bluuebunny/crossref_metadata_2025 huggingface dataset:
Apparent reductions in COVID-19 Case Fatality Rates reflect changes in average age of those testing positive
Authors: Grant Alastair
Published: September 2020

Numbers of COVID-19 infections are rising in many countries, while death and hospitalisation rates remain low. Infection Fatality Rates (IFR) for individual year classes calculated from seroprevalence data and the ages of those dying in England show a very strong log-linear relationship with age, and allow us to predict fatality rates for those testing positive on each day based on their ages. Since the peak of the epidemic, reductions in the ages of cases account for an eight fold fall in fatality rates. Over the same period, increased testing intensity appears to have increased infections detected amongst the most vulnerable by a factor of at least five, and between 15 and 24 fold in the population as a whole. Together these two factors are sufficient to explain the large observed change in the ratio of deaths to reported cases. We can also use these methods to give a more precise early warning system of future increases in mortality rates than raw case numbers. Although case numbers are currently increasing markedly, a continuing reduction in numbers of older individuals being infected means that the predicted increase in mortality rates is much slower.
COPD in the time of COVID-19: An analysis of acute exacerbations and reported behavioural changes in patients with COPD
Authors: McAuley Hamish , Hadley Kate , Elneima Omer , Brightling Christopher E , Evans Rachael A , Steiner Michael C , Greening Neil J
Published: September 2020

Introduction

The impact of the SARS-CoV-2 pandemic, and lockdown measures, on acute exacerbations of COPD (AECOPD) is unknown. We aimed to evaluate the change in AECOPD treatment frequency during the first six weeks of lockdown in the UK compared with 2019 and assess changes in self-reported behaviour and well-being.

Methods

In this observational study patients with established COPD were recruited. Exacerbation frequency was measured in the first six weeks of COVID lockdown and compared with the same period in 2019 using electronic health records. A telephone survey was used to assess changes in anxiety, inhaler adherence, physical activity, shopping and visitor behaviour during the pre-lockdown and lockdown periods compared to normal.

Results

160 participants were recruited (mean [SD] age 67.3 [8.1] years, 88 [55%] male, FEV1 34.3 [13] % predicted) and 140 [88%] reported at least one AECOPD in the previous year. Significantly more community treated exacerbations were observed in 2020 compared with 2019 (126 vs 99, p=0.026). The increase was as a result of multiple courses of treatment, with a similar proportion of patients receiving at least one course (34.4% vs 33.8%).

During “lockdown” participants reported significantly increased anxiety, adherence to their preventative inhalers, and good adherence to shielding advice (all p<0.001). A significant reduction in self-reported physical activity and visitors was reported (both p<0.001).

Discussion

Treatment for AECOPD events increased during the first six weeks of the SARS-CoV-2 pandemic in the UK compared to 2019. This was associated with increased symptoms of anxiety and significant behavioural change.

What is the key question?

How has the COVID-19 pandemic lockdown affected exacerbation patterns and behaviour in patients with COPD?

What is the bottom line?

A 38% increase in the number of community treated exacerbations was seen in 2020 compared with 2019. Increased symptoms of anxiety were seen in patients, alongside increased inhaler adherence and reduced physical activity.

Why read on?

The impact of the COVID-19 pandemic has led to significant changes in treatment for exacerbations of COPD in the community, as well as increased anxiety amongst patients.
On the relationship between serial interval, infectiousness profile and generation time
Authors: Lehtinen Sonja , Ashcroft Peter , Bonhoeffer Sebastian
Published: September 2020

The timing of transmission plays a key role in the dynamics and controllability of an epidemic. However, observing the distribution of generation times (time interval between the points of infection of an infector and infectee in a transmission pair) requires data on infection times, which are generally unknown. The timing of symptom onset is more easily observed; the generation time distribution is therefore often estimated based on the serial interval distribution (distribution of time intervals between symptom onset of an infector and an infectee). This estimation follows one of two approaches: i) approximating the generation time distribution by the serial interval distribution; or ii) deriving the generation time distribution from the serial interval and incubation period (time interval between infection and symptom onset in a single individual) distributions. These two approaches make different – and not always explicitly stated – assumptions about the relationship between infectiousness and symptoms, resulting in different generation time distributions with the same mean but unequal variances. Here, we clarify the assumptions that each approach makes and show that neither set of assumptions is plausible for most pathogens. However, the variances of the generation time distribution derived under each assumption can reasonably be considered as upper (approximation with serial interval) and lower (derivation from serial interval) bounds. Thus, we suggest a pragmatic solution is to use both approaches and treat these as edge cases in downstream analysis. We discuss the impact of the variance of the generation time distribution on the controllability of an epidemic through strategies based on contact tracing, and we show that underestimating this variance is likely to overestimate controllability.
“Average of neck circumference in Latin American adults: protocol for a systematic review and meta-analysis”
Authors: Lopez Patricia Espinoza , Landeo Kelly Fernández , Silva Mercado Rodrigo Pérez , Ardela Jesús Quiñones , Larco Rodrigo Carillo
Published: September 2020

