bluuebunny/crossref_metadata_2025 huggingface dataset:
A pattern categorization of CT findings to predict outcome of COVID-19 pneumonia
Authors: Jin Chao , Wang Yan , Wu Carol C. , Zhao Huifang , Liang Ting , Liu Zhe , Jian Zhijie , Li Runqing , Wang Zekun , Li Fen , Zhou Jie , Cai Shubo , Liu Yang , Li Hao , Li Zhongyi , Liang Yukun , Zhou Heping , Wang Xibin , Ren Zhuanqin , Yang Jian
Published: May 2020

Abstracts

Purpose

As global healthcare system is overwhelmed by novel coronavirus disease (COVID-19), early identification of risks of adverse outcomes becomes the key to optimize management and improve survival. This study aimed to provide a CT-based pattern categorization to predict outcome of COVID-19 pneumonia.

Methods

165 patients with COVID-19 (91 men, 4-89 years) underwent chest CT were retrospectively enrolled. CT findings were categorized as Pattern0 (negative), Pattern1 (bronchopneumonia), Pattern2 (organizing pneumonia), Pattern3 (progressive organizing pneumonia) and Pattern4 (diffuse alveolar damage). Clinical findings were compared across different categories. Time-dependent progression of CT patterns and correlations with clinical outcomes, i.e. discharge or adverse outcome (admission to ICU, requiring mechanical ventilation, or death), with pulmonary sequelae (complete absorption or residuals) on CT after discharge were analyzed.

Results

Of 94 patients with outcome, 81(86.2%) were discharged, 3(3.2%) were admitted to ICU, 4(4.3%) required mechanical ventilation, 6(6.4%) died. 31(38.3%) had complete absorption at median day 37 after symptom-onset. Significant differences between pattern-categories were found in age, disease-severity, comorbidity and laboratory results (all P<0.05). Remarkable evolution was observed in Pattern0-2 and Pattern3-4 within 3 and 2 weeks after symptom-onset, respectively; most of patterns remained thereafter. After controlling for age, CT pattern significantly correlated with adverse outcomes (Pattern4 vs. Pattern0-3 [reference]; hazard-ratio[95%CI], 18.90[1.91-186.60], P=0.012). CT pattern (Pattern3-4 vs. Pattern0-2 [reference]; 0.26[0.08-0.88], P=0.030) and C-reactive protein (>10 vs. ≤10mg/L [reference]; 0.31[0.13-0.72], P=0.006) were risk-factors associated with pulmonary residuals.

Conclusion

CT pattern categorization allied with clinical characteristics within 2 weeks after symptom-onset would facilitate early prognostic stratification in COVID-19 pneumonia.
A Modelling Analysis of Strategies for Relaxing COVID-19 Social Distancing
Authors: Milne George J , Xie Simon , Poklepovich Dana
Published: May 2020

Background

The ability of countries to contain and control COVID-19 virus transmission via social distancing is critical in the absence of a vaccine. Early activation of robust measures has been shown to control the daily infection rate, and consequential pressure on the health care system. As countries begin to control COVID-19 spread an understanding of how to ease social distancing measures to prevent a rebound in cases and deaths is required.

Methods

Using COVID-19 transmission data from the outbreak source in Hubei Province, China prior to activation of containment measures, we adapted an established individual-based simulation model of the city of Newcastle, Australia. Simulation of virus transmission in this model, with and without, social distancing measures activated permitted us to quantify social distancing effectiveness. Optimal strategies for relaxing social distancing were determined under two settings: with high numbers of daily cases, as in New York; and where early social distancing activation resulted in limited ongoing transmission, as in Perth, Australia.

Findings

In countries where strong social distancing measures were activated after the COVID-19 virus had spread widely, our study found these measures are required to be maintained for significant periods before being eased, to return to a situation where daily case numbers become low. In countries where early responses to the COVID-19 pandemic have been highly successful, as in Australia, we show that a staged relaxation of social distancing prevents a rebound in cases.

Interpretation

Modelling studies and direct observation have shown that robust and timely social distancing have the most effect in containing the spread of the COVID-19 virus. Questions arise as to the duration of strong social distancing measures, given they are highly disruptive to society and economic activity. This study demonstrates the necessity of holding robust social distancing in place until COVID-19 virus transmission has significantly decreased, and how they may then be safely eased.
Diligent medical activities of a publicly designated medical institution for infectious diseases pave the way for overcoming COVID-19: A positive message to people working at the cutting edge
Authors: Nagano Tatsuya , Arii Jun , Nishimura Mitsuhiro , Yoshida Naofumi , Iida Keiji , Nishimura Yoshihiro , Mori Yasuko
Published: May 2020

The analysis of systematically collected data for COVID-19 infectivity and death rates has revealed in many countries around the world a typical oscillatory pattern with a 7-days (circaseptan) period. Additionally, in some countries the 3.5-days (hemicircaseptan) and 14-days periodicities have been also observed. Interestingly, the 7-days infectivity and death rates oscillations are almost in phase, showing local maxima on Thursdays/Fridays and local minima on Sundays/Mondays. These observations are in stark contrast with a known pattern, correlating the death rate with the reduced medical staff in hospitals on the weekends. One possible hypothesis addressing these observations is that they reflect a gradually increasing stress with the progressing week, which can trigger the maximal death rates observed on Thursdays/Fridays. Moreover, assuming the weekends provide the likely time for new infections, the maximum number of new cases might fall again on Thursdays/Fridays. These observations deserve further study to provide better understanding of the COVID-19 dynamics.
Immunochromatographic test for the detection of SARS-CoV-2 in saliva
Authors: Kashiwagi Katsuhito , Ishii Yoshikazu , Aoki Kotaro , Yagi Shintaro , Maeda Tadashi , Miyazaki Taito , Yoshizawa Sadako , Aoyagi Katsumi , Tateda Kazuhiro
Published: May 2020

