb blocks the interaction of the S protein with ACE2

Neutralizing antibodies are minimally mutated
Single-molecule 3D orientation imaging reveals nanoscale compositional heterogeneity in lipid membranes
Authors: Lu Jin , Mazidi Hesam , Ding Tianben , Zhang Oumeng , Lew Matthew D.
Published: May 2020

In soft matter, thermal energy causes molecules to continuously translate and rotate, even in crowded environments, impacting the spatial organization and function of most molecular assemblies, such as lipid membranes. Directly measuring the orientation and spatial organization of large collections (>3000 molecules/μm2) of single molecules with nanoscale resolution remains elusive. We present SMOLM, single-molecule orientation localization microscopy, to directly measure the orientation spectra (3D orientation plus “wobble”) of lipophilic probes transiently bound to lipid membranes, revealing that Nile red’s (NR) orientation spectra are extremely sensitive to membrane chemical composition. SMOLM images resolve nanodomains and enzyme-induced compositional heterogeneity within membranes, where NR within liquid-ordered vs. liquid-disordered domains shows a ~4° difference in polar angle and a ~0.3π sr difference in wobble angle. As a new type of imaging spectroscopy, SMOLM exposes the organizational and functional dynamics of lipid-lipid, lipid-protein, and lipid-dye interactions with single-molecule, nanoscale resolution.
The effect of inclusion criteria on the functional properties reported in mouse visual cortex
Authors: Mesa Natalia , Waters Jack , de Vries Saskia E. J.
Published: May 2020

Neurophysiology studies require the use of inclusion criteria to identify neurons responsive to the experimental stimuli. Five recent studies used calcium imaging to measure the preferred tuning properties of layer 2/3 pyramidal neurons in mouse visual areas. These five studies employed different inclusion criteria and report different, sometimes conflicting results. Here, we examine how different inclusion criteria can impact reported tuning properties, modifying inclusion criteria to select different sub-populations from the same dataset of almost 10,000 layer 2/3 neurons from the Allen Brain Observatory. The choice of inclusion criteria greatly affected the mean tuning properties of the resulting sub-populations; indeed, the differences in mean tuning due to inclusion criteria were often of comparable magnitude to the differences between studies. In particular, the mean preferred temporal frequencies of visual areas changed markedly with inclusion criteria, such that the rank ordering of visual areas based on their temporal frequency preferences changed with the percentage of neurons included. It has been suggested that differences in temporal frequency tuning support a hierarchy of mouse visual areas. These results demonstrate that our understanding of the functional organization of the mouse visual cortex obtained from previous experiments critically depends on the inclusion criteria used.
Super Resolution Microscopy and Deep Learning Identify Zika Virus Reorganization of the Endoplasmic Reticulum
Authors: Long Rory K. M. , Moriarty Kathleen P. , Cardoen Ben , Gao Guang , Vogl A. Wayne , Jean François , Hamarneh Ghassan , Nabi Ivan R.
Published: May 2020

The endoplasmic reticulum (ER) is a complex subcellular organelle composed of diverse structures such as tubules, sheets and tubular matrices. Flaviviruses such as Zika virus (ZIKV) induce reorganization of endoplasmic reticulum (ER) membranes to facilitate viral replication. Here, using 3D super resolution microscopy, ZIKV infection is shown to induce the formation of dense tubular matrices associated with viral replication in the central ER. Viral non-structural proteins NS4B and NS2B associate with replication complexes within the ZIKV-induced tubular matrix and exhibit distinct ER distributions outside this central ER region. Deep neural networks trained to identify ZIKV-infected versus mock-infected cells successfully identified ZIKV-induced central ER tubular matrices as a determinant of viral infection. Super resolution microscopy and deep learning are therefore able to identify and localize morphological features of the ER and may be of use to screen for inhibitors of infection by ER-reorganizing viruses.
Planning phase-2 for the endoscopic units in Northern Italy after COVID-19 lockdown: an exit strategy with a lot of critical issues and a few opportunities.
Authors: Manes Gianpiero , Repici alessandro , Radaelli Franco , Saibeni Simone , Bezzio Cristina , Colombo Matteo , Pace Fabio
Published: May 2020