Background

Because these are inexpensive and (fairly) easy to conduct, anthropometric measurements have been widely used as risk factors for many diseases (e.g., cardiovascular or cancer). Recently, there have been several reports pinpointing the association between neck circumference and obstructive sleep apnea, cardiovascular and metabolic diseases. These conditions are highly prevalent Latin American and the Caribbean (LAC), where they carry a large disease and disability burden. Neck circumference arises as a potential complement of established anthropometric measurements, namely weight, height and waist/hip circumference. However, unlike these well-known measurements, evidence about neck circumference is scarce and has not been systematically collected in LAC.

Objective

To summarize the average neck circumference in LAC adults; and, exploratorily, to summarize the prevalence of large neck circumference (i.e., neck/cervical obesity).

Methods

Systematic review and meta-analysis. We will conduct a search in OVID (MEDLINE, Embase, Global Health) and LILACS. Search terms include those related to neck circumference, along with countries in LAC. We seek observational studies with a random sample of the general population, closed populations (e.g., workers), and patients; results will be presented for each of these groups. We will screen titles and abstracts; we will study in detail the selected papers. Both phases will be conducted by two reviewers independently. We will develop an extraction form to collate: country/year of data collection, methods of data collection, average neck circumference and, if available, prevalence of large neck circumference. Data extraction will be conducted by two reviewers independently. We will use the tool proposed by Hoy et al. and the Newcastle-Ottawa scale to assess the risk of bias.

Conclusions

This systematic review and meta-analysis will provide the average neck circumference in LAC adults. Currently, evidence about neck circumference in LAC has not been systematically studied, appraised or summarized. This work will provide information about this novel anthropometric measurement, and spark attention about its role as a potential anthropometric indicator and health risk factor.

Conflicts of interest

All authors declare to have no conflicts of interest.

Funding

Rodrigo M Carrillo-Larco is supported by a Wellcome Trust International Training Fellowship (214185/Z/18/Z).
Cortical actin properties controlled byDrosophilaFos aid macrophage infiltration against surrounding tissue resistance
Authors: Belyaeva Vera , Wachner Stephanie , Gyoergy Attila , Emtenani Shamsi , Gridchyn Igor , Akhmanova Maria , Linder Markus , Roblek Marko , Sibilia Maria , Siekhaus Daria
Published: September 2020

The infiltration of immune cells into tissues underlies the establishment of tissue resident macrophages, and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here we find that the tissue invasion ofDrosophilamacrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by theDrosophilamember of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio which are themselves required for invasion. Both the filamin and the tetraspanin enhance the cortical activity of Rho1 and the formin Diaphanous and thus the assembly of cortical actin, which is a critical function since expressing a dominant active form of Diaphanous can rescue theDfosmacrophage invasion defect.In vivoimaging shows that Dfos enhances the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the properties of the macrophage nucleus from affecting tissue entry. We thus identify strengthening the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues.
Distributed sensory coding by cerebellar complex spikes in units of cortical segments
Authors: Michikawa Takayuki , Yoshida Takamasa , Kuroki Satoshi , Ishikawa Takahiro , Kakei Shinji , Itohara Shigeyoshi , Miyawaki Atsushi
Published: September 2020

Sensory processing is essential for motor control. Climbing fibers from the inferior olive transmit sensory signals to Purkinje cells, but how the signals are represented in the cerebellar cortex remains elusive. We examined the olivocerebellar organization of the mouse brain by optically measuring complex spikes (CSs) evoked by climbing fiber inputs over the entire dorsal surface of the cerebellum. We discovered that the surface was divided into approximately 200 segments each composed of ∼100 Purkinje cells that fired CSs synchronously. Ourin vivoimaging of evoked responses revealed that whereas stimulation of four limb muscles individually similar global CS responses across nearly all segments, the timing and location of a stimulus were derived by Bayesian inference from coordinated activation and inactivation of multiple segments on a single trial basis. Our findings suggest that the cerebellum performs segment-based distributed population coding by assembling probabilistic sensory representation in individual segments.
Cerebrospinal fluid proteome maps detect pathogen-specific host response patterns in meningitis
Authors: Bakochi Anahita , Mohanty Tirthankar , Pyl Paul Theodor , Malmström Lars , Linder Adam , Malmström Johan
Published: September 2020