We evaluated the rapid immunochromatographic test for SARS-CoV-2 antigen detection using 16 saliva specimens collected from 6 COVID-19 hospitalized patients, and detected N-antigen in 4 of 7 RT-PCR positive specimens. The POCT antigen test using saliva is highly considered to be a game-changer for COVID-19 diagnosis.
Epidemiological study to detect active SARS-CoV-2 infections and seropositive persons in a selected cohort of employees in the Frankfurt am Main metropolitan area
Authors: Krähling Verena , Kern Martin , Halwe Sandro , Müller Helena , Rohde Cornelius , Savini Massimiliano , Schmidt Michael , Wilhelm Jochen , Becker Stephan , Ciesek Sandra , Gottschalk René
Published: May 2020

So far, 170,000 Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections have been confirmed in Germany, of which more than 5,000 have been detected in the Frankfurt am Main metropolitan region. When examining 1,000 nasopharyngeal swabs and serum samples from healthy volunteers from this region, one RT-PCR-positive and five antibody-positive persons were identified. The five positive serum samples were confirmed to be specific. Four of the five positive sera cross-neutralized SARS-CoV.
Spread of COVID-19: Investigation of universal features in real data
Authors: Das Subir K.
Published: May 2020

We present results on the existence of various common patterns in the growth of the total number of patients affected by COVID-19, a disease acquired through infection by a novel coronavirus, in different countries. For this purpose we propose a scaling model that can have general applicability in the understanding of real data of epidemics. This is analogous to the finite-size scaling, a technique used in the literature of phase transition to identify universality classes. In the disease model, the size of a system is proportional to the volume of the population, within a geographical region, that have been infected at the death of the epidemic or are eventually going to be infected when an epidemic ends. Outcome of our study, for COVID-19, via application of this model, suggests that in most of the countries, after the ‘onset’ of spread, the growths are described by rapid exponential function, for significantly long periods. In addition to accurately identifying this superuniversal feature, we point out that the model is helpful in grouping countries into universality classes, based on the late time behavior, characterized by physical distancing practices, in a natural way. This feature of the model can provide direct comparative understanding of the effectiveness of lockdown-like social measures adopted in different places.
Risk factors affecting COVID-19 case fatality rate: A quantitative analysis of top 50 affected countries
Authors: Goh Hui Poh , Mahari Wafiah Ilyani , Ahad Norhadyrah Izazie , Chaw Li Ling , Kifli Nurolaini , Goh Bey Hing , Yeoh Siang Fei , Ming Long Chiau
Published: May 2020

Background

Latest clinical data on treatment on coronavirus disease 2019 (COVID-19) indicated that older patients and those with underlying history of smoking, hypertension or diabetes mellitus might have poorer prognosis of recovery from COVID-19. We aimed to examine the relationship of various prevailing population-based risk factors in comparison with mortality rate and case fatality rate (CFR) of COVID-19.

Methods

Demography and epidemiology data which have been identified as verified or postulated risk factors for mortality of adult inpatients with COVID-19 were used. The number of confirmed cases and the number of deaths until April 16, 2020 for all affected countries were extracted from Johns Hopkins University COVID-19 websites. Datasets for indicators that are fitting with the factors of COVID-19 mortality were extracted from the World Bank database. Out of about 185 affected countries, only top 50 countries were selected to be analyzed in this study. The following seven variables were included in the analysis, based on data availability and completeness: 1) proportion of people aged 65 above, 2) proportion of male in the population, 3) diabetes prevalence, 4) smoking prevalence, 5) current health expenditure, 6) number of hospital beds and 7) number of nurses and midwives. Quantitative analysis was carried out to determine the correlation between CFR and the aforementioned risk factors.

Results

United States shows about 0.20% of confirmed cases in its country and it has about 4.85% of CFR. Luxembourg shows the highest percentage of confirmed cases of 0.55% but a low 2.05% of CFR, showing that a high percentage of confirmed cases does not necessarily lead to high CFR. There is a significant correlation between CFR, people aged 65 and above (p = 0.35) and diabetes prevalence (p = 0.01). However, in our study, there is no significant correlation between CFR of COVID-19, male gender (p = 0.26) and smoking prevalence (p = 0.60).

