bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic analysis and comparative multiple sequences of SARS-CoV2
Authors: Chang Tai-Jay , Yang De-Ming , Wang Mong-Lien , Liang Kung-How , Tsai Ping-Hsing , Chiou Shih-Hwa , Lin Ta-Hsien , Wang Chin-Tien
Published: April 2020

Background:

China announced an outbreak of new coronavirus in the city of Wuhan on December 31, 2019; lash to now, the virus transmission has become pandemic worldwide. Severe cases from the Huanan Seafood Wholesale market in Wuhan were confirmed pneumonia with a novel coronavirus (2019-nCoV). Understanding the molecular mechanisms of genome selection and packaging is critical for developing antiviral strategies. Thus, we defined the correlation in 10 severe acute respiratory syndrome coronavirus (SARS-CoV2) sequences from different countries to analyze the genomic patterns of disease origin and evolution aiming for developing new control pandemic processes.

Methods:

We apply genomic analysis to observe SARS-CoV2 sequences from GenBank (http://www.ncbi.nim.nih.gov/genebank/): MN 908947 (China, C1), MN985325 (USA: WA, UW), MN996527 (China, C2), MT007544 (Australia: Victoria, A1), MT027064 (USA: CA, UC), MT039890 (South Korea, K1), MT066175 (Taiwan, T1), MT066176 (Taiwan, T2), LC528232 (Japan, J1), and LC528233 (Japan, J2) for genomic sequence alignment analysis. Multiple Sequence Alignment by Clustalw (https://www.genome.jp/tools-bin/clustalw) web service is applied as our alignment tool.

Results:

We analyzed 10 sequences from the National Center for Biotechnology Information (NCBI) database by genome alignment and found no difference in amino acid sequences within M and N proteins. There are two amino acid variances in the spike (S) protein region. One mutation found from the South Korea sequence is verified. Two possible “L” and “S” SNPs found in ORF1ab and ORF8 regions are detected.

Conclusion:

We performed genomic analysis and comparative multiple sequences of SARS-CoV2. Studies about the biological symptoms of SARS-CoV2 in clinic animals and humans will manipulate an understanding on the origin of pandemic crisis.
The Association Between Fear of Movement, Pain Catastrophizing, Pain Anxiety, and Protective Motor Behavior in Persons With Peripheral Joint Conditions of a Musculoskeletal Origin
Authors: De Baets Liesbet , Matheve Thomas , Timmermans Annick
Published: April 2020

Objective

The aim of the study was to investigate alterations in motor behavior related to pain-related beliefs in persons with peripheral joint conditions.

Design

This is a systematic review.

Results

Our database search (PubMed, Web of Science, Embase, PsycINFO) identified 7390 articles (until September 2019), and nine articles (344 participants) were selected based on the eligibility criteria for selecting studies, i.e., studies in adults with primary peripheral joint conditions, assessing the influence of fear of movement, catastrophizing or anxiety on motor behavior in terms of kinematics, kinetics, and muscle activity during active movements.

In the acute stage after knee or radius surgery, more catastrophizing and fear were associated with less active joint motion in the operated and adjacent joints. In knee patients in the chronic stage after surgery, increased hip adduction and knee valgus were linked to increased fear of movement during the performance of challenging tasks. Similar results were found in persons with nonsurgical chronic knee pain. During gait, no relation between lower limb kinematics and fear of movement was observed.

Conclusions

Kinematic alterations appear in tandem with pain-related perceptions in acute stages after surgery. Altered kinematics influenced by pain-related beliefs are also seen in persons with chronic nonsurgical and surgical knee pain, when challenging tasks are performed.
The Impact of Social Media on Plastic Surgery Residency Applicants
Authors: Irwin Timothy J. , Riesel Johanna N. , Amador Ricardo O. , Helliwell Lydia A. , Lin Samuel J. , Eberlin Kyle R.
Published: April 2020

Background

Plastic surgeons have been early adopters of social media, and the efficacy and ethics of this practice have been studied. In addition, plastic and reconstructive surgery (PRS) training programs have begun using social media to connect with the public, including prospective PRS applicants. The ability of social media to attract prospective residency applicants is unknown. This study aims to examine the influence of social media on prospective residency applicants and their perception of a plastic surgery program.

Methods

In the academic years 2018 and 2019, we conducted an anonymous, voluntary survey among applicants applying to both the integrated and independent Harvard PRS residency programs. The survey collected data regarding demographics, social media usage, online information gathering, and PRS programs' social media influence on applicants' perception/rank position of programs.

Results

One hundred nine surveys were completed (23%). Ninety-seven percent of respondents reported searching online for information about residency programs. Twenty percent of respondents noted that a residency program's social media platform “influenced their perception of a program or intended rank position of a program” and 72% of those respondents indicated a positive effect on their perception of a program and its rank list position. At least 15% of respondents were concerned that engaging with a program's social media account would attract attention to their own social media accounts.