Meningitis is a potentially life-threatening infection characterized by the inflammation of the leptomeningeal membranes. Many different viral and bacterial pathogens can cause meningitis, with differences in mortality rates, risk of developing neurological sequelae and treatment options. Here we constructed a compendium of digital cerebrospinal fluid (CSF) proteome maps to define pathogen-specific host response patterns in meningitis. The results revealed a drastic and pathogen-type specific influx of tissue-, cell- and plasma proteins in the CSF, where in particular a large increase of neutrophil derived proteins in the CSF correlated with acute bacterial meningitis. Additionally, both acute bacterial and viral meningitis result in marked reduction of brain-enriched proteins. Generation of a multi-protein LASSO regression model resulted in an 18-protein panel of cell and tissue associated proteins capable of classifying acute bacterial meningitis and viral meningitis. The same protein panel also enabled classification of tick-borne encephalitis, a subgroup of viral meningitis, with high sensitivity and specificity. The work provides insights into pathogen specific host response patterns in CSF from different disease etiologies to support future classification of pathogen-type based on host response patterns in meningitis.
CIB2 regulates autophagy via Rheb-mTORC1 signaling axis
Authors: Sethna Saumil , Bernstein Steven L. , Jian Xiaoying , Riazuddin Sheikh , Randazzo Paul A. , Riazuddin Saima , Ahmed Zubair M.
Published: September 2020

Age-related macular degeneration (AMD), a multifactorial neurodegenerative disorder, is the most common cause of vision loss in the elderly. Deficits in autophagy have been associated with age-related retinal pigment epithelium (RPE) pathology in mice, and dry-AMD in humans. In this study, we establish that the calcium and integrin binding protein 2 (CIB2) regulates autophagy in the RPE via Rheb-mTORC1 signaling axis.Cib2mutant mice have reduced autophagic clearance in RPE and increased mTORC1 signaling – a negative regulator of autophagy. Concordant molecular deficits were also observed in RPE/choroid tissues from humans affected with dry AMD. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in aging, Tuberous sclerosis complex (TSC), and lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts andTsc2null cell line down-regulates hyperactive mTORC1 signaling. Thus, our findings have significant ramifications for the etiology of AMD and mTORC1 hyperactivity disorders and treatments.
APC-mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness
Authors: Kawasaki Yoshihiro , Hamaji Tomoko , Owada Koji , Hayashi Akiko , Wu Yuping , Nogi Taisaku , Okada Miwa , Sakai Shoko , Tokushige Naoko , Kouyama Yuta , Niida Atsushi , Mimori Koshi , Kuroda Toshihiko , Senda Takao , Ohsugi Miho , Fumoto Katsumi , Kikuchi Akira , Widlund Per O. , Kiyosue Kazuyuki , Yamashita Norio , Morita Masahiko , Yokota Hideo , Arjunan Satya N. V. , Chew Wei-Xiang , Takahashi Koichi , Legant Wesley R. , Chen Bi-Chang , Betzig Eric , Smits Ron , Fodde Riccardo , Oshima Hiroko , Oshima Masanobu , Taketo M. Mark , Akiyama Tetsu , Mimori-Kiyosue Yuko
Published: September 2020

Certain copy number alterations (CNAs) are strongly associated with particular cancer types. However, the mechanisms that underlie selection of specific CNAs remain unknown. Here, we identified functional relationships between recurrent CNAs in colorectal cancers (CRCs) andadenomatous polyposis coli(APC) mutations. Quantitative phenotyping of mitotic spindles highlighted APC functions at centrosomes where APC positively regulated Aurora A kinase (AURKA). Upon APC inactivation, elevated β-catenin levels blocked AURKA activation, which caused chromosome instability and suppressed proliferation, resulting in the generation and selection of AURKA-activating CNAs. Arm-level amplification of chromosomes that contained AURKA and AURKA activator genes was observed inAPC-mutant CRCs, early stage mouse tumours, and cells in culture, which was concomitant with an increase in growth potential. Our findings demonstrate a mechanism that restores tumour cell fitness through compensatory chromosome alterations to overcome adverse effects of prior mutations, which may affect the course of cancer type-specific CNA formation.
Joint language production: an electrophysiological investigation of simulated lexical access on behalf of task partner
Authors: Kuhlen Anna K. , Abdel Rahman Rasha
Published: September 2020

This study investigates in a joint action setting a well-established effect in speech production, cumulative semantic interference, an increase in naming latencies when naming a series of semantically related pictures. In a joint action setting, two task partners take turns naming pictures. Previous work in this setting demonstrated that naming latencies increase not only with each semantically related picture speakers named themselves, but also with each picture named by the partner (Hoedemaker, Ernst, Meyer, & Belke, 2017; Kuhlen & Abdel Rahman, 2017). This suggests that speakers pursue lexical access on behalf of their partner. In two electrophysiological experiments (N=30 each) we investigated the neuro-cognitive signatures of such simulated lexical access. As expected, in both experiments speakers’ naming latency increased with successive naming instances within a given semantic category. Correspondingly, speakers’ EEG showed an increasing posterior positivity between 250-400ms, an ERP modulation typically associated with lexical access. However, unlike previous experiments, speakers were not influenced by their partner’s picture naming. Accordingly, we found no electrophysiological evidence of lexical access. To reconcile these findings we pooled behavioral data from five experiments (N=144). Within this large sample we find empirical evidence for partner-elicited interference. Furthermore, our data suggests that speakers may be less affected by their partner’s naming response in settings with remotely located task partners (as in present experiments). We conclude that speakers do not always represent their partner’s naming response and that our experimental setting may have limited the participants’ evaluation of the task as a joint action.
Genomic approach for conservation and the sustainable management of endangered species of the Amazon
Authors: Fazzi-Gomes Paola , Aguiar Jonas , Cabral Gleyce Fonseca , Marques Diego , Palheta Helber , Moreira Fabiano , Rodrigues Marilia , Cavalcante Renata , Souza Jorge , Silva Caio , Hamoy Igor , Santos Sidney
Published: September 2020