Conclusion

Older people above 65 years old and diabetic patients are significant risk factors for COVID-19. Nevertheless, gender differences and smoking prevalence failed to prove a significant relationship with COVID-19 mortality rate and CFR.
Engineered membranes for residual cell trapping on microfluidic blood plasma separation systems. A comparison between porous and nanofibrous membranes
Authors: Lopresti Francesco , Keraite Ieva , Ongaro Alfredo E. , Howarth Nicola M. , La Carrubba Vincenzo , Kersaudy-Kerhoas Maïwenn
Published: May 2020

Blood-based clinical diagnostics require challenging limit-of-detection for low abundance, circulating molecules in plasma. Micro-scale blood plasma separation (BPS) has achieved remarkable results in terms of plasma yield or purity, but rarely achieving both at the same time. Here, we proposed the first use of electrospun polylactic-acid (PLA) membranes as filters to remove residual cell population from continuous hydrodynamic-BPS devices. The membranes hydrophilicity was improved by adopting a wet chemistry approach via surface aminolysis as demonstrated through Fourier Transform Infrared Spectroscopy and Water Contact Angle analysis. The usability of PLA-membranes was assessed through degradation measurements at extreme pH values. Plasma purity and hemolysis were evaluated on plasma samples with residual red blood cell content (1, 3, 5% hematocrit) corresponding to output from existing hydrodynamic BPS systems. Commercially available membranes for BPS were used as benchmark. Results highlighted that the electrospun membranes are suitable for downstream residual cell removal from blood, permitting the collection of up to 2 mL of pure and low-hemolyzed plasma. Fluorometric DNA quantification revealed that electrospun membranes did not significantly affect the concentration of circulating DNA. PLA-based electrospun membranes can be combined with hydrodynamic BPS in order to achieve high volume plasma separation at over 99% plasma purity.
Body size and climate as predictors of plumage colouration and sexual dichromatism in parrots
Authors: Carballo Luisana , Delhey Kaspar , Valcu Mihai , Kempenaers Bart
Published: May 2020

Psittaciformes (parrots, cockatoos and lorikeets) comprise one of the most colourful clades of birds. Their unique pigments and cavity nesting habits are two potential explanations for their colourful character. However, plumage colour varies substantially between parrot species and sometimes also between males and females of the same species. Here, we use comparative analyses to evaluate what factors correlate with colour elaboration, colour diversity and sexual dichromatism. Specifically, we test the association between different aspects of parrot colouration and (1) the intensity of sexual selection and social interactions, (2) variation along the slow-fast life-history continuum and (3) climatic variation. We show that larger species and species that live in warm environments display more elaborated colours, yet smaller species have higher levels of sexual dichromatism. Larger parrots tend to have darker and more blue and red colours. Parrots that live in humid environments are darker and redder, whilst species inhabiting warm regions have more blue plumage colours. In general, the variables we considered explain small to moderate amounts of variation in parrot colouration (up to 20%). Our data suggest that sexual selection may be acting more strongly on males in small, short-lived parrots leading to sexual dichromatism. More elaborate colouration in both males and females of the larger, long-lived species with slow tropical life-histories suggests that mutual mate choice and reduced selection for crypsis may be important in these species, as has been shown for passerines.
Effects of anesthesia and oral cleft types on academic achievement
Authors: Nadal Saskia Gladys
Published: May 2020

Objective

Research looking simultaneously at the effects of anesthesia and oral cleft types on academic achievement is scarce. Available results are contradictory: some studies suggest that anesthesia exposure is responsible for underachievement, and others that responsibility falls instead on the type of orofacial cleft. This study investigates the potential compound effects of exposure to anesthesia and orofacial cleft types on the risk of academic underachievement.

Design

Centre Labio Palatin Albert Coninck, Cliniques universitaires Saint-Luc, Brussels, Belgium, nationwide register-based study.

Setting

Birth cohort 1995-2007.

Patients

Twenty-nine children with isolated orofacial clefts exposed to anesthesia.

Interventions

Average duration of exposure to anesthesia before the Certificat d Etudes de Base (CEB) exam was 382 minutes.

Main Outcome Measure(s)

Scores obtained by patients at the CEB exam were compared with the scores of the 6th grade Belgian general population who passed the same exam controlling for gender, school year, year they passed the exam, medical illnesses, duration of exposure to anesthesia in minutes and socioeconomic confounders.

Results

Doubling the time of anesthesia exposure produces a 17 percentage point increase in the probability that patients will underachieve. Cleft lip reduces while cleft right-left increases the duration of anesthesia exposure relative to cleft lip palate. Results do not change when anesthesia exposure only up to 4 years and socioeconomic factors are considered.

Conclusions

Both exposure to anesthesia and different types of orofacial cleft may result in underachievement at the CEB exam.
Novel missense mutation E585K in retinitis pigmentosa leads to compromisedRPGRsplicing diversity
Authors: Liu Yan-Shan , Wan Ji-Feng , Ren Chun-Yan , Xu Zhou-Heng , Pan Xu-Bin , Pan Jia-Qi , Gao Ruo-Nan , Liu Shao-Qiang , Zhang Jia-Li , Yao Qian-Hao , Wang Ji-Hong , Li En-Min , Rao Jun-Hua , Hou Ping , Chen Jian-Huan
Published: May 2020

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP). Herein we used whole-exome sequencing to screen possible novelRPGRmutations in RP patients, and identified a novel missense mutation E585K in a patient with early onset but slow disease progression, and a frameshift deletion E998Gfs*78 in a patient with RP sine pigmento and high myopia. Intriguingly, bioinformatic analysis indicated that E585K probably affectedRPGRRNA splicing instead of the protein sequence directly. Mini-gene assays in 293T cells revealed that splicing events of the E585K mutant were found to be also exist in wildtype, but with a shifted pattern. In the E585K mini-gene usage of an upstream alternative 5′ splice site (5′ ss) of exon 14 was enhanced, and other splicing events were suppressed, including the canonical 5′ ss of exon 14, skipping of exon 14/15 and retention of intron 14. As a result,RPGRsplicing products of the E585K mini-gene were predominated by transcripts containing a 4-bp deletion, with a small fraction of in-frame transcripts containing a retended intron 14, which might explain the slow disease progression in the patient carrying the mutation. RNA-Seq analysis further confirmed existence of these splicing events in endogenousRPGRRNA in human retina, pointing to compromised splicing diversity in the E585K mutant. Our findings thus added to the understanding of genotype-phenotype correlation in RP, and suggested that compromisedRPGRsplicing diversity might play a role in molecular mechanism of the disease.
Interpreting the pathogenicity of Joubert Syndrome missense variants inCaenorhabditis elegans
Authors: Lange Karen I. , Tsiropoulou Sofia , Kucharska Katarzyna , Blacque Oliver E.
Published: May 2020