Background and aims: Restarting activity in Endoscopic Departments (ED) after COVID-19 lockdown raises critical issues. This survey investigates strategies and uncertainties on resumption of elective activity.
Methods: Directors of 55 EDs in Northern Italy received a questionnaire focusing on the impact of pandemic on activity and organization and on the resources available at re-opening. A section was devoted to gather forecasts and proposals on the return path to normality.
Results: All centres had reduced their activities of at least 50% of the pre-COVID-19 period. A rate of endoscopists (13.6%), nurses (25.2%), and health assistants (14%) were not available since infected, or relocated to other departments. One third of endoscopic rooms were converted to COVID-19 care. Two third had the waiting or the recovery areas too small for distancing. A dedicated pathway for infected patients could not be guaranteed in 20% of EDs. Only one third of EDs judged realistic to completely restore a pre-crisis workload by the next months. Optimizing appropriateness of procedures, closer interaction with GPs and triaging patients with telemedicine were the proposals to re-open EDs.
Conclusions: The critical issues while re-opening EDs calls for reducing the workload in the endoscopy units through appropriate rescheduling of procedures.
Exact and fast calculation of the X-ray pair distribution function
Authors: Neder Reinhard B. , Proffen Thomas
Published: May 2020

A fast and exact algorithm to calculate the powder pair distribution function (PDF) for the case of periodic structures is presented. The new algorithm calculates the PDF by a detour via reciprocal space. The calculated normalized total powder diffraction pattern is transferred into the PDF via the sine Fourier transform. The calculation of the PDF via the powder pattern avoids the conventional simplification of X-ray and electron atomic form factors. It is thus exact for these types of radiation, as is the conventional calculation for the case of neutron diffraction. The new algorithm further improves the calculation speed. Additional advantages are the improved detection of errors in the primary data, the handling of preferred orientation, the ease of treatment of magnetic scattering and a large improvement to accommodate more complex instrumental resolution functions.
A novel experimental approach for nanostructure analysis: simultaneous small-angle X-ray and neutron scattering
Authors: Metwalli Ezzeldin , Götz Klaus , Lages Sebastian , Bär Christian , Zech Tobias , Noll Dennis M. , Schuldes Isabel , Schindler Torben , Prihoda Annemarie , Lang Herbert , Grasser Jürgen , Jacques Mark , Didier Luc , Cyril Amrouni , Martel Anne , Porcar Lionel , Unruh Tobias
Published: May 2020

Exploiting small-angle X-ray and neutron scattering (SAXS/SANS) on the same sample volume at the same time provides complementary nanoscale structural information in two different contrast situations. Unlike an independent experimental approach, the truly combined SAXS/SANS experimental approach ensures the exactness of the probed samples, particularly forin situstudies. Here, an advanced portable SAXS system that is dimensionally suitable for installation in the D22 zone of ILL is introduced. The SAXS apparatus is based on a Rigaku switchable copper/molybdenum microfocus rotating-anode X-ray generator and a DECTRIS detector with a changeable sample-to-detector distance of up to 1.6 m in a vacuum chamber. A case study is presented to demonstrate the uniqueness of the newly established method. Temporal structural rearrangements of both the organic stabilizing agent and organically capped gold colloidal particles during gold nanoparticle growth are simultaneously probed, enabling the immediate acquisition of correlated structural information. The new nano-analytical method will open the way for real-time investigations of a wide range of innovative nanomaterials and will enable comprehensivein situstudies on biological systems. The potential development of a fully automated SAXS/SANS system with a common control environment and additional sample environments, permitting a continual and efficient operation of the system by ILL users, is also introduced.
Two ZnII-based MOFs constructed with biphenyl-2,2′,5,5′-tetracarboxylic acid and flexible N-donor ligands: syntheses, structures and properties
Authors: Su Feng , Yu Jinyang , Zhou Chengyong , Li Shaodong , Ma Pengyi , Zhang Xuhui , Wang Zhijun
Published: May 2020