Conclusions

Applicants routinely rely on online resources to gather information regarding prospective residency programs. Fear of attracting attention to their own personal social media pages may limit applicants' engagement with PRS programs on social media. However, residency programs can still utilize social media to deliver important messages, especially as social media usage continues to grow.
The role of cryoprecipitate in massively transfused patients: Results from the Trauma Quality Improvement Program database may change your mind
Authors: Ditillo Michael , Hanna Kamil , Castanon Lourdes , Zeeshan Muhammad , Kulvatunyou Narong , Tang Andrew , Sakran Joseph , Gries Lynn , Joseph Bellal
Published: April 2020

BACKGROUND

Cryoprecipitate was developed for the treatment of inherited and acquired coagulopathies. The role of cryoprecipitate in hemorrhaging trauma patients is still speculative. The aim of our study was to assess the role of cryoprecipitate as an adjunct to transfusion in trauma patients.

METHODS

We performed a 2-year (2015–2016) analysis of the American College of Surgeons-Trauma Quality Improvement Program data set and included all adult trauma patients who received 4 or greater packed red blood cells (pRBCs)/4 hours. Patients were stratified based on receipt of cryoprecipitate within the first 24 hours (cryoprecipitate vs. no-cryoprecipitate). Outcomes were blood products transfused, in-hospital complications, and mortality. Regression analyses were performed.

RESULTS

A total of 19,643 (cryoprecipitate, 4,945; no-cryoprecipitate, 14,698) were included. Mean age was 40 ± 22 years, median Injury Severity Score was 27 [18–40], and Glasgow Coma Scale score was 9 [3–14]. The overall complication rate was 45%, mortality was 47%, and 29% of the patients died in the first 24 hours. Patients in the cryoprecipitate group received a lower volume of plasma (p < 0.01), and pRBCs (p < 0.01). Additionally, patients who received cryoprecipitate had lower rates of 24-hour mortality (p < 0.01) and in-hospital mortality (p < 0.01). However, there was no difference between the two groups regarding complications (p = 0.36) or volume of platelet transfused (p = 0.22). On multivariate logistic regression, the use of cryoprecipitate was associated with decreased (odds ratio [OR], 0.78 [0.63–0.84]; p = 0.02), in-hospital mortality (OR, 0.79 [0.77–0.87]; p = 0.01), but had no association with in-hospital complications (OR, 1.48 [0.71–1.99]; p = 0.31). On linear regression analysis, the use of cryoprecipitate was not associated with 24-hour pRBCs (β = −0.12 [−0.28 to 0.27], p = 0.47), 24-hour plasma (β = −0.06 [−0.21 to 0.43], p = 0.29), and 24-hour platelets (β = −0.24 [−0.09 to 0.33], p = 0.17) transfusion requirements.

CONCLUSION

The adjunctive use of cryoprecipitate in hemorrhaging trauma patients may reduce mortality without affecting in-hospital complications and transfusion requirements. Further studies are needed to better understand its potentially beneficial effects.

LEVEL OF EVIDENCE

Therapeutic, level IV.
Mimicry diversification in
Papilio dardanus
via a genomic inversion in the regulatory region of
engrailed
–
invected
Authors: Timmermans Martijn J. T. N. , Srivathsan Amrita , Collins Steve , Meier Rudolf , Vogler Alfried P.
Published: April 2020

Polymorphic Batesian mimics exhibit multiple protective morphs that each mimic a different noxious model. Here, we study the genomic transitions leading to the evolution of different mimetic wing patterns in the polymorphic Mocker Swallowtail
Papilio dardanus.
We generated a draft genome (231 Mb over 30 chromosomes) and re-sequenced individuals of three morphs. Genome-wide single nucleotide polymorphism (SNP) analysis revealed elevated linkage disequilibrium and divergence between morphs in the regulatory region of
engrailed,
a developmental gene previously implicated in the mimicry switch
.
The diverged region exhibits a discrete chromosomal inversion (of 40 kb) relative to the ancestral orientation that is associated with the
cenea
morph, but not with the bottom-recessive
hippocoonides
morph or with non-mimetic allopatric populations. The functional role of this inversion in the expression of the novel phenotype is currently unknown, but by preventing recombination, it allows the stable inheritance of divergent alleles enabling geographic spread and local coexistence of multiple adaptive morphs.
Real-time estimation of R0 for supporting public-health policies against COVID-19
Authors: Contreras Sebastián , Villavicencio H. Andrés , Medina-Ortiz David , Saavedra Claudia P. , Olivera-Nappa Álvaro
Published: April 2020

Background

In the absence of a consensus protocol to slow down the current SARS-CoV2 spread, policy makers are in need of real-time indicators to support decisions in public health matters. The Basic Reproduction Number (R0) represents viral spread rate and can be dramatically modified by the application of effective public control measures. However, current methodologies to calculate R0 from data remain cumbersome and unusable during an outbreak.

Objective

To provide a simple mathematical formulation for obtaining R0 in Real-Time, and apply it to assess the effectiveness of public-health policies in different iconic countries.

Study design

By modifying the equations describing the spread of the virus, we derived a real-time R0 estimator that can be readily calculated from daily official case reports.