Ciliopathies are inherited disorders caused by cilia defects. Variants in ciliopathy genes are frequently pleiotropic and represent excellent case studies for interrogating genotype-phenotype correlation. We have employedCaenorhabditis elegansand gene editing to characterise two pathogenic biallelic missense variants (P74S, G155S) in B9D2/mksr-2associated with Joubert Syndrome (JBTS). B9D2 functions within the MKS module at the transition zone (TZ) ciliary subcompartment, and regulates the cilium’s molecular composition and signaling function. Quantitative assays of cilium/TZ structure and function, together with knock-in reporters, confirm both variant alleles are pathogenic. G155S causes a more severe overall phenotype and disrupts endogenous MKSR-2 organisation at the TZ. Recapitulation of the patient biallelic genotype shows that heterozygous worms phenocopy worms homozygous for P74S. This study also reveals a close functional association between the B9 complex and TMEM216/MKS-2. These data establishC. elegansas a paradigm for interpreting JBTS mutations, and provide insight into MKS module organisation.
Reciprocal regulation of vacuolar calcium transport and V-ATPase activity, and the effects of Phosphatidylinositol 3,5-bisphosphate
Authors: Miner Gregory E. , Rivera-Kohr David A. , Zhang Chi , Sullivan Katherine D. , Guo Annie , Fratti Rutilio A.
Published: May 2020

Yeast vacuoles are acidified by the V-ATPase, a protein complex comprised of the membrane embedded VOcomplex and the soluble cytoplasmic V1complex. The assembly of the V1-VOholoenzyme is required for the transfer of H+into the vacuole lumen for acidification. The assembly of the V1-VOholoenzyme is stabilized by the lipid phosphatidylinositol 3,5-bisphospate (PI(3,5)P2) made by the PI3P 5-kinase Fab1/PIKfyve. The absence of PI(3,5)P2leads to the dissociation of the V1complex from the membrane. Separately, PI(3,5)P2has been shown to modulate Ca2+transport across the vacuole membrane during fission and fusion. Here we examined whether the regulation of H+and Ca2+by PI(3,5)P2are interdependent. We show that modulating extraluminal Ca2+concentrations inhibit V-ATPase activity. As extraluminal CaCl2levels are raised, the activity of H+pumping is reduced. Conversely, chelating free Ca2+with EGTA stimulated vacuole acidification. Not only did Ca2+levels affect H+translocation, we also show that blocking V-ATPase activity inhibited Ca2+transport into the vacuole lumen. Together, these data illustrate that Ca2+transport and V-ATPase regulation are interconnected through the modulation of vacuolar lipid profiles.

Summary Statement

Here we show that Ca2+and H+transport across the vacuole membrane is reciprocally regulated and that it is linked to the production of Phosphatidylinositol 3,5-bisphoshpate.
Recurrent mutations in topoisomerase 2a cause a novel mutator phenotype in human cancers
Authors: Boot Arnoud , Rozen Steven G.
Published: May 2020

Topoisomerases are essential for genome stability. Here, we link the p.K743N mutation in topoisomerase TOP2A to a previously undescribed mutator phenotype in human cancers. This phenotype primarily generates a distinctive pattern of duplications of 2 to 4 base pairs and deletions of 6 to 8 base pairs, which we call ID_TOP2A. All tumors carrying the TOP2A p.K743N mutation showed ID_TOP2A, which was absent in all of 12,269 other tumors. We also report evidence of structural variation associated with TOP2A p.K743N. All tumors with ID_TOP2A mutagenesis had several indels in known cancer genes, including frameshift mutations inPTENandTP53and an in-frame activating mutation inBRAF. Thus, ID_TOP2A mutagenesis almost certainly contributed to tumorigenesis in these tumors. This is the first report of topoisomerase-associated mutagenesis in human cancers, and sheds further light on TOP2A’s role in genome maintenance. We also postulate that tumors showing ID_TOP2A mutagenesis might be especially sensitive to topoisomerase inhibitors.
Mortality of the COVID-19 outbreak in Sweden in relation to previous severe disease outbreaks
Authors: Ledberg Anders
Published: May 2020

Influenza viruses have caused disease outbreaks in human societies for a long time. Influenza often has rapid onset and relatively short duration, both in the individual and in the population. The case fatality rate varies for different strains of the virus, as do the effects on total mortality. Outbreaks related to coronavirus infections have recently become a global concern but much less is known about the dynamics of these outbreaks and their effects on mortality.

In this work, disease outbreaks in Sweden, in the time period of 1860-2020, are characterized and compared to the currently ongoing COVID-19 outbreak. The focus is on outbreaks with a sharp increase in all-cause mortality. Outbreak onset is defined as the time point when deaths counts starts to increase consistently for a period of 10 days. The duration of the outbreak is defined as the time period in which mortality rates are elevated. Excess mortality is estimated by standard methods.