Two new Zn2+-based metal–organic frameworks (MOFs) based on biphenyl-2,2′,5,5′-tetracarboxylic acid, i.e. H4(o,m-bpta), and N-donor ligands, namely, poly[[(μ4-biphenyl-2,2′,5,5′-tetracarboxylato)bis{[1,3-phenylenebis(methylene)]bis(1H-imidazole)}dizinc(II)] dimethylformamide monosolvate dihydrate], {[Zn2(C16H6O8)(C14H14N4)2]·C3H7NO·2H2O}
n
or {[Zn2(o,m-bpta)(1,3-bimb)2]·C3H7NO·2H2O}
n
(1) {1,3-bimb = [1,3-phenylenebis(methylene)]bis(1H-imidazole)}, and poly[[(μ4-biphenyl-2,2′,5,5′-tetracarboxylato)bis{[1,4-phenylenebis(methylene)]bis(1H-imidazole)}dizinc(II)] monohydrate], {[Zn2(C16H6O8)(C14H14N4)2]·H2O}
n
or {[Zn2(o,m-bpta)(1,4-bimb)2]·H2O}
n
(2) {1,4-bimb = [1,4-phenylenebis(methylene)]bis(1H-imidazole)}, have been synthesized under solvothermal conditions. The complexes were characterized by IR spectroscopy, elemental analysis, single-crystal X-ray diffraction and powder X-ray diffraction analysis. Structurally, the (o,m-bpta)4− ligands are fully deprotonated and combine with Zn2+ ions in μ4-coordination modes. Complex 1 is a (3,4)-connected porous network with honeycomb-like [Zn2(o,m-bpta)]
n
sheets formed by 4-connected (o,m-bpta)4− ligands. Complex 2 exhibits a (2,4)-connected network formed by 4-connected (o,m-bpta)4− ligands linking Zn2+ ions in left-handed helical chains. The cis-configured 1,3-bimb and 1,4-bimb ligands bridge Zn2+ ions to form multi-membered [Zn2(bimb)2] loops. Optically, the complexes show strong fluorescence and display larger red shifts compared to free H4(o,m-bpta). Complex 2 shows ferroelectric properties due to crystallizing in the C
2v
polar point group.
Crystal structure and photoreactivity of a halogen-bonded cocrystal based upon 1,2-diiodoperchlorobenzene and 1,2-bis(pyridin-4-yl)ethylene
Authors: Bosch Eric , Battle Jessica D. , Groeneman Ryan H.
Published: May 2020

The formation of a photoreactive cocrystal based upon 1,2-diiodoperchlorobenzene (1,2-C6I2Cl4
) and trans-1,2-bis(pyridin-4-yl)ethylene (BPE) has been achieved. The resulting cocrystal, 2(1,2-C6I2Cl4
)·(BPE) or C6Cl4I2·0.5C12H10N2, comprises planar sheets of the components held together by the combination of I...N halogen bonds and halogen–halogen contacts. Notably, the 1,2-C6I2Cl4
molecules π-stack in a homogeneous and face-to-face orientation that results in an infinite column of the halogen-bond donor. As a consequence of this stacking arrangement and I...N halogen bonds, molecules of BPE also stack in this type of pattern. In particular, neighbouring ethylene groups in BPE are found to be parallel and within the accepted distance for a photoreaction. Upon exposure to ultraviolet light, the cocrystal undergoes a solid-state [2 + 2] cycloaddition reaction that produces rctt-tetrakis(pyridin-4-yl)cyclobutane (TPCB) with an overall yield of 89%. A solvent-free approach utilizing dry vortex grinding of the components also resulted in a photoreactive material with a similar yield.
Feasibility study for the analysis of coconut water using fluorescence spectroscopy coupled with PARAFAC and SVM methods
Authors: Gu Haiyang , Liu Kaiqi , Huang Xingyi , Chen Quansheng , Sun Yanhui , Tan Chin Ping
Published: May 2020

Purpose

Parallel factor analysis (PARAFAC) coupled with support-vector machine (SVM) was carried out to identify and discriminate between the fluorescence spectroscopies of coconut water brands.

Design/methodology/approach

PARAFAC was applied to reduce three-dimensional data of excitation emission matrix (EEM) to two-dimensional data. SVM was applied to discriminate between six commercial coconut water brands in this study. The three largest variation data from fluorescence spectroscopy were extracted using the PARAFAC method as the input data of SVM classifiers.

Findings

The discrimination results of the six commercial coconut water brands were achieved by three SVM methods (Ga-SVM, PSO-SVM and Grid-SVM). The best classification accuracies were 100.00%, 96.43% and 94.64% for the training set, test set and CV accuracy.

Originality/value

The above results indicate that fluorescence spectroscopy combined with PARAFAC and SVM methods proved to be a simple and rapid detection method for coconut water and perhaps other beverages.
A comment on the multifaceted relationship between multinational enterprises and within-country inequality
Authors: Narula Rajneesh , van der Straaten Khadija
Published: May 2020

Purpose

Whether by direct or indirect action (or by inaction), multinational enterprises (MNEs) can have both a positive and a negative effect on within-country social and economic inequality. This paper aims to comment on this multifaceted relationship between MNEs and within-country inequality.

Design/methodology/approach

Given the absence of either robust theory or evidence in the neglected realm of MNEs and within-countries inequalities, this paper offers some general observations, highlights some of the key issues and illustrates possible avenues for future research studies.

Findings

The capacity of MNEs to upgrade economic activity in the host country is a key policy objective. MNEs have arguably contributed to reducing income inequalities between countries. However, the limited evidence available suggests that the gains of FDI are rarely evenly distributed within recipient countries, and many of the underlying dynamics need further investigation.

