bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations in resting-state activity and functional connectivity in children with 22q11.2 deletion syndrome
Authors: Doherty Joanne L. , Cunningham Adam C. , Chawner Samuel J.R.A. , Moss Hayley M. , Dima Diana C. , Linden David E. J. , Owen Michael J. , van den Bree Marianne B.M. , Singh Krish D.
Published: September 2021

Background

While genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. Despite this, few studies have investigated electrophysiological activity and connectivity in this high-risk group.

Methods

Magnetoencephalography (MEG) was used to investigate resting-state cortical oscillatory patterns in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, IQ and neurodevelopmental symptoms.

Results

Children with 22q11.2DS had atypical oscillatory activity and functional connectivity across multiple frequency bands. In the 22q11.2DS group, low frequency (alpha band) activity was positively associated with cognitive ability, while connectivity was negatively associated with ASD and ADHD symptoms. Frontal high frequency (gamma band) activity and connectivity were positively associated with ASD and ADHD symptoms respectively, while posterior gamma activity was negatively associated with ASD symptoms.

Conclusions

These findings highlight that haploinsufficiency at the 22q11.2 locus alters both local and long-range cortical circuitry, which could be a mechanism underlying neurodevelopmental vulnerability in this high risk group.
Multiplex PCR Assay to Detect High Risk Lineages of Salmonella Typhi and Paratyphi A
Authors: Khokhar Fahad A , Pickard Derek DJ , Dyson Zoe A , Iqbal Junaid , Pragasam Agila K , John Jobin Jacob , Veeraraghavan Balaji , Qamar Farah N , Dougan Gordon , MacQueen Hilary , Rigas Sushila H , Holmes Mark A , Mutreja Ankur
Published: September 2021

Enteric fever infections remain a significant public health issue, with up to 20 million infections per year. Increasing rates of antibiotic resistant strains have rendered many first-line antibiotics potentially ineffective. Genotype 4.3.1 (H58) is the main circulating lineage of S. Typhi in many South Asian countries and is associated with high levels of antibiotic resistance. The emergence and spread of extensively drug resistant (XDR) typhoid strains has increased the need for a rapid molecular test to identify and track these high-risk lineages for surveillance and vaccine prioritisation. Current methods require samples to be cultured for several days, followed by DNA extraction and sequencing to determine the specific lineage. We designed and evaluated the performance of a new multiplex PCR assay, targeting S. Paratyphi A as well as the H58 and XDR lineages of S. Typhi on a collection of bacterial strains. Our assay was 100% specific for the identification of lineage specific S. Typhi and S. Paratyphi A, when tested with a mix of non-Typhi Salmonella and non-Salmonella strains. With additional testing on clinical and environmental samples, this assay will allow rapid lineage level detection of typhoid of clinical significance, at a significantly lower cost to whole-genome sequencing. To our knowledge, this is the first report of a SNP-based multiplex PCR assay for the detection of lineage specific serovars of Salmonella Typhi.

Data Statement

All supporting data, code and protocols have been provided within the article or through supplementary data files.
SARS-CoV-2 Delta variant of concern in Brazil - multiple introductions, communitary transmission, and early signs of local evolution
Authors: Patané José , Viala Vincent , Lima Loyze , Martins Antonio , Barros Claudia , Marqueze Elaine , Bernardino Jardelina , Moretti Debora , Slavov Svetoslav , Bezerra Rafael , Rodrigues Evandra , Santos Elaine , Brassaloti Ricardo , Cassano Raquel , Mariani Pilar , Kitajima João , Santos Bibiana , Assato Patricia , Costa Felipe , Poleti Mirele , Lesbon Jessika , Chicaroni Elisangela , Banho Cecilia , Sacchetto Lívia , Moraes Marília , Palmieri Melissa , Vilanova Fabiana , Martininghi Maiara , Grotto Rejane , Souza-Neto Jayme , Giovanetti Marta , Alcantara Luiz , Nogueira Maurício , Fukumasu Heidge , Coutinho Luiz , Calado Rodrigo , Kashima Simone , Neto Raul , Covas Dimas , Elias Carolina , Coccuzzo Sandra
Published: September 2021

The dissemination of the Delta VOC in Brazil is still unclear, despite the frequent reports of isolated cases from different Brazilian states. In this report we characterize the dissemination of the Delta VOC in Brazil and where the introductions of this lineage fall within the global Delta phylogeny. We also examined the mutational profile of the largest clade within the Brazilian Delta VOCs, with a focus on samples which were obtained in the State of São Paulo, and especially in the city of São Paulo, the largest metropolis of South America, and a national and international transportation hub.
Metabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation
Authors: Bell Kirstine J. , Saad Sonia , Tillett Bree J. , McGuire Helen M. , Bordbar Sara , Yap Yu Anne , Nguyen Long T. , Wilkins Marc R. , Corley Susan , Brodie Shannon , Duong Sussan , Wright Courtney J. , Twigg Stephen , de St Groth Barbara Fazekas , Harrison Leonard C. , Mackay Charles R. , Gurzov Esteban N. , Hamilton-Williams Emma E. , Mariño Eliana
Published: September 2021

Background

Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the microbiota in alignment with modulation of the immune system status.