In total there were 15 outbreaks detected in the time period, the first 14 were likely caused by influenza virus infections, the last by SARS-CoV-2. The mortality dynamics of the SARS-CoV-2 outbreak is shown to be similar to outbreaks due to influenza virus, and in terms of the number of excess deaths, it is the worst outbreak in Sweden since the ’Spanish flu’ of 1918-1919.
Conditions for a second wave of COVID-19 due to interactions between disease dynamics and social processes
Authors: Pedro Sansao A. , Ndjomatchoua Frank T. , Jentsch Peter , Tchuenche Jean M. , Anand Madhur , Bauch Chris T.
Published: May 2020

In May 2020, many jurisdictions around the world began lifting physical distancing restrictions against the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), giving rise to concerns about a possible second wave of coronavirus disease 2019 (COVID-19). These restrictions were imposed as a collective population response to the presence of COVID-19 in communities. However, lifting restrictions is also a population response to their socio-economic impacts, and is expected to increase COVID-19 cases, in turn. This suggests that the COVID-19 pandemic exemplifies a coupled behaviour-disease system. Here we develop a minimal mathematical model of the interaction between social support for school and workplace closure and the transmission dynamics of SARS-CoV-2. We find that a second wave of COVID-19 occurs across a broad range of plausible model input parameters, on account of instabilities generated by behaviour-disease interactions. We conclude that second waves of COVID-19–should they materialize–can be interpreted as the outcomes of nonlinear interactions between disease dynamics and population behaviour.
The OncoSim-Breast cancer microsimulation model
Authors: Yong J.H.E. , Nadeau C. , Flanagan W. , Coldman A. , Asakawa K. , Garner R. , Fitzgerald N. , Yaffe M. , Miller A.B.
Published: May 2020

Background

The increasing demand for health care resources requires measures to evaluate the impact of cancer control approaches. A cancer simulation model can help integrate new knowledge to inform clinical and policy decisions. OncoSim-Breast is a breast cancer simulation model. This paper aims to describe the key assumptions in the OncoSim-Breast model and how well it reproduces more recent breast cancer trends and the observed effects in a randomized screening trial.

Methods

The OncoSim-Breast model simulates the onset, growth and spread of invasive and ductal carcinoma in situ tumours. The model combines Canadian cancer incidence, mortality, screening program and cost data to project population-level outcomes. Users can change the model input to answer specific policy questions. Here we report three validation exercises. First, we compared the model’s projected breast cancer incidence and stage distributions with the observed data in the Canadian Cancer Registry. Second, we compared OncoSim’s projected breast cancer mortality with the Vital Statistics. Third, we replicated the UK Age trial to compare the model’s projections with the trial’s observed screening effects.

Results

OncoSim-Breast’s projected incidence, mortality and stage distribution of breast cancer were close to the observed data in the Canadian Cancer Registry and the Vital Statistics. OncoSim-Breast also reproduced the breast cancer screening effects observed in the UK Age trial.

Interpretation

OncoSim-Breast’s ability to reproduce the observed population-level breast cancer trends and the screening effects in a randomized trial increases the confidence of using its results to inform policy decisions related to early detection of breast cancer.
In silicoProteome analysis of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Authors: Baruah Chittaranjan , Devi Papari , Sharma Dhirendra K.
Published: May 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2019-nCoV), is a positive-sense, single-stranded RNA coronavirus. The virus is the causative agent of coronavirus disease 2019 (COVID-19) and is contagious through human-to-human transmission. The present study reports sequence analysis, complete coordinate tertiary structure prediction andin silicosequence-based and structure-based functional characterization of full SARS-CoV-2 proteome based on the NCBI reference sequence NC_045512 (29903 bp ss-RNA) which is identical to GenBank entryMN908947andMT415321. The proteome includes 12 major proteins namely orf1ab polyprotein (includes 15 proteins), surface glycoprotein, ORF3a protein, envelope protein, membrane glycoprotein, ORF6 protein, ORF7a protein, orf7b, ORF8, Nucleocapsid phosphoprotein and ORF10 protein. Each protein of orf1ab polyprotein group has been studied separately. A total of 25 polypeptides have been analyzed out of which 15 proteins are not yet having experimental structures and only 10 are having experimental structures with known PDB IDs. Out of 15 newly predicted structures six (6) were predicted using comparative modeling and nine (09) proteins having no significant similarity with so far available PDB structures were modeled usingab-initiomodeling. Structure verification using recent tools QMEANDisCo 4.0.0 and ProQ3 for global and local (per-residue) quality estimates indicate that the all-atom model of tertiary structure of high quality and may be useful for structure-based drug designing targets. The study has identified nine major targets (spike protein, envelop protein, membrane protein, nucleocapsid protein, 2’-O-ribose methyltransferase, endoRNAse, 3’-to-5’ exonuclease, RNA-dependent RNA polymerase and helicase) for which drug design targets could be considered. There are other 16 nonstructural proteins (NSPs), which may also be percieved from the drug design angle. The protein structures have been deposited to ModelArchive. Tunnel analysis revealed the presence of large number of tunnels in NSP3, ORF 6 protein and membrane glycoprotein indicating a large number of transport pathways for small ligands influencing their reactivity.
Model-Based Feature Selection and Clustering of Rna-Seq Data for Unsupervised Subtype Discovery
Authors: Lim David K. , Rashid Naim U. , Ibrahim Joseph G.
Published: May 2020