Results

We show the application of a time trend analysis of the R0 estimator to assess the efficacy and promptness of public health measures that impacted on the development of the COVID-19 epidemic in iconic countries.

Conclusions

We propose our simple estimator and method as useful tools to follow and assess in real time the effectiveness of public health policies on COVID-19 evolution.
An age-structured epidemiological model of the Belgian COVID-19 epidemic
Authors: Deforche Koen
Published: April 2020

COVID-19 has prompted many countries to implement extensive social distancing to stop the rapid spread of the virus, in order to prevent over-loading health care systems. Yet, the main epidemic parameters of this virus are not well understood. In the absence of broad testing or serological surveillance, it is hard to evaluate or predict the impact of different strategies to exit implemented lock-down measures. An age-structured epidemiological model was developed, which distinguishes between the younger versus older population (e.g. < 65 and ≥ 65). Because the illness severity is markedly different for these two populations, such a separation is necessary when estimating the model based on death and hospitalization incidence data. The model was applied to data of the Belgian epidemic and used to predict how the epidemic would react to a relaxing of social distancing measures.
A Model for SARS-CoV-2 Infection with Treatment
Authors: Chatterjee Amar Nath , Basir Fahad Al
Published: April 2020

The current emergence of coronavirus (SARS-CoV-2) puts the world in threat. The structural research on the receptor recognition by SARS-CoV-2 has identified the key interactions between SARS-CoV-2 spike protein and its host (epithelial cell) receptor, also known as angiotensin-converting enzyme 2 (ACE2). It controls both the crossspecies and human-to-human transmissions of SARS-CoV-2. In view of this, we propose and analyze a mathematical model for investigating the effect of CTL responses over the viral mutation to control the viral infection when a postinfection immunostimulant drug (pidotimod) is administered at regular intervals. Dynamics of the system with and without impulses have been analyzed using the basic reproduction number. This study shows that the proper dosing interval and drug dose both are important to eradicate the viral infection.
Sputum microbiota profiles of treatment-naïve TB patients in Uganda before and during first-line therapy
Authors: Kateete David Patrick , Mbabazi Monica M , Nakazzi Faith , Katabazi Fred A , Kigozi Edgar , Ssengooba Willy , Nakiyingi Lydia , Namiiro Sharon , Okwera Alphonse , Joloba Moses L , Muwonge Adrian
Published: April 2020

There is limited information on microbiota dynamics in tuberculosis (TB) in Africa. Here, we investigated changes in microbiota composition, abundance, co-occurrence and community remodelling relative to clinical parameters, among treatment-naïve pulmonary TB patients at Mulago National Referral Hospital in Kampala, Uganda. We sequenced 205 sputum samples from 120 patients before initiating anti-TB therapy (baseline) and during treatment follow-up (at months 2 and 5). A total of 8.6 million high quality sequences were generated, yielding 8,180 operational taxonomic units (OTUs), 18 phyla and 333 genera. A sputum sample on average generated 44,992 sequences, yielding 6,580 OTUs, 4 phyla and 36 genera. The sputum microbiota core comprised of 34 genera and it was remarkably stable during treatment. Month 2 was characterized by a significant mean reduction in core microbiota biomass, limited variance changes and general lack of entropy. However, variance and entropy recovered at month 5. Co-occurrence patterns were predominated by accessory genera at baseline but their abundance significantly reduced during treatment. Our findings reveal discernible sputum microbiota signals associated with first-line anti-TB therapy, with potential to inform treatment response monitoring in developing countries.
Concentration-dependent mortality of chloroquine in overdose
Authors: Watson James A , Tarning Joel , Hoglund Richard M , Baud Frederic J , Mégarbane Bruno , Clemessy Jean-Luc , White Nicholas J
Published: April 2020

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence they are clinically effective. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 μmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarisation is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality. Pharmacokinetic modelling combined with these lethality data predicts that the majority of chloroquine regimens trialled in COVID-19 should not cause serious cardiovascular toxicity.
Laboratory Findings of COVID-19 Infection are Conflicting in Different Age Groups and Pregnant Women: A Literature Review
Authors: Vakili Sina , Savardashtaki Amir , Jamalnia Sheida , Tabrizi Reza , Nematollahi Mohammad Hadi , Jafarinia Morteza , Akbari Hamed
Published: April 2020

Coronavirus disease 2019 (COVID-19), a new type and rapidly spread viral pneumonia, is now producing an outbreak of pandemic proportions. The clinical features and laboratory results of different age groups are different due to the general susceptibility of the disease. The laboratory findings of COVID-19 in pregnant women are also conflicting. Para-clinical investigations including laboratory tests and radiologic findings play an important role in early diagnosis and treatment monitoring of severe acute respiratory syndrome and coronavirus-2 (SARS-CoV-2). The majority of previous reports on the SARS-CoV-2 laboratory results were based on data from the general population and limited information is available based on age difference and pregnancy status. This review aimed to describe the COVID-19 laboratory findings in neonates, children, adults, elderly and pregnant women altogether for the first time. The most attracting and reliable markers of COVID-19 in patients were: normal C-reactive protein (CRP) and very different and conflicting laboratory results regardless of clinical symptoms in neonates, normal or temporary elevated CRP, conflicting WBC count results and procalcitonin elevation in children, lymphopenia and elevated lactate dehydrogenase (LDH) in adult patients, lymphopenia and elevated CRP and LDH in the elderly people and high CRP, leukocytosis and elevated neutrophil ratio in pregnant women.
Lopinavir-ritonavir alone or combined with arbidol in the treatment of 73 hospitalized patients with COVID-19: a pilot retrospective study
Authors: Lan Xiu , Shao Chuxiao , Zeng Xu , Wu Zhenbo , Xu Yanyan
Published: April 2020