Results

HAMSAB supplement was administered for six weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control.Bifidobacterium longum,Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention.

Conclusion

Changes in gut microbiota composition, function, and immune profile following six weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance and improve glycemic control for the treatment of T1D.

Trial registration

ACTRN12618001391268. Registered 20 August 2018,https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792
Design and implementation of multiplexed amplicon sequencing panels to serve genomic epidemiology of infectious disease: a malaria case study
Authors: LaVerriere Emily , Schwabl Philipp , Carrasquilla Manuela , Taylor Aimee R. , Johnson Zachary M. , Shieh Meg , Panchal Ruchit , Straub Timothy J. , Kuzma Rebecca , Watson Sean , Buckee Caroline O. , Andrade Carolina M. , Portugal Silvia , Crompton Peter D. , Traore Boubacar , Rayner Julian C. , Corredor Vladimir , James Kashana , Cox Horace , Early Angela M. , MacInnis Bronwyn L. , Neafsey Daniel E.
Published: September 2021

Multiplexed PCR amplicon sequencing (AmpSeq) is an increasingly popular application for cost-effective monitoring of threatened species and managed wildlife populations, and shows strong potential for genomic epidemiology of infectious disease. AmpSeq data for infectious microbes can inform disease control in multiple ways, including measuring drug resistance marker prevalence, distinguishing imported from local cases, and determining the effectiveness of therapeutics. We describe the design and comparative evaluation of two new AmpSeq assays for Plasmodium falciparum malaria parasites: a four-locus panel (‘4CAST’) composed of highly diverse antigens, and a 129-locus panel (‘AMPLseq’) composed of drug resistance markers, highly diverse loci for measuring relatedness, and a locus to detect Plasmodium vivax co-infections. We explore the performance of each panel in various public health use cases with in silico simulations as well as empirical experiments. We find that the smaller 4CAST panel performs reliably across a wide range of parasitemia levels without DNA pre-amplification, and could be highly informative for evaluating the number of distinct parasite strains within samples (complexity of infection), and distinguishing recrudescent infections from new infections in therapeutic efficacy studies. The AMPLseq panel performs similarly to two existing panels of comparable size for relatedness measurement, despite differences in the data and approach used for designing each panel. Finally, we describe an R package (paneljudge) that facilitates design and comparative evaluation of AmpSeq panels for relatedness estimation, and we provide general guidance on the design and implementation of AmpSeq panels for genomic epidemiology of infectious disease.
Stakeholders’ views on an institutional dashboard with metrics for responsible research
Authors: Haven Tamarinde , Holst Martin , Strech Daniel
Published: September 2021

Background

Concerns about research waste have fueled debate about incentivizing individual researchers and research institutions to conduct responsible research. Instead of looking at impact factors or grants, research institutions should be assessed based on indicators that pertain to responsible research. In this study, we showed stakeholders a proof-of-principle dashboard with quantitative metrics that visualized responsible research performance on a German University Medical Center (UMC) level. Our research question was: What are stakeholders’ views on a dashboard that displays the adoption of responsible research practices on a UMC-level?

Methods

We recruited different stakeholders to participate in an online interview. Stakeholders included UMC leadership, support staff, funders, and experts in responsible research. We asked interviewees to reflect on the strengths and weaknesses of this institutional dashboard approach and enquired their perceptions of the metrics it included. The interviews were recorded and transcribed. We applied content analysis to understand what stakeholders considered the Strengths, Weaknesses, Opportunities, and Threats of the dashboard and its metrics.

Results

We interviewed 28 international stakeholders (60% German). Overall, interviewees thought the dashboard was helpful in seeing where an institution stands and appreciated the fact that the metrics were based on concrete behaviors. Main weaknesses included the lack of a narrative explaining the choice of the metrics covered. Interviewees considered the dashboard a good opportunity to initiate change and hoped the dashboard could be supplemented with other indicators in the future. They feared that making the dashboard public might risk incorrect interpretation of the metrics and put UMCs in a bad light.