A broad panel of potentially amplifiable microsatellite loci and a multiplex system were developed for the Amazonian symbol fish species Arapaima gigas, which is currently in high danger of extinction due to the disorderly fishing exploitation. Several factors have contributed to the increase of this threat, among which we highlight the lack of genetic information about the structure and taxonomic status of the species, as well as the lack of accurate tools for evaluation of the effectivity of current management programs. Based on Arapaima gigas’ whole genome, available at the NCBI database (ID: 12404), a total of 95,098 unique perfect microsatellites were identified, including their proposed primers. From this panel, a multiplex system containing 12 tetranucleotide microsatellite markers was validated. These tools are valuable for research in as many areas as bioinformatics, ecology, genetics, evolution and comparative studies, since they are able to provide more accurate information for fishing management, conservation of wild populations and genetic management of aquaculture.
Compartmentalization of mRNAs in the giant, unicellular green algaeAcetabularia acetabulum
Authors: Andresen Ina J. , Orr Russell J. S. , Shalchian-Tabrizi Kamran , Bråte Jon
Published: September 2020

Acetabularia acetabulumis a single-celled green alga previously used as a model species for studying the role of the nucleus in cell development and morphogenesis. The highly elongated cell, which stretches several centimeters, harbors a single nucleus located in the basal end. AlthoughA. acetabulumhistorically has been an important model in cell biology, almost nothing is known about its gene content, or how gene products are distributed in the cell. To study the composition and distribution of mRNAs inA. acetabulum, we have used quantitative RNA-seq to sequence the mRNA content of four sections of adultA. acetabulumcells. We found that although mRNAs are present throughout the cell, there are large pools of distinct mRNAs localized to the different subcellular sections. Conversely, we also find that gene transcripts related to intracellular transport are evenly distributed throughout the cell. This distribution hints at post-transcriptional regulation and selective transport of mRNAs as mechanisms to achieve mRNA localization inA. acetabulum.
Unexpected redundancy of Gpr56 and Gpr97 during hematopoietic cell development and differentiation
Authors: Maglitto A. , Mariani S.A. , de Pater E. , Rodriguez-Seoane C. , Vink C.S. , Piao X. , Lukke M.-L. , Dzierzak E.
Published: September 2020

Integrated molecular signals regulate cell fate during embryonic hematopoietic stem cell (HSC) generation. The G-protein coupled receptor 56 (Gpr56) is the most highly-upregulated receptor gene in cells that take on hematopoietic fate and it is expressed by adult bone marrow HSCs. Although Gpr56 is required for hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos, its function in mammalian hematopoiesis remains unclear. Here we examine the role of Gpr56 in HS/PC development in Gpr56 conditional knockout (cKO) mouse embryos and Gpr knockout (KO) embryonic stem cell (ESC) hematopoietic differentiation cultures. Our results show a myeloid bias of Gpr56 cKO fetal liver HSCs and an increased definitive myeloid progenitor cell frequency in Gpr56KO ESC differentiation cultures. Surprisingly, we find that mouse Gpr97 rescues Gpr56 morphant zebrafish hematopoietic generation, and that Gpr97 expression is upregulated in mouse Gpr56 deletion models. When both Gpr56 and Gpr97 are deleted in ESCs, no/few HS/PCs are generated upon ESC differentiation. Together, our results reveal novel and redundant functions for these two G-protein coupled receptors in normal mammalian hematopoietic cell development and differentiation.
Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I
Authors: Formosa Luke E. , Reljic Boris , Sharpe Alice J. , Muellner-Wong Linden , Stroud David A. , Ryan Michael T.
Published: September 2020

Mitochondrial disease is a debilitating condition with a diverse genetic aetiology. Here, we report that TMEM126A, a protein that is mutated in patients with autosomal recessive optic atrophy, participates directly in the assembly of mitochondrial complex I. Using a combination of genome editing, interaction studies and quantitative proteomics, we find that loss of TMEM126A results in an isolated complex I deficiency and that TMEM126A interacts with a number of complex I subunits and assembly factors. Pulse-labelling interaction studies reveal that TMEM126A associates with the newly synthesised mtDNA-encoded ND4 subunit of complex I. Our findings indicate that TMEM126A is involved in the assembly of the ND4 distal membrane module of complex I. Importantly, we clarify that the function of TMEM126A is distinct from its paralogue TMEM126B, which acts in assembly of the ND2-module of complex I, helping to explain the differences in disease aetiology observed between these two genes.
Eicosanoid content in fetal calf serum accounts for reproducibility challenges in cell culture
Authors: Niederstaetter Laura , Neuditschko Benjamin , Brunmair Julia , Janker Lukas , Bileck Andrea , Del Favero Giorgia , Gerner Christopher
Published: September 2020