Social implications

The authors broaden the engagement with inequality beyond income levels, as this is just one aspect of inequality that shapes or impedes human development. They believe it is necessary – for both MNEs and policymakers – to have a more nuanced understanding of how, and under what circumstances, the presence of MNEs affects inequality in host economies.

Originality/value

This paper relates the large literature on inequality (going beyond the mainstream focus on income inequality) to the mainstream understanding of MNE-assisted development.
Top-down reconstruction and the failure to “build back better” resilient communities after disaster: lessons from the 2009 L'Aquila Italy earthquake
Authors: Imperiale Angelo Jonas , Vanclay Frank
Published: May 2020

Purpose

We consider what happened in the initial reconstruction interventions following the 6 April 2009 earthquake in L'Aquila (Italy). Using the disaster risk reduction and resilience paradigm, we discuss the cognitive and interactional failures of top-down approaches, and we analyse the main constraints to enacting inclusive social learning and socially-sustainable transformation and building back better more resilient communities in post-disaster reconstruction.

Design/methodology/approach

Our evidence comes from participant observation, action anthropology and analytic auto-ethnography conducted during the reconstruction phase following the L'Aquila earthquake. Findings were triangulated with document analysis, media analysis and retrospective interviewing conducted in 2013 and 2017.

Findings

The shift from civil defence to civil protection did not bring any advance in disaster management and development practice in terms of DRR and resilience. The militaristic command-and-control approach, which is still in vogue among civil protection systems, means that local political leaders become the civil protection authorities in a disaster area. As in the L'Aquila case, this exacerbates local social and environmental risks and impacts, inhibits local communities from learning and restricts them from participating in post-disaster interventions.

Originality/value

Most previous commentary on disaster recovery and reconstruction following the L'Aquila earthquake has focussed on the top-down approach carried out by the national government and the Italian Department of Civil Protection (DCP). This paper is unique in that it sheds light on how the command-and-control approach was also implemented by local authority figures and on how this undermined building back better more resilient communities.
CNN-based minor fabric defects detection
Authors: Wen Zhijie , Zhao Qikun , Tong Lining
Published: May 2020

Purpose

The purpose of this paper is to present a novel method for minor fabric defects detection.

Design/methodology/approach

This paper proposes a PETM-CNN algorithm. PETM-CNN is designed based on self-similar estimation algorithm and Convolutional Neural Network. The PE (Patches Extractor) algorithm extracts patches that are possible to be defective patches to preprocess the fabric image. Then a TM-CNN (Triplet Metric CNN) method is designed to predict labels of the patches and the final label of the image. The TM-CNN can perform better than normal CNN.

Findings

This algorithm is superior to other algorithms on the data set of fabric images with minor defects. The proposed method achieves accurate classification of fabric images whether it has minor defects or not. The experimental results show that the approach is effective.

Originality/value

Traditional fabric defects detection is not effective as minor defects detection, so this paper develops a method of minor fabric images classification based on self-similar estimation and CNN. This paper offers the first investigation of minor fabric defects.
Conventional futures: derivatives in Islamic law of contract
Authors: Uddin Md Akther , Ahmad Abu Umar Faruq
Published: May 2020

Purpose

This paper aims to compare and contrast the concept of conventional futures contract from the Islamic law of contract perspectives. The underlying theory and practice of Islamic finance is based on the principles of Islamic law of contract. Although the necessity of derivative instruments such as the case with futures contract is essential for developments in Islamic finance, the permissibility of using these instruments still remains a debatable issue.

Design/methodology/approach

The paper discusses arguments for and against using derivative instruments as in futures, for example, in light with the Qur’an and Sunnah (the Prophet’s traditions), as well as the views of classical scholars, jurists and contemporary researchers. Arguments for and against are analysed systematically to derive a logical conclusion.

Findings

The study finds that majority scholars consider futures contracts as non-compliant with the Islamic law due to the fact that selling something that does not exist, deferment in the both counter values, gharar or ambiguity and excessive risk taking, pure speculation and sale of one debt for another.

Research limitations/implications

The study focuses narrowly on conventional futures contract. Analysing other financial derivative contracts could be a future research endeavour.

Practical implications

The study has so far found the verdict of impermissibility of conventional futures contract in its current form as has been argued by majority scholars in the premise that they do not comply with the Islamic law. Policymakers and industry practitioners need to take this opinion of majority scholars while developing new Islamic financial derivatives.

Originality/value

To the best of the author's knowledge, the present research is the first attempt so far that explained the validity of conventional futures by analysing arguments of classical and contemporary jurists, scholars and researchers.