Discussion

While the feedback was given specifically to our proof-of-principle dashboard, our findings indicate that discussion with stakeholders is needed to develop an overarching framework governing responsible research on an institutional level, and to involve research-performing organizations.
Detailed Quantification of Glomerular Structural Lesions Associates with Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome
Authors: Hodgin Jeffrey B. , Mariani Laura H. , Zee Jarcy , Liu Q , Smith Abigail R. , Eddy Sean , Hartman John , Hamidi Habib , Gaut Joseph P. , Palmer Matthew B. , Nast Cynthia C. , Chang Anthony , Hewitt Stephen , Gillespie Brenda W. , Kretzler Matthias , Holzman Lawrence B. , Barisoni Laura ,   for the Nephrotic Syndrome Study Network (NEPTUNE)
Published: September 2021

The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies, nor the clinical and molecular heterogeneity of these diseases. The Nephrotic Syndrome Study Network (NEPTUNE) Digital Pathology Scoring System (NDPSS) was applied to 221 NEPTUNE FSGS/MCD digital kidney biopsies for glomerular scoring using 37 descriptors. The descriptor-based glomerular profiles were used to cluster patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for association with time to proteinuria remission and disease progression by using adjusted Cox models, and eGFR measures over time by using linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes (DEG) between clusters and identify genes associated with individual descriptors driving cluster membership. Three clusters were identified: X (N=56), Y (N=68), and Z (N=97). Clusters Y and Z had higher probabilities of proteinuria remission (HR [95% CI]= 1.95 [0.99, 3.85] and 3.29 [1.52, 7.13], respectively), lower hazards of disease progression 0.22 [0.08, 0.57] and 0.11 [0.03, 0.45], respectively), and greater loss of eGFR over time compared with X. Cluster X had 1920 DEGs compared to Y+Z, which reflected activation of pathways of immune response and inflammation. Six individual descriptors driving the clusters individually correlated with clinical outcomes and gene expression. The NDPSS allows for characterization of FSGS/MCD patients into clinically and biologically relevant categories and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.

TRANSLATIONAL STATEMENT

FSGS and MCD are heterogeneous diseases that manifest with a variety of structural changes often not captured by conventional classification systems. This study shows that a detailed morphologic analysis and quantification of these changes allows for better representation of the structural abnormalities within each patient and for grouping patients with similar morphologic profiles into categories that are clinically and biologically relevant.
Deep Learning Segmentation of Glomeruli on Kidney Donor Frozen Sections
Authors: Davis Richard C. , Li Xiang , Xu Yuemei , Wang Zehan , Souma Nao , Sotolongo Gina , Bell Jonathan , Ellis Matthew , Howell David , Shen Xiling , Lafata Kyle , Barisoni Laura
Published: September 2021

Purpose

Recent advances in computational image analysis offer the opportunity to develop automatic quantification of histologic parameters as aid tools for practicing pathologists. This work aims to develop deep learning (DL) models to quantify non-sclerotic and sclerotic glomeruli on frozen sections from donor kidney biopsies.

Approach

A total of 258 whole slide images (WSI) from cadaveric donor kidney biopsies performed at our institution (n=123) and at external institutions (n=135) were used in this study. WSIs from our institution were divided at the patient level into training and validation datasets (Ratio: 0.8:0.2) and external WSIs were used as an independent testing dataset. Non-sclerotic (n=22767) and sclerotic (n=1366) glomeruli were manually annotated by study pathologists on all WSIs. A 9-layer convolutional neural network based on the common U-Net architecture was developed and tested for the segmentation of non-sclerotic and sclerotic glomeruli. DL-derived, manual segmentation and reported glomerular count (standard of care) were compared.

Results

The average Dice Similarity Coefficient testing was 0.90 and 0.83. and the F1, Recall, and Precision scores were 0.93, 0.96, and 0.90, and 0.87, 0.93, and 0.81, for non-sclerotic and sclerotic glomeruli, respectively. DL-derived and manual segmentation derived glomerular counts were comparable, but statistically different from reported glomerular count.

Conclusions

DL segmentation is a feasible and robust approach for automatic quantification of glomeruli. This work represents the first step toward new protocols for the evaluation of donor kidney biopsies.
Genome-wide Meta-analysis of Alcohol Use Disorder in East Asians
Authors: Zhou Hang , Kalayasiri Rasmon , Sun Yan , Nuñez Yaira Z. , Deng Hong-Wen , Chen Xiang-Ding , Justice Amy C. , Kranzler Henry R. , Chang Suhua , Lu Lin , Shi Jie , Sanichwankul Kittipong , Mutirangura Apiwat , Malison Robert T. , Gelernter Joel
Published: September 2021

BACKGROUND

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ∼30 AUD risk genes in European populations, but many fewer in East Asians.