Reproducibility issues regardingin vitrocell culture experiments are related to genetic fluctuations and batch-wise variations of biological materials such as fetal calf serum (FCS). Genome sequencing may control the former, while the latter may remain unrecognized. Using a U937 macrophage model for cell differentiation and inflammation, we investigated whether the formation of effector molecules was dependent on the FCS batch used for cultivation. High resolution mass spectrometry was used to identify FCS constituents and to explore their effects on cultured cells evaluating secreted cytokines, eicosanoids and other inflammatory mediators. Remarkably, the FCS eicosanoid composition showed more batch-dependent variations than the protein composition. Efficient uptake of fatty acids from medium by U937 macrophages and inflammation-induced release thereof was evidenced using C13-labelled arachidonic acid, highlighting rapid lipid metabolism. For functional testing, FCS batch-dependent nanomolar concentration differences of two selected eicosanoids, 5-HETE and 15-HETE, were balanced out by spiking in. Culturing U937 cells at these defined conditions indeed resulted in significant proteome alterations indicating HETE-induced PPARγ activation, independently corroborated by HETE-induced formation of peroxisomes observed by high-resolution microscopy. In conclusion, the present data demonstrate that FCS-contained eicosanoids, subject to substantial batch-wise variation, may modulate cellular effector functions in cell culture experiments.
Remarkable recent changes in genetic diversity of the avirulence geneAvrStb6in global populations of the wheat pathogenZymoseptoria tritici
Authors: Stephens Christopher , Ölmez Fatih , Blyth Hannah , McDonald Megan , Bansal Anuradha , Turgay Emine Burcu , Hahn Florian , Saintenac Cyrille , Nekrasov Vladimir , Solomon Peter , Milgate Andrew , Fraaije Bart , Rudd Jason , Kanyuka Kostya
Published: September 2020

Septoria tritici blotch (STB), caused by the fungusZymoseptoria tritici, is one of the most economically important diseases of wheat. Recently, both factors of a gene-for-gene interaction betweenZ. triticiand wheat, the wheat receptor-like kinase Stb6 and theZ. triticisecreted effector protein AvrStb6, have been identified. Previous analyses revealed a high diversity ofAvrStb6alleles present in historicZ. triticiisolate collections, with up to ~ 18% of analysed isolates possessing the avirulence isoform of AvrStb6 identical to that originally identified in the reference isolate IPO323. WithStb6present in many commercial wheat cultivars globally, we aimed to assess potential changes inAvrStb6genetic diversity and the incidence of alleles allowing evasion ofStb6-mediated resistance in more recentZ. triticipopulations. Here we show, using targeted re-sequencing ofAvrStb6,that this gene is universally present in field isolates sampled from major wheat-growing regions of the world between 2013–2017. However, in contrast to the data from studies of historic isolates, our study revealed a complete absence of the originally described avirulence isoform of AvrStb6 amongst modernZ. triticiisolates. Moreover, a remarkably small number of alleles, each encoding AvrStb6 protein isoforms conditioning virulence onStb6-containing wheat, were found to predominate among modernZ. triticiisolates. A single virulence isoform of AvrStb6 was found to be particularly abundant throughout the global population. These findings indicate that, despite the ability ofZ. triticito sexually reproduce on resistant hosts,AvrStb6avirulence alleles tend to be eliminated in subsequent populations.
The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity
Authors: Bolouri Hamid , Speake Cate , Skibinski David , Long S. Alice , Hocking Anne M. , Campbell Daniel J. , Hamerman Jessica A. , Malhotra Uma , Buckner Jane H. ,   the BRI COVID-19 Research Team
Published: September 2020

Despite a rapidly growing body of literature on COVID-19, our understanding of the immune correlates of disease severity, course and outcome remains poor. Using mass cytometry, we assessed the immune landscape in longitudinal whole blood specimens from 59 patients presenting with acute COVID-19, and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls. We found that the immune landscape in COVID-19 forms three dominant clusters, which correlate with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who have a moderate disease course, whereas those with severe disease have features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade. The hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease.
Scribblemutation disrupts convergent extension and apical constriction during mammalian neural tube closure
Authors: Lesko Alyssa C. , Keller Raymond , Chen Ping , Sutherland Ann
Published: September 2020