Clustering is a form of unsupervised learning that aims to un-cover latent groups within data based on similarity across a set of features. A common application of this in biomedical research is in delineating novel cancer subtypes from patient gene expression data, given a set of informative genes. However, it is typically unknowna prioriwhat genes may be informative in discriminating between clusters, and what the optimal number of clusters are. Few methods exist for performing unsupervised clustering of RNA-seq samples, and none currently adjust for between-sample global normalization factors, select cluster-discriminatory genes, or account for potential confounding variables during clustering. To address these issues, we propose the Feature Selection and Clustering of RNA-seq (FSCseq): a model-based clustering algorithm that utilizes a finite mixture of regression (FMR) model and utilized the quadratic penalty method with a SCAD penalty. The maximization is done by a penalized Classification EM algorithm, allowing us to include normalization factors and confounders in our modeling framework. Given the fitted model, our framework allows for subtype prediction in new patients via posterior probabilities of cluster membership. Based on simulations and real data analysis, we show the advantages of our method relative to competing approaches.
Transcriptional re-wiring by mutation of the yeast Hsf1 oligomerization domain
Authors: Morton Elizabeth A. , Dorrity Michael W. , Zhou Wei , Fields Stanley , Queitsch Christine
Published: May 2020

Response to heat stress is mediated by heat shock transcription factors (HSFs), which possess conserved DNA-binding and oligomerization domains. The oligomerization domain is required for HSF1 to transition under heat stress from a monomer to a homotrimer, which alters DNA-binding specificity and affinity. Sequence variation in the oligomerization domain affects HSF1 activity, although this link is poorly understood. We performed a deep mutational scan of >400,000 variants of the oligomerization domain ofSaccharomyces cerevisiaeHsf1 and measured fitness under stress and non-stress conditions. We identify mutations that confer temperature-specific phenotypes; some exceptional Hsf1variants lead to enhanced growth under heat stress and changes toin vivoDNA-binding and transcriptional programs. The link between Hsf1 oligomerization and DNA-binding domain is evolutionarily conserved, with co-evolving residues between these domains found among fungi. Mutation of transcription factor oligomerization domains may represent a path toward re-wiring transcriptional programs without mutation of DNA-binding domains.
SARS-CoV-2 lethality did not change over time in two Italian Provinces
Authors: Flacco Maria Elena , Martellucci Cecilia Acuti , Bravi Francesca , Parruti Giustino , Mascitelli Alfonso , Mantovani Lorenzo , Boccia Stefania , Manzoli Lamberto
Published: May 2020

Background

Some experts recently reported that SARS-CoV-2 lethality decreased considerably, but no evidence is yet available. This retrospective cohort study aimed to evaluate whether SARS-CoV-2 case-fatality rate decreased with time, adjusting for several potential confounders.

Methods

We included all subjects diagnosed with SARS-CoV-2 infection in Ferrara and Pescara provinces, Italy. Information were collected from local registries, clinical charts, and electronic health records. We compared the case-fatality rate (after ≥28 days of follow-up) of the subjects diagnosed during April and March, 2020. We used Cox proportional hazards analysis and random-effect logistic regression, adjusting for age, gender, hypertension, type II diabetes, major cardiovascular diseases (CVD), chronic obstructive pulmonary diseases (COPD), cancer and renal disease.

Results

The sample included 2493 subjects (mean age 58.6y; 47.7% males). 258 persons deceased, after a mean of 16.1 days of follow-up. The mean age of those who died substantially increased from March (78.1±11.0y) to April (84.3±10.2y). From March to April, the case-fatality rate did not decrease in the total sample (9.5% versus 12.1%; adjusted hazard ratio 0.93; 95% Confidence Interval: 0.71-1.21; p=0.6), and in any age-class.

Conclusions

In this sample, SARS-CoV-2 case-fatality rate did not decrease over time, in contrast with recent claims of a substantial improvement of SARS-CoV-2 clinical management. The findings require confirmation from larger datasets.

Author summary

Why was this study done?

Some experts recently reported that SARS-CoV-2 lethality decreased considerably, but no evidence is yet available.

What did the researchers do and find?

We carried out a retrospective cohort study on 2493 SARS-CoV-2 infected subjects from two Italian provinces, evaluating the potential variation of the case-fatality rate over time.

From March to April, SARS-CoV-2 case-fatality rate did not decrease, overall and in any age-class.

What do these findings mean?

The therapies and clinical management of SARS-CoV-2 infected subjects did not determine a substantial change of the clinical course of the disease from March to April, 2020.
Structural basis of bile acid receptor activation and Gs coupling
Authors: Yang Fan , Mao Chunyou , Guo Lulu , Lin Jingyu , Ming Qianqian , Xiao Peng , Wu Xiang , Shen Qingya , Guo Shimeng , Shen Dan-Dan , Lu Ruirui , Zhang Linqi , Huang Shenming , Ping Yuqi , Zhang Chenlu , Ma Cheng , Zhang Kai , Liang Xiaoying , Shen Yuemao , Nan Fajun , Yi Fan , Luca Vincent C , Zhou Jiuyao , Jiang Changtao , Sun Jin-Peng , Xie Xin , Yu Xiao , Zhang Yan
Published: May 2020