METHODS

We conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from four cohorts: 1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP)sample; 2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort;3) AD in a Han Chinese-Cyto (array) cohort; and 4) two AD datasets in a Thai cohort. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2,254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4,464 East Asians (Kaiser Permanente data from dbGaP). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS.

RESULTS

Two risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, se = 0.067, p = 2.47×10−10) and nominally associated with pack years of smoking (beta = 0.09, se = 0.05, p = 4.52×10−2) and ever vs. never smoking (beta = 0.06, se = 0.02, p = 1.14×10−2).

CONCLUSIONS

This is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.
Decreased door-to-balloon time in patients with ST-segment elevation myocardial infarction during the early COVID-19 pandemic in South Korea – an observational study
Authors: Ryu Sukhyun , Kim Dasom , Jung Lae Young , Kim Baekjin , Lee Chang-Seop
Published: September 2021

Background

The coronavirus disease 2019 (COVID-19) resulted in a marked decrease in the number of patient visits for acute myocardial infarction (AMI) and delayed patient response and intervention in several countries. This study evaluated the effect of the COVID-19 pandemic on the number of patients, patient response time (pain-to-door), and intervention time (door-to-balloon) for patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).

Methods

Patients with STEMI or NSTEMI visiting a hospital in South Korea who underwent primary coronary intervention during the COVID-19 pandemic (January 29, 2020, to December 31, 2020) were compared with those in the equivalent period in 2018 to 2019. Patient response and intervention times were compared for the COVID-19 pandemic window (2020) and the equivalent period in 2018 to 2019.

Results

We observed no decrease in the number of patients with STEMI (P=0.50) and NSTEMI (P=0.94) during the COVID-19 pandemic compared to that in the previous years. Patient response times (STEMI: P=0.34; NSTEMI: P=0.89) during the overall COVID-19 pandemic period did not differ significantly. However, we identified a significant decrease in time to intervention among patients with STEMI (14%; p<0.01) during the early COVID-19 pandemic.

Conclusions

We found that the number of patient with STEMI and NSTEMI was consistent during the COVID-19 pandemic and that no time delays in patient response and intervention occurred. However, the door-to-balloon time among patients with STEMI significantly reduced during the early COVID-19 pandemic, which could be attributed to reduced emergency care utilization during the early pandemic.
COVID-19 Acceleration and Vaccine Status in France - Summer 2021
Authors: Baunez Christelle , Degoulet Mickael , Luchini Stéphane , Pintus Patrick A. , Teschl Miriam
Published: September 2021

Objectives

This note provides an assessment of COVID-19 acceleration among groups with different vaccine status in France.

Methods

We assess viral acceleration using a novel indicator introduced in Baunez et al. (2021). The acceleration index relates the percentage change of tests that have been performed on a given day to the percentage change in the associated positive cases that same day. We compare viral acceleration among vaccinated and unvaccinated individuals in France over the period May 31st - August 29, 2021.

Results

Once the state of the epidemic within each groups is accounted for, it turns out that viralaccelerationhas since mid-July converged to similar levels among vaccinated and unvaccinated individuals in France, even though viralspeedis larger for the latter group compared to the former.

Conclusion

Our results call for an increasing testing effort forbothvaccinated and unvaccinated individuals, in view of the fact that viral circulation is currently accelerating at similar levels for both groups in France.
Alterations in CD39/CD73 Axis of T cells associated with COVID-19 severity
Authors: Dorneles Gilson P , Teixeira Paula C , da Silva Igor M , Schipper Lucas L , Santana Filho Paulo C , Rodrigues Júnior Luiz Carlos , Bonorino Cristina , Peres Alessandra , Gonçalves Fonseca Simone , Monteiro Marta Chagas , Boeck Carina Rodrigues , Eller Sarah , Oliveira Tiago F , Wendland Eliana M , Romão Pedro R T
Published: September 2021

Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in COVID-19 patients. Lower plasma ATP and adenosine levels were identified in mild and severe COVID-19 patients associated with proinflammatory cytokine profiles compared to healthy controls. Mild COVID-19 patients presented lower frequencies of CD4+CD25+CD39+ (activated/memory Treg) and CD4+CD25+CD39+CD73+ T cells, and increased frequencies of high differentiated (CD27-CD28-) CD8+T cells compared to health controls. Severe COVID-19 patients also showed higher frequencies of CD4+CD39+, CD4+CD25-CD39+ (memory T effector cell), high differentiated CD8+ T cells (CD27-CD28-) and diminished frequencies of CD4+CD73+, CD4+CD25+CD39+ mTreg, CD4+CD25+CD39+CD73+, CD8+CD73+ and low-differentiated CD8+ T cells (CD27+CD28+) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8+ T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4+Annexin-V+ and CD8+Annexin-V+ T cells, showing increased T cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4+ and CD8+ T cells of a healthy donor. Interestingly, the in vitro incubation of PBMC from severe COVID-19 patients with adenosine reduced the NF-kB activation in T cells and monocytes. Together, these data add new knowledge regarding the immunopathology of COVID-19 through purinergic regulation, especially concerning adenosine deficiency.