Objectives

This study aimed to evaluate the antiviral efficacy of lopinavir/ritonavir alone or combined with arbidol in the treatment of hospitalized patients with common coronavirus disease-19 (COVID-19).

Methods

In this retrospective observational study, COVID-19 hospitalized patients were identified and divided into two groups based on the antiviral agents used during their hospitalization. Group-LR patients were treated with single antiviral drug of lopinavir-ritonavir. Group-LR+Ar patients were treated with lopinavir-ritonavir combined with arbidol for antiviral therapy at least 3 days. Patients were assessed for different clinical outcomes.

Results

A total of 34 and 39 patients were identified for Group-LR and Group-LR+Ar, respectively. Treatment with lopinavir–ritonavir alone was not difference from lopinavir-ritonavir combined with arbidol in overall cure rate of COVID-19 hospitalized patients (92.3% and 97.1%, respectively). In a modified intention-to-treat analysis, lopinavir–ritonavir combined with abidol led to a median time of hospital stay that was shorter by 1.5 days than group-LR (12.5 days vs. 14 days). The percentages of COVID-19 RNA clearance was 92.3 in group-LR and 97.1 in group-LR+Ar. The mean time of virus turning negative was 11.5±9.0 days in group-LR+Ar that were longer than group-LR. Treatment of lopinavir-ritonavir combined with arbidol did not significantly accelerate main symptoms improvement and promote the image absorption of pulmonary inflammation.

Conclusion

No benefit was observed in the anti-virus effect of lopinavir–ritonavir combined with arbidol compared with lopinavir-ritonavir alone in the hospitalized patients with COVID-19. More clinical observations in COVID-19 patients may help to confirm or exclude the effect of antiviral agents.
FIRST DETECTION OF SARS-COV-2 IN UNTREATED WASTEWATERS IN ITALY
Authors: La Rosa Giuseppina , Iaconelli Marcello , Mancini Pamela , Ferraro Giusy Bonanno , Veneri Carolina , Bonadonna Lucia , Lucentini Luca , Suffredini Elisabetta
Published: April 2020

Several studies have demonstrated the advantages of environmental surveillance through the monitoring of sewer systems for the assessment of viruses circulating in a given community (wastewater-based epidemiology, WBE).

During the COVID-19 public health emergency, many reports have described the presence of SARS-CoV-2 RNA in stools from COVID-19 patients, and a few studies reported the occurrence of SARS-CoV-2 in wastewaters worldwide. Italy is among the world’s worst-affected countries in the COVID-19 pandemic, but so far there are no studies assessing the presence of SARS-CoV-2 in Italian wastewaters. To this aim, twelve influent sewage samples, collected between February and April 2020 from Wastewater Treatment Plants in Milan and Rome, were tested adapting, for concentration, the standard WHO procedure for Poliovirus surveillance. Molecular analysis was undertaken with three nested protocols, including a newly designed SARS-CoV-2 specific primer set.

SARS-CoV-2 RNA detection occurred in volumes of 250 mL of wastewaters collected in both areas at high (Milan) and low (Rome) epidemic circulation, according to clinical data. Overall, 6 out of 12 samples were positive. One of the positive results was obtained in a Milan wastewater sample collected a few days after the first notified Italian case of autochthonous SARS-CoV-2.

The study shows that WBE has the potential to be applied to SARS-CoV-2 as a sensitive tool to study spatial and temporal trends of virus circulation in the population.
Effects of latency and age structure on the dynamics and containment of COVID-19
Authors: Blyuss K.B. , Kyrychko Y.N.
Published: April 2020

In this paper we develop an SEIR-type model of COVID-19, with account for two particular aspects: non-exponential distribution of incubation and recovery periods, as well as age structure of the population. For the mean-field model, which does not distinguish between different age groups, we demonstrate that including a more realistic Gamma distribution of incubation and recovery periods may not have an effect on the total number of deaths and the overall size of an epidemic, but it has a major effect in terms of increasing the peak numbers of infected and critical care cases, as well as on changing the timescales of an epidemic, both in terms of time to reach the peak, and the overall duration of an outbreak. In order to obtain more accurate estimates of disease progression and investigate different strategies for introducing and lifting the lockdown, we have also considered an age-structured version of the model, which has allowed us to include more accurate data on age-specific rates of hospitalisation and COVID-19 related mortality. Applying this model to three comparable neighbouring regions in the UK has delivered some fascinating insights regarding the effect of quarantine in regions with different population structure. We have discovered that for a fixed quarantine duration, the timing of its start is very important in the sense that the second epidemic wave after lifting the quarantine can be significantly smaller or larger depending on the specific population structure. Also, the later the fixed-duration quarantine is introduced, the smaller is the resulting final number of deaths at the end of the outbreak. When the quarantine is introduced simultaneously for all regions, increasing quarantine duration postpones and slightly reduces the epidemic peak, though without noticeable differences in peak magnitude between different quarantine durations.
HRIBO- High-throughput analysis of bacterial ribosome profiling data
Authors: Gelhausen Rick , Heyl Florian , Svensson Sarah L. , Froschauer Kathrin , Hadjeras Lydia , Sharma Cynthia M. , Eggenhofer Florian , Backofen Rolf
Published: April 2020