G protein-coupled bile acid receptor (GPBAR) is a membrane receptor that senses bile acids to regulate diverse functions through Gs activation. Here, we report the cryo-EM structures of GPBAR–Gs complexes stabilized by either high-affinity P395 or the semisynthesized bile acid derivative INT-777 at 3-Å resolution. These structures revealed a large oval-shaped ligand pocket with several sporadic polar groups to accommodate the amphipathic cholic core of bile acids. A fingerprint of key residues recognizing diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias property were identified through structural analysis and mutagenesis studies. Moreover, structural comparison of GPBAR with other GPCRs uncovered an atypical mode of receptor activation and G-protein– coupling, featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only provides unique structural features of GPBAR in bile acid recognition, allosteric effects and biased signaling, but also suggests that distinct allosteric connecting mechanisms between the ligand binding pocket and the G protein binding site exist in the GPCR superfamily.
ZDHHC5 targets Protocadherin 7 to the cell surface by a palmitoylation-dependent mechanism to promote successful cytokinesis
Authors: Özkan Küçük Nazlı Ezgi , Yiğit Berfu Nur , Değirmenci Beste Senem , Qureshi Mohammad Haroon , Kamacıoğlu Altuğ , Bavili Nima , Kiraz Alper , Özlü Nurhan
Published: May 2020

Cell division requires dramatic reorganization of the cell cortex that is primarily driven by the actomyosin network. We previously reported that Protocadherin 7 (PCDH7) enriches at the cell surface during mitosis which is required for building up the full mitotic rounding pressure. Here we showed that PCDH7 gets palmitoylated and interacts with the palmitoyltransferase, ZDHHC5. Both PCDH7 and ZDHHC5 co-localize at the mitotic cell surface, and they translocate to the cleavage furrow during cytokinesis. PCDH7’s localization depends on palmitoylation activity of ZDHHC5. Loss of expression of PCDH7 impairs active RhoA and phospho-myosin levels at the cleavage furrow and increases the rate of multinucleated cells. This work uncovers a palmitoylation-dependent translocation mechanism for PCDH7 and attributes a regulatory role to contributing actomyosin activity during cytokinesis.
A Two-Part Strategy using Genomic Selection in Hybrid Crop Breeding Programs
Authors: Powell Owen , Gaynor R. Chris , Gorjanc Gregor , Werner Christian R. , Hickey John M.
Published: May 2020

Hybrid crop breeding programs using a two-part strategy produced the most genetic gain, but a maximum avoidance of inbreeding crossing scheme was required to increase long-term genetic gain. The two-part strategy uses outbred parents to complete multiple generations per year to reduce the generation interval of hybrid crop breeding programs. The maximum avoidance of inbreeding crossing scheme manages genetic variance by maintaining uniform contributions and inbreeding coefficients across all crosses. This study performed stochastic simulations to quantify the potential of a two-part strategy in combination with two crossing schemes to increase the rate of genetic gain in hybrid crop breeding programs. The two crossing schemes were: (i) a circular crossing scheme, and (ii) a maximum avoidance of inbreeding crossing scheme. The results from this study show that the implementation of genomic selection increased the rate of genetic gain, and that the two-part hybrid crop breeding program generated the highest genetic gain. This study also shows that the maximum avoidance of inbreeding crossing scheme increased long-term genetic gain in two-part hybrid crop breeding programs completing multiple selection cycles per year, as a result of maintaining higher levels of genetic variance over time. The flexibility of the two-part strategy offers further opportunities to integrate new technologies to further increase genetic gain in hybrid crop breeding programs, such as the use of outbred training populations. However, the practical implementation of the two-part strategy will require the development of bespoke transition strategies to fundamentally change the data, logistics, and infrastructure that underpin hybrid crop breeding programs.

Key message

Hybrid crop breeding programs using a two-part strategy produced the most genetic gain by using outbred parents to complete multiple generations per year. However, a maximum avoidance of inbreeding crossing scheme was required to manage genetic variance and increase long-term genetic gain.
Daphnia magnamodifies its gene expression extensively in response to caloric restriction revealing a novel effect on haemoglobin isoform preference
Authors: Hearn Jack , Clark Jessica , Wilson Philip J. , Little Tom J.
Published: May 2020

Caloric restriction (CR) produces clear phenotypic effects within and between generations of the model crustaceanDaphnia magna. We have previously established that micro RNAs and cytosine methylation change in response to CR in this organism, and we demonstrate here that CR has a dramatic effect on gene expression. Over 6000 genes were differentially expressed between CR and well-fedD. magna, with a bias towards up-regulation of genes under caloric restriction. We identified a highly expressed haemoglobin gene that responds to CR by changing isoform proportions. Specifically, a transcript containing three erythrocruorin domains was strongly down-regulated under CR in favour of transcripts containing fewer or no such domains. This change in the haemoglobin mix is similar to the response to hypoxia inDaphnia,which is mediated through the transcription factor hypoxia-inducible factor 1, and ultimately the mTOR signalling pathway. This is the first report of a role for haemoglobin in the response to CR. We also observed high absolute expression of super-oxide dismutase (SOD) in normally-fed individuals, which contrasts with observations of high SOD levels under in CR in other taxa. However, key differentially expressed genes, like SOD, were not targeted by differentially expressed micro-RNAs. Whether the link between Haemoglobin and CR is the case in other organisms, or is related to the aquatic lifestyle, remains to be tested. It suggests that one response to CR may be to simply transport less oxygen and lower respiration.
Discovery and characterization of a novel family of prokaryotic nanocompartments involved in sulfur metabolism
Authors: Nichols Robert J. , LaFrance Benjamin , Phillips Naiya R. , Oltrogge Luke M. , Valentin-Alvarado Luis E. , Bischoff Amanda J. , Nogales Eva , Savage David F.
Published: May 2020