Morphogenesis of the vertebrate neural tube occurs by elongation and bending of the neural plate, tissue shape changes that are driven at the cellular level by polarized cell intercalation and cell shape changes, notably apical constriction and cell wedging. Coordinated cell intercalation, apical constriction, and wedging undoubtedly require complex underlying cytoskeletal dynamics and remodeling of adhesions. Mutations of the gene encoding Scribble result in neural tube defects in mice, however the cellular and molecular mechanisms by which Scrib regulates neural cell behavior remain unknown. Analysis of Scribble mutants revealed defects in neural tissue shape changes, and live cell imaging of mouse embryos showed that the Scrib mutation results in defects in polarized cell intercalation, particularly in rosette resolution, and failure of both cell apical constriction and cell wedging.Scribmutant embryos displayed aberrant expression of the junctional proteins ZO-1, Par3, Par6, E- and N-cadherins, and the cytoskeletal proteins actin and myosin. These findings show that Scribble has a central role in organizing the molecular complexes regulating the morphomechanical neural cell behaviors underlying vertebrate neurulation, and they advance our understanding of the molecular mechanisms involved in mammalian neural tube closure.

Highlights

Polarized cell intercalation is lost inScribmutant embryos

Scribmutation has specific effects on rosette formation and resolution

Scribmutation disrupts apical constriction and cell shape changes necessary for neural tube closure

Adherens and tight junction composition is altered in the neural epithelial cells ofScribmutants
A dual-reporter system for investigating and optimizing protein translation and folding inE. coli
Authors: Zutz Ariane , Nielsen Louise Hamborg , Pedersen Lasse Ebdrup , Kassem Maher M. , Papaleo Elena , Koza Anna , Herrgård Markus J. , Teilum Kaare , Lindorff-Larsen Kresten , Nielsen Alex Toftgaard
Published: September 2020

Strategies for investigating and optimising the expression and folding of proteins for biotechnological and pharmaceutical purposes are in high demand. Here, we describe a dual-reporter biosensor system that simultaneously assessesin vivoprotein translation and protein folding, thereby enabling rapid screening of mutant libraries. We have validated the dual-reporter system on five different proteins and find an excellent correlation between reporter intensity signals and the levels of protein expression and solubility of the proteins. We further demonstrate the applicability of the dual-reporter system as a screening assay for deep mutational scanning experiments. The system enables high throughput selection of protein variants with high expression levels and altered protein stability. Next generation sequencing analysis of the resulting libraries of protein variants show a good correlation between computationally predicted and experimentally determined protein stabilities. We furthermore show that the mutational experimental data obtained using this system may be useful for protein structure calculations.
The P2X7 receptor localizes to the mitochondria, modulates mitochondrial energy metabolism and enhances physical performance
Authors: Sarti Alba Clara , Vultaggio-Poma Valentina , Falzoni Simonetta , Missiroli Sonia , Giuliani Anna Lisa , Boldrini Paola , Bonora Massimo , Faita Francesco , Di Lascio Nicole , Kusmic Claudia , Solini Anna , Novello Salvatore , Morari Michele , Rossato Marco , Wieckowski Mariusz R. , Giorgi Carlotta , Pinton Paolo , Di Virgilio Francesco
Published: September 2020

Basal expression of the P2X7 receptor (P2X7R) improves mitochondrial metabolism, ATP synthesis and overall fitness of immune and non-immune cells. We investigated P2X7R contribution to energy metabolism and subcellular localization in fibroblasts (mouse embryo fibroblasts and HEK293 human fibroblasts), mouse microglia (primary brain microglia and the N13 microglia cell line), and heart tissue. The P2X7R localizes to mitochondria, and its lack a) decreases basal respiratory rate, ATP-coupled respiration, maximal uncoupled respiration, resting mitochondrial potential, mitochondrial matrix Ca2+level, b) modifies expression pattern of oxidative phosphorylation (OxPhos) enzymes, and c) severely affects cardiac performance. Hearts fromP2rx7-deleted versus WT mice are larger, heart mitochondria smaller, and stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and cardiac output (CO), are significantly decreased. Accordingly, physical fitness of P2X7R-null mice is severely reduced. Thus, the P2X7R is a key modulator of mitochondrial energy metabolism and a determinant of physical fitness.
Genetic models suggest single and multiple origins of dihydrofolate reductase mutations inPlasmodium vivax
Authors: Shaukat Ayaz , Ali Qasim , Raud Lucy , Wahab Abdul , Khan Taj Ali , Rashid Imran , Rashid Muhammad , Hussain Mubashir , Saleem Mushtaq A. , Sargison Neil D. , Chaudhry Umer
Published: September 2020