Motivation

Ribosome profiling (Ribo-seq) is a powerful approach based on ribosome-protected RNA fragments to explore the translatome of a cell, and is especially useful for the detection of small proteins (<=70 amino acids) that are recalcitrant to biochemical andin silicoapproaches. While pipelines are available to analyze Ribo-seq data, none are designed explicitly for the analysis of Ribo-seq data from prokaryotes, nor are they focused on the discovery of unannotated open reading frames (ORFs) in bacteria.

Results

We presentHRIBO(High-throughput annotation by Ribo-seq), a workflow to enable reproducible and high-throughput analysis of bacterial Ribo-seq data. The workflow performs all required pre-processing and quality control steps. Importantly,HRIBOoutputs annotation-independent ORF predictions based on two complementary bacteria-focused tools, and integrates them with additional features. This facilitates the rapid discovery of novel ORFs and their prioritization for functional characterization.

Availability

HRIBOis a free and open source project available under the GPL-3 license at:https://github.com/RickGelhausen/HRIBO
Geometric model incorporating prey’s turn and predator attack endpoint explains multiple preferred escape trajectories
Authors: Kawabata Yuuki , Akada Hideyuki , Shimatani Ken-ichiro , Nishihara Gregory N. , Kimura Hibiki , Nozomi Nishiumi , Domenici Paolo
Published: April 2020

The escape trajectory (ET) of prey – measured as the angle relative to the predator’s approach path – plays a major role in avoiding predation. Previous geometric models predict a single ET; however, many species show highly variable ETs with multiple preferred directions. Although such a high ET variability may confer unpredictability to avoid predation, the reasons why animals prefer specific multiple ETs remain unclear. Here, we constructed a novel geometric model that incorporates the time required for prey to turn and the predator’s position at the end of its attack. The optimal ET was determined by maximizing the time difference of arrival at the edge of the safety zone between the prey and predator. By fitting the model to the experimental data of fishPagrus majorwe show that the model can clearly explain the observed multiple preferred ETs. By using the same model, we were able to explain different patterns of ETs empirically observed in other species (e.g., insects and frogs): a single preferred ET and multiple preferred ETs at small (20–50°) and large (150–180°) angles from the predator. Our results open new avenues of investigation for understanding how animals choose their ETs from behavioral and neurosensory perspectives.
Drosophila suzukiioxidative stress response involvesJhehgene cluster but not transposable elements
Authors: Marin Pierre , Jacquet Angelo , Henri Hélène , Gibert Patricia , Vieira Cristina
Published: April 2020

The study of the mechanisms involved in adaptation remains a timely issue, particularly in the context of global changes. To better understand these mechanisms of rapid adaptation, invasive species are a good model because they are subjected to new and/or different environmental factors. Using different lines of different geographical origin of the invasive pestDrosophila suzukii, we characterized the phenotypic response to oxidative stress. Subsequently, we tested the involvement of theJhehgene cluster in this response and the possible role of transposable elements. We show that the resistance to oxidative stress of the lines appears to be related to their invasive status and we confirm the role of theJhehgene cluster in this response. We have not identified any transposable elements in this gene region that could influence the expression of the gene.

Summary statement

The responses to oxidative stress of the invasive species, Drosophila suzukii, show variability between genotypes related to their invasion status. The genes of the juvenile hormone epoxide hydrolase cluster are involved in this response.
Titration ofin-cellulaaffinities of protein-protein interactions
Authors: Cluet David , Vergier Blandine , Levy Nicolas-Pierre , Dehau Lucie , Thurman Alexandre , Amri Ikram , Spichty Martin
Published: April 2020

A genetic assay permits simultaneous quantification of two interacting proteins and their bound fraction at the single-cell level using flow cytometry.In-cellulaaffinities of protein-protein interactions can be extracted from the acquired data through a titration-like analysis. The applicability of this approach is demonstrated on a diverse set of interactions with proteins from different families and organisms and within-vitrodissociation constants ranging from picomolar to micromolar.
Predicting microbiomes through a deep latent space
Authors: García-Jiménez Beatriz , Muñoz Jorge , Cabello Sara , Medina Joaquín , Wilkinson Mark D.
Published: April 2020

Motivation

Microbial communities influence their environment by modifying the availability of compounds such as nutrients or chemical elicitors. Knowing the microbial composition of a site is therefore relevant to improving productivity or health. However, sequencing facilities are not always available, or may be prohibitively expensive in some cases. Thus, it would be desirable to computationally predict the microbial composition from more accessible, easily-measured features.