Prokaryotic nanocompartments, also known as encapsulins, are a recently discovered proteinaceous organelle in prokaryotes that compartmentalize cargo enzymes. While initial studies have begun to elucidate the structure and physiological roles of encapsulins, bioinformatic evidence suggests that a great diversity of encapsulin nanocompartments remains unexplored. Here, we describe a novel encapsulin in the freshwater cyanobacterium Synechococcus elongatus PCC 7942. This nanocompartment is upregulated upon sulfate starvation and encapsulates a cysteine desulfurase enzyme via an N-terminal targeting sequence. Using cryoelectron microscopy, we have determined the structure of the nanocompartment complex to 2.2 Å resolution. Lastly, biochemical characterization of the complex demonstrated that the activity of the cysteine desulfurase is enhanced upon encapsulation. Taken together, our discovery, structural analysis, and enzymatic characterization of this prokaryotic nanocompartment provide a foundation for future studies seeking to understand the physiological role of this encapsulin in various bacteria.
Draft Genome Sequences of Seven Strains ofDickeya dadantii, a Quick Decline-causing Pathogen in Fruit Trees, Isolated from Japan
Authors: Fujikawa Takashi , Hatomi Hiroe , Ota Nobuyoshi
Published: May 2020

Plant pathogenic bacteriumDickeya dadantiicauses quick decline in fruit trees (apple, Japanese pear, and peach). In this study, we report on the draft genome sequences of seven strains ofD. dadantiiisolated from fruit trees with typical quick decline symptoms in Japan.
A proteogenomics workflow to uncover the world of small proteins inStaphylococcus aureus
Authors: Fuchs Stephan , Kucklick Martin , Lehmann Erik , Beckmann Alexander , Wilkens Maya , Kolte Baban , Mustafayeva Ayten , Ludwig Tobias , Diwo Maurice , Wissing Josef , Jänsch Lothar , Ahrens Christian H. , Ignatova Zoya , Engelmann Susanne
Published: May 2020

Small proteins play diverse and essential roles in bacterial physiology and virulence. Despite their importance, automated genome annotation algorithms still cannot accurately annotate all respective small open reading frames (sORFs), as they usually provide insufficient sequence information for domain and homology searches, tend to be species specific and only a few experimentally validated examples are covered in standard proteomics studies. The accuracy and reliability of genome annotations, particularly for sORFs, can be significantly improved by integrating protein evidence from experimental approaches that enrich for small proteins. Here we present a highly optimized and flexible workflow for bacterial proteogenomics, which covers all steps from (i) creation of protein databases, (ii) database searches, (iii) peptide-to-genome mapping to (iv) result interpretation and whose automated execution is supported by two open source tools (SALT&Pepper). We used the workflow to identify high quality peptide spectrum matches (PSMs) for both annotated and unannotated small proteins (≤ 100 aa; SP100) inStaphylococcus aureusNewman. Proteins isolated from cells at the exponential and stationary growth phase were digested with different endopeptidases (trypsin, Lys-C, AspN), the resulting peptides fractionated by gel-based and gel-free methods and measured with highly sensitive mass spectrometers. PSMs or sORF predictions from sORFfinder were stringently filtered allowing us to detect 185 soluble SP100, 69 of which were missing in the used genome annotation. Most interestingly, almost half of the identified SP100 were basic, suggesting a role in binding to more acidic molecules such as nucleic acids or phospholipids. In addition, phage-related functions were proposed for 30 SP100, based on the localization of their coding sequences in the genome.
Cloud computing in SMEs: towards delegation of the CIO role
Authors: Bouaynaya Wafa
Published: May 2020

Purpose

The purpose of this paper is to contribute to a growing body of research on information systems security, by studying open source alternatives for cloud computing. Several questions have been raised about the reliability of these promising but ambiguous offers, as the adoption of a cloud solution within an enterprise is generally accompanied by a change in the chief information officer (CIOs) role and loss of expertise.

Design/methodology/approach

The research uses a mixed research methodology: a first step is based on a questionnaire survey to investigate the security aspects of open source and understand the role of CIOs in the migration process. The investigation involved nearly 800 companies operating in the cloud computing sector in 16 European countries between November 2015 and January 2016. Then, this paper completes the research with a qualitative study by examining the activity of two sample companies.

Findings

Research confirms that open source cloud solutions offer a higher level of security than proprietary solutions. It is also noted that the role of CIOs is delegated to a third external actor: a transition CIO. Transition CIO is the guarantor of the strategic and security choices of small and medium enterprises.

Research limitations/implications

These findings have important implications and great value to managers and cloud computing providers, in terms of formulating better cloud computing solutions. This study can also assist in increasing their understanding of the new role of CIO in the migration process to cloud computing.

Originality/value

This study contributes to the body of research on cloud computing. It is first of its kind with its focus on open source alternatives. Another novelty of this research is that it suggests a new conception for the CIOs role in the migration to cloud computing. Finally, the findings of this study would serve as a European market study to different companies interested in cloud computing.