Pyrimethamine was first introduced for the treatment of malaria in Asia and Africa during the early 1980s, replacing chloroquine, and has become the first line of drugs in many countries. In recent years, development of pyrimethamine resistance inPlasmodium vivaxhas become a barrier to effective malaria control strategies. Here, we describe the use of meta-barcoded deep amplicon sequencing technology to assess the evolutionary origin of pyrimethamine resistance by analysing the flanking region of dihydrofolate reductase (dhfr) locus. The genetic modelling suggests that 58R and 173L single mutants and 58R/117N double mutants are present on a single lineage; suggesting a single origin of these mutations. The triple mutants (57L/58R/117N, 58R/61M/117N and 58R/117N/173L) share the lineage of 58R/117N, suggesting a common origin. In contrast, the 117N mutant is present on two separate lineages suggesting that there are multiple origins of this mutation. We characterised the allele frequency of theP. vivax dhfrlocus. Our results support the view that the single mutation of 117N and double mutations of 58R/117N arise commonly, whereas the single mutation of 173L and triple mutations of 57L/58R/117N, 58R/61M/117N and 58R/117N/173L are less common. Our work will help to inform mitigation strategies for pyrimethamine resistance inP. vivax.
Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1
Authors: Robert Vincent , Therreau Ludivine , Huang Arthur J.Y. , Boehringer Roman , Polygalov Denis , McHugh Thomas , Chevaleyre Vivien , Piskorowski Rebecca A.
Published: September 2020

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. We found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). We found that parvalbumin-expressing basket cells as responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulates CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.
USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling
Authors: Seget-Trzensiok Katarzyna , Bernhard Sara Vanessa , Kuffer Christian , Krastev Dragomir B , Theis Mirko , Keuper Kristina , Boekenkamp Jan-Eric , Kschischo Maik , Buchholz Frank , Storchova Zuzana
Published: September 2020

Tetraploidy is frequent in cancer and whole genome doubling shapes the evolution of cancer genomes, thereby driving the transformation, metastasis and drug resistance. Yet, human cells usually arrest when they become tetraploid due to p53 activation that leads to CDKN1A expression, cell cycle arrest, senescence or apoptosis. To uncover the barriers that block proliferation of tetraploids, we performed an RNAi mediated genome-wide screen in a human cancer cell line. We identified 140 genes whose depletion improved survival of tetraploids and characterized in depth two of them: SPINT2 and USP28. We show that SPINT2 is a general regulator of CDKN1A, regulating its transcription via histone acetylation. By mass spectrometry and immunoprecipitation, we show that USP28 interacts with NuMA1 and affects centrosome clustering. Moreover, tetraploid cells accumulate DNA damage and loss of USP28 reduces checkpoint activation. Our results indicate three aspects that contribute to survival of tetraploid cells: i) increased mitogenic signaling and reduced expression of cell cycle inhibitors, ii) the ability to establish functional bipolar spindle, and iii) reduced DNA damage signaling.
A neuroskeletal atlas of the mouse limb
Authors: Lorenz Madelyn R. , Brazill Jennifer M. , Beeve Alec , Shen Ivana , Scheller Erica L.
Published: September 2020

Nerves in bone play well-established roles in pain and vasoregulation and have been associated with progression of skeletal disorders including osteoporosis, fracture, arthritis and tumor metastasis. However, isolation of the region-specific mechanisms underlying these relationships is limited by our lack of comprehensive maps of skeletal innervation. To overcome this, we mapped sympathetic adrenergic and sensory peptidergic axons within the limb in two strains of mice (B6 and C3H). In the periosteum, these maps were related to the surrounding musculature, including entheses and myotendinous attachments to bone. Locally, three distinct patterns of innervation (Type I, II, III) were defined within established sites that are important for bone pain, bone repair, and skeletal homeostasis. In addition, we mapped the major nerve branches and areas of specialized mechanoreceptors. This work is intended to serve as a guide during the design, implementation, and interpretation of future neuroskeletal studies and was compiled as a resource for the field as part of the NIH SPARC consortium.
Genes involved in cholesterol cascades are linked to brain connectivity in one third of autistic patients
Authors: Rasero Javier , Jimenez-Marin Antonio , Diez Ibai , Hasan Mazahir T. , Cortes Jesus M.
Published: September 2020

The authors have withdrawn their manuscript because after a peer-review process of four different reviewers, several important points were raised, which made us go over all concerns. One major concern involved a gene-wise statistical control for multiple testing, which, after implementation, changed the main conclusion of the study. Other points included a more restrictive filtering of subjects with large head-motion, the exploration of subtyping at different resolutions, a subtyping stability analysis, and the consideration of spatial autocorrelations in the associations between brain connectivity and transcriptomics data. Therefore, the authors do not wish the current work here to be cited as reference for the project anymore. If you have further questions, please contact the corresponding author.
A global timing mechanism regulates cell-type specific wiring programs
Authors: Jain Saumya , Lin Ying , Kurmangaliyev Yerbol Z. , Valdes-Aleman Javier , LoCascio Samuel A. , Mirshahidi Parmis , Parrington Brianna , Zipursky S. Lawrence
Published: September 2020