Results

Integrating Deep Learning techniques with microbiome data, we propose an artificial neural network architecture based on heterogeneous autoencoders to condense the long vector of microbial abundance values into a deep latent space representation. Then, we design a model to predict the deep latent space and, consequently, to predict the complete microbial composition using environmental features as input. The performance of our system is examined using the rhizosphere microbiome of Maize. We reconstruct the microbial composition (717 taxa) from the deep latent space (10 values) with high fidelity (¿0.9 Pearson correlation). We then successfully predict microbial composition from environmental variables such as plant age, temperature or precipitation (0.73 Pearson correlation, 0.42 Bray-Curtis). We extend this to predict microbiome composition under hypothetical scenarios, such as future climate change conditions. Finally, via transfer learning, we predict microbial composition in a distinct scenario with only a hundred sequences, and distinct environmental features. We propose that our deep latent space may assist microbiome-engineering strategies when technical or financial resources are limited, through predicting current or future microbiome compositions.

Availability

Software, results, and data are available athttps://github.com/jorgemf/DeepLatentMicrobiome
C. elegans BRC-1-BRD-1 functions at an early step of DSB processing and inhibits supernumerary crossovers during male meiosis
Authors: Li Qianyan , Hariri Sara , Engebrecht JoAnne
Published: April 2020

Meiosis is regulated in a sex-specific manner to produce two distinct gametes, sperm and oocytes, for sexual reproduction. To determine how meiotic recombination is regulated in spermatogenesis, we analyzed the meiotic phenotypes of mutants in the tumor suppressor E3 ubiquitin ligase BRC-1-BRD-1 complex inCaenorhabditis elegansmale meiosis. Unlike in mammals, this complex is not required for meiotic sex chromosome inactivation, the process whereby hemizygous sex chromosomes are transcriptionally silenced. Interestingly,brc-1andbrd-1mutants showed meiotic recombination phenotypes that are largely opposing to those previously reported for female meiosis. Fewer meiotic recombination foci marked by the recombinase RAD-51 were observed inbrc-1andbrd-1mutants, and the reduction in RAD-51 foci can be suppressed by mutation of nonhomologous end joining proteins. We show that concentration of BRC-1-BRD-1 to sites of meiotic recombination is dependent on DNA end resection, suggesting that BRC-1-BRD-1 regulates the processing of meiotic double strand breaks to promote repair by homologous recombination, similar to a role for the complex in somatic cells. We also show that BRC-1-BRD-1 is important to promote progeny viability when male meiosis is perturbed by mutations that block the pairing and synapsis of different chromosome pairs, although the complex is not required to stabilize the RAD-51 filament as in female meiosis under the same conditions. Analyses of crossover designation and formation reveal that BRC-1-BRD-1 inhibits supernumerary crossovers when meiosis is perturbed. Together, our findings suggest that BRC-1-BRD-1 regulates different aspects of meiotic recombination in male and female meiosis.
Permutation-based Identification of Important Biomarkers for Complex Diseases via Black-box Models
Authors: Mi Xinlei , Zou Baiming , Zou Fei , Hu Jianhua
Published: April 2020

Study of human disease remains challenging due to convoluted disease etiologies and complex molecular mechanisms at genetic, genomic, and proteomic levels. Many machine learning-based methods, including deep learning and random forest, have been developed and widely used to alleviate some analytic challenges in complex human disease studies. While enjoying the modeling flexibility and robustness, these model frameworks suffer from non-transparency and difficulty in interpreting the role of each individual feature due to their intrinsic black-box natures. However, identifying important biomarkers associated with complex human diseases is a critical pursuit towards assisting researchers to establish novel hypotheses regarding prevention, diagnosis and treatment of complex human diseases. Herein, we propose a Permutation-based Feature Importance Test (PermFIT) for estimating and testing the feature importance, and for assisting interpretation of individual feature in various black-box frameworks, including deep neural networks, random forests, and support vector machines. PermFIT (available athttps://github.com/SkadiEye/deepTL) is implemented in a computationally efficient manner, without model refitting for each permuted data. We conduct extensive numerical studies under various scenarios, and show that PermFIT not only yields valid statistical inference, but also helps to improve the prediction accuracy of black-box models with top selected features. With the application to the Cancer Genome Atlas (TCGA) kidney tumor data and the HITChip atlas BMI data, PermFIT clearly demonstrates its practical usage in identifying important biomarkers and boosting performance of black-box predictive models.
Resolving an underrepresented circulating tumor cell population in lung cancer enabled by Hexokinase 2 analysis
Authors: Yang Liu , Yan Xiaowei , Chen Jie , Zhan Qiong , Hua Yingqi , Xu Shili , Dong Yu , Li Ziming , Wang Zhuo , Zuo Dongqing , Xue Min , Tang Yin , Herschman Harvey R. , Lu Shun , Shi Qihui , Wei Wei
Published: April 2020

Unlike other epithelial cancer types, circulating tumor cells (CTCs) are less frequently detected in the peripheral blood of non-small cell lung cancer (NSCLC) patients using epithelial marker-based detection approaches, despite the aggressive nature of NSCLC. Here we demonstrate hexokinase-2 (HK2) as a metabolic function-associated marker for detection of CTCs, with significantly improved detection rates and high specificity, in 33 NSCLC patients. Use of the HK2 marker identified underrepresented cytokeratin-negative (HK2high/CKneg) CTCs present in many blood samples but rarely detected in pleural effusions or cerebrospinal fluids of NSCLC patients. HK2high/CKnegCTCs exhibited smaller sizes but consistent copy number variation profiles compared to CKposCTCs. Surprisingly, CK expression levels were found to be independent of CTC epithelial-to-mesenchymal transition (EMT) status as measured by single-cell transcriptome profiling, challenging the long-standing association between CK expression and EMT. Our approach improves sensitivity of CTC detection in NSCLC and can potentially resolve a more complete spectrum of CTCs, regardless of their CK expression levels or epithelial traits.
Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctivede novoDNA methylation mechanisms
Authors: Gao Linfeng , Emperle Max , Guo Yiran , Grimm Sara A , Ren Wendan , Adam Sabrina , Uryu Hidetaka , Zhang Zhi-Min , Chen Dongliang , Yin Jiekai , Dukatz Michael , Anteneh Hiwot , Jurkowska Renata Z. , Lu Jiuwei , Wang Yinsheng , Bashtrykov Pavel , Wade Paul A , Wang Gang Greg , Jeltsch Albert , Song Jikui
Published: April 2020

Mammalian DNA methylation patterns are established by twode novoDNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals crucial and distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.
A data-driven geospatial workflow to improve mapping species distributions and assessing extinction risk under the IUCN Red List
Authors: Palacio Ruben Dario , Negret Pablo Jose , Velásquez-Tibatá Jorge , Jacobson Andrew P.
Published: April 2020

Species distribution maps are essential for assessing extinction risk and guiding conservation efforts. Here, we developed a data-driven, reproducible geospatial workflow to map species distributions and evaluate their conservation status consistent with the guidelines and criteria of the IUCN Red List. Our workflow follows five automated steps to refine the distribution of a species starting from its Extent of Occurrence (EOO) to Area of Habitat (AOH) within the species range. The ranges are produced with an Inverse Distance Weighted (IDW) interpolation procedure, using presence and absence points derived from primary biodiversity data. As a case-study, we mapped the distribution of 2,273 bird species in the Americas, 55% of all terrestrial birds found in the region. We then compared our produced species ranges to the expert-drawn IUCN/BirdLife range maps and conducted a preliminary IUCN extinction risk assessment based on criterion B (Geographic Range). We found that our workflow generated ranges with fewer errors of omission, commission, and a better overall accuracy within each species EOO. The spatial overlap between both datasets was low (28%) and the expert-drawn range maps were consistently larger due to errors of commission. Their estimated Area of Habitat (AOH) was also larger for a subset of 741 forest-dependent birds. We found that incorporating geospatial data increased the number of threatened species by 52% in comparison to the 2019 IUCN Red List. Furthermore, 103 species could be placed in threatened categories (VU, EN, CR) pending further assessment. The implementation of our geospatial workflow provides a valuable alternative to increase the transparency and reliability of species risk assessments and improve mapping species distributions for conservation planning and decision-making.
The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits
Authors: Coban-Akdemir Zeynep , Song Xiaofei , Ceballos Francisco C. , Pehlivan Davut , Karaca Ender , Bayram Yavuz , Mitani Tadahiro , Gambin Tomasz , Yozgatli Tugce Bozkurt , Jhangiani Shalini N. , Muzny Donna M. , Lewis Richard A. ,   Baylor Hopkins Center for Mendelian Genomics, Liu Pengfei , Boerwinkle Eric , Hamosh Ada , Gibbs Richard A. , Sutton V. Reid , Sobreira Nara , Carvalho Claudia M. B. , Shaw Chad A. , Posey Jennifer E. , Valle David , Lupski James R.
Published: April 2020

Purpose

The variome of the Turkish (TK) population, a population with a considerable history of admixture and consanguinity, has not been deeply investigated deeply for its potential impact on the genomic architecture of disease traits.

Methods

We generated and analyzed a database of variants derived from exome sequencing (ES) data of 773 TK unrelated, clinically affected individuals with various suspected Mendelian disease traits, and 643 unaffected relatives.

Results

Using uniform manifold approximation and projection (UMAP), we showed that the TK genomes are more similar to those of Europeans and consist of two main subpopulations: clusters 1 and 2 (N=235 and 1,181) that differ in admixture proportion and variome (https://turkishvariomedb.shinyapps.io/tvdb/). Furthermore, the higher inbreeding coefficient (F) values observed in the TK affected compared to unaffected individuals correlated with a larger median span of long-sized (>2.64 Mb) runs of homozygosity (ROH) regions (p-value=2.09e-18). We show that long-sized ROHs are more likely to be formed on recently configured haplotypes enriched for rare homozygous deleterious variants in the TK-affected compared to TK-unaffected individuals (p-value= 3.35e-11). Analysis of genotype-phenotype correlations reveals that genes with rare homozygous deleterious variants in long-sized ROHs provide the most comprehensive set of molecular diagnoses for the observed disease traits with a systematic quantitative analysis of HPO (Human Phenotype Ontology) terms.