The assembly of neural circuits is dependent upon precise spatiotemporal expression of cell recognition molecules1–6. Factors controlling cell-type specificity have been identified7–9, but how timing is determined remains unknown. Here we describe the induction of a cascade of transcription factors by a steroid hormone (Ecdysone) in all fly visual system neurons spanning target recognition and synaptogenesis. We demonstrate through single cell sequencing that the Ecdysone pathway regulates the expression of a common set of targets required for synaptic maturation and cell-type specific targets enriched for cell surface proteins regulating wiring specificity. Transcription factors in the cascade regulate the expression of the same wiring genes in complex ways, including activation in one cell-type and repression in another. We show that disruption of the Ecdysone-pathway generates specific defects in dendritic and axonal processes and synaptic connectivity, with the order of transcription factor expression correlating with sequential steps in wiring. We also identify shared targets of a cell-type specific transcription factor and the Ecdysone pathway which regulate specificity. We propose neurons integrate a global temporal transcriptional module with cell-type specific transcription factors to generate different cell-type specific patterns of cell recognition molecules regulating wiring.
Crystal structure and Hirshfeld surface analysis of the elusive trichlorobis(diethyl ether)oxomolybdenum(V)
Authors: Shaw Thomas E. , LeMagueres Pierre , Sattelberger Alfred P. , Jurca Titel
Published: September 2020

First reported in 1930, MoCl3O(Et2O)2 is a by-product of the reductive synthesis of MoCl4(OEt2)2 from MoCl5. We report herein the X-ray crystal structure and Hirshfeld surface characteristics of mer-MoCl3O(Et2O)2, or [MoCl3O(C4H10O)2]. The compound crystallizes in the orthorhombic space group P212121. The molybdenyl (Mo=O) bond length is 1.694 (3) Å and the cis- and trans-Mo—O distances are 2.157 (3) and 2.304 (3) Å, respectively. Intermolecular Mo=O...H bonding is present in the lattice, with the shortest distance being 2.572 Å.
Identifying the success factors of advergames: a mixed-method approach
Authors: Jami Pour Mona , Sadeghi Sahar , Yahyaei Elahe
Published: September 2020

Purpose

Advergame as a new approach in advertising has recently attracted the attention of many researchers and practitioners. Despite the growing investment, managers still do not have a comprehensive understanding of the success factors of advergames. To the authors’ knowledge, there are no studies that address success factors in advergames. The purpose of this paper is to comprehensively explore the success factors of advergames to enhance the markets' insight regarding the implementation of advergames.

Design/methodology/approach

This study investigates the success factors of advergames implementation using the mixed-method approach. For this purpose, along with a literature review, some semistructured interviews with experts were conducted and the obtained data were analyzed using the thematic analysis. Then a survey was conducted to validate the extracted factors and criteria. The quantitative data were analyzed by Student t-test and factor analysis.

Findings

The results indicated that the main success factors of advergames are game design factors, brand/product-related factors, players' personality-related factors and technical factors. The rank orders of the mentioned factors and their subcriteria were identified using their respective variance.

Practical implications

In advergame initiatives, technical issues must be considered along with game design factors, brand/product-related factors and players' personality-related factors simultaneously. The findings can assist managers to understand all aspects of advergames adaptation and assess the weaknesses and strengths of adervgame projects.

Originality/value

Although the intersection between digital games and advertising has had a growing trend in both practical and academic contexts, there are few studies on what factors must be considered during advergames development and implementation. The main contribution of this study is to explore the important aspects of advergames success and their priorities. The findings provide a comprehensive insight on the interdisciplinary aspects of advergames.
Public art and ritual transformation in Northern Ireland
Authors: Downey Hilary , Sherry John F.
Published: September 2020

Purpose

The actual uses to which public art is put have been virtually ignored, leaving multifarious dynamics related to its esthetic encounters unexplored. Both audience agency in placemaking and sensemaking and the agentic role of place as more than a mere platform or stage dressing for transformation are routinely neglected. Such transformative dynamics are analyzed and interpreted in this study of the Derry–Londonderry Temple, a transient mega-installation orchestrated by bricoleur artist David Best and co-created by sectarian communities in 2015.

Design/methodology/approach

A range of ethnographic methods and supplemental netnography were employed in the investigation.

Findings

Participants inscribed expressions of their lived experience of trauma on the Temple's infrastructure, on wood scrap remnants or on personal artifacts dedicated for interment. These inscriptions and artifacts became objects of contemplation for all participants to consider and appreciate during visitation, affording sectarian citizens opportunity for empathic response to the plight of opposite numbers. Thousands engaged with the installation over the course of a week, registering sorrow, humility and awe in their interactions, experiencing powerful catharsis and creating temporary cross-community comity. The installation and the grief work animating it were introjected by co-creators as a virtual legacy of the engagement.

Originality/value

The originality of the study lies in its theorizing of the successful delivery of social systems therapy in an esthetic modality to communities traditionally hostile to one another. This sustained encounter is defined as traumaturgy. The sacrificial ritual of participatory public art becomes the medium through which temporary cross-community cohesion is achieved.