Conclusion

Our findings support the notion that novel rare variants on newly configured haplotypes arising within the recent past generations of a family or clan contribute significantly to recessive disease traits in the TK population.
Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations
Authors: Martin Alicia R. , Atkinson Elizabeth G. , Chapman Sinéad B. , Stevenson Anne , Stroud Rocky E. , Abebe Tamrat , Akena Dickens , Alemayehu Melkam , Ashaba Fred K. , Atwoli Lukoye , Bowers Tera , Chibnik Lori B. , Daly Mark J. , DeSmet Timothy , Dodge Sheila , Fekadu Abebaw , Ferriera Steven , Gelaye Bizu , Gichuru Stella , Injera Wilfred E. , James Roxanne , Kariuki Symon M. , Kigen Gabriel , Koenen Karestan C. , Kwobah Edith , Kyebuzibwa Joseph , Majara Lerato , Musinguzi Henry , Mwema Rehema M. , Neale Benjamin M. , Newman Carter P. , Newton Charles R. J. C. , Pickrell Joseph K. , Ramesar Raj , Shiferaw Welelta , Stein Dan J. , Teferra Solomon , van der Merwe Celia , Zingela Zukiswa ,   NeuroGAP-Psychosis Consortium
Published: April 2020

Background

Genetic studies of biomedical phenotypes in underrepresented populations identify disproportionate numbers of novel associations. However, current genomics infrastructure--including most genotyping arrays and sequenced reference panels--best serves populations of European descent. A critical step for facilitating genetic studies in underrepresented populations is to ensure that genetic technologies accurately capture variation in all populations. Here, we quantify the accuracy of low-coverage sequencing in diverse African populations.

Results

We sequenced the whole genomes of 91 individuals to high-coverage (≥20X) from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study, in which participants were recruited from Ethiopia, Kenya, South Africa, and Uganda. We empirically tested two data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole genome sequencing data. We show that low-coverage sequencing at a depth of ≥4X captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1X) performed comparable to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation, with 4X sequencing detecting 45% of singletons and 95% of common variants identified in high-coverage African whole genomes.

Conclusion

These results indicate that low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, including those that capture variation most common in Europeans and Africans. Low-coverage sequencing effectively identifies novel variation (particularly in underrepresented populations), and presents opportunities to enhance variant discovery at a similar cost to traditional approaches.
Asynchrony between virus diversity and antibody selection limits influenza virus evolution
Authors: Morris Dylan H. , Petrova Velislava N. , Rossine Fernando W. , Parker Edyth , Grenfell Bryan T. , Neher Richard A. , Levin Simon A. , Russell Colin A.
Published: April 2020

Seasonal influenza viruses create a persistent global disease burden by evolving to escape immunity induced by prior infections and vaccinations. New antigenic variants have a substantial selective advantage at the population level, but these variants are rarely selected within-host, even in previously immune individuals. Using a mathematical model, we show that the temporal asynchrony between within-host virus exponential growth and antibody-mediated selection could limit within-host antigenic evolution. If selection for new antigenic variants acts principally at the point of initial virus inoculation, where small virus populations encounter well-matched mucosal antibodies in previously infected individuals, there can exist protection against reinfection that does not regularly produce observable new antigenic variants within individual infected hosts. Our results provide a theoretical explanation for how virus antigenic evolution can be highly selective at the global level but nearly neutral within host. They also suggest new avenues for improving influenza control.
Topologically correct synthetic reconstruction of pathogen social behavior found in deep tissue sites
Authors: Clark Stacie A. , Thibault Derek , Shull Lauren M. , Davis Kimberly M. , Aunins Emily , van Opijnen Tim , Isberg Ralph R.
Published: April 2020

Within deep tissue sites, extracellular bacterial pathogens often replicate in clusters that are surrounded by immune cells. Disease is modulated by interbacterial interactions as well as bacterial-host cell interactions resulting in microbial growth, phagocytic attack and secretion of host antimicrobial factors. To overcome the limited ability to manipulate these infection sites, we established a system forYersinia pseudotuberculosis(Yptb)growth in microfluidics-driven microdroplets that regenerates microbial social behavior in tissues. Chemical generation of nitric oxide (NO) in the absence of immune cells was sufficient to reconstruct microbial social behavior, as witnessed by expression of the NO-inactivating protein Hmp on the extreme periphery of microcolonies, mimicking spatial regulation in tissues. Similarly, activated macrophages that expressed inducible NO synthase (iNOS) drove peripheral expression of Hmp, allowing regeneration of social behavior observed in tissues. These results argue that topologically correct microbial tissue growth and associated social behavior can be reconstructed in culture.