Brief Commentary

Background

Host factors modulates the type and the strength of the immune response during the viral infection, as well as the disease outcomes. However, to date, the role of purinergic signaling in SARS-CoV-2 infection remains unclear. We sought to evaluate alterations in extracellular adenine nucleotides and CD39/CD73 axis in T cells and their relationship with acute COVID-19 immunopathogenesis.

Translational Significance

COVID-19 patients present lower extracellular ATP and adenosine levels associated with altered CD39 and CD73 expression in CD4+ and CD8+ T cells. Purinergic signaling correlated with alterations in the differentiation status of CD8+ T cells, lymphocyte mitochondrial membrane polarization and T cell apoptosis. Our demonstration of the lower NF-κB activation in T cells and monocytes afterin vitroadenosine treatment may indicate the regulatory effect of adenosine in the inflammation and cytokine storm of COVID-19. This study adds new knowledge regarding the immunopathology of COVID-19 through purinergic regulation.
Genomic analysis of SARS-CoV-2 breakthrough infections from Varanasi, India
Authors: Zaveri Lamuk , Singh Royana , Basu Priyoneel , Banu Sofia , Mukherjee Payel , Vishwakarma Shani , Sahni Chetan , Kaur Manpreet , Singh Nitish Kumar , Yadav Abhay Kumar , Yadav Ajay Kumar , Ashish  , Mishra Shivani , Tiwari Shivam , Mishra Surendra Pratap , Vodapalli Amareshwar , Bollu Himasri , Das Debashruti , Singh Prajjval Pratap , Chaubey Gyaneshwer , Sowpati Divya Tej , Tallapaka Karthik Bharadwaj
Published: September 2021

Studies worldwide have shown that the available vaccines are highly effective against SARS-CoV-2. However, there are growing laboratory reports that the newer variants of concerns (VOCs e.g. Alpha, Beta, Delta etc) may evade vaccine induced defense. In addition to that, there are few ground reports on health workers having breakthrough infections. In order to understand VOC driven breakthrough infection we investigated 14 individuals who tested positive for SARS-CoV-2 after being administered a single or double dose of Covishield (ChAdOx1, Serum Institute of India) from the city of Varanasi, which is located in the Indian state of Uttar Pradesh. Genomic analysis revealed that 78.6% (11/14) of the patients were infected with the B.1.617.2 (Delta) variant. Notably, the frequency (37%) of this variant in the region was significantly lower (p<0.01), suggesting that the vaccinated people were asymmetrically infected with the Delta variant. Most of the patients tested displayed mild symptoms, indicating that even a single dose of the vaccine can help in reducing the severity of the disease. However, more comprehensive epidemiological studies are required to understand the effectiveness of vaccines against the newer VOCs.
Comparative analysis of genome-encoded viral sequences reveals the evolutionary history of flavivirids (family Flaviviridae)
Authors: Bamford Connor G. G. , de Souza William M. , Parry Rhys , Gifford Robert J.
Published: September 2021

The flavivirids (family Flaviviridae) are a group of positive-strand RNA viruses that pose serious risks to human and animal health on a global scale. Here we use flavivirid-derived DNA sequences, identified in animal genomes, to reconstruct the long-term evolutionary history of family Flaviviridae. We demonstrate that flavivirids are >100 million years old and show that this timing can be combined with dates inferred from co-phyletic analysis to produce a cohesive overview of their evolution, distribution and diversity wherein the main flavivirid subgroups originate in early animals and broadly co-diverge with major animal phyla. In addition, we reveal evidence that the ‘classical flaviviruses’ of vertebrates, most of which are transmitted via blood-feeding arthropod vectors, originally evolved in hematophagous arachnids and later acquired the capacity to be transmitted by insects. Our findings imply that the biological properties of flavivirids have been acquired gradually over the course of animal evolution. Thus, broad-scale comparative analysis will likely reveal fundamental insights into their biology. We therefore published our results via an open, extensible, database (Flavivirid-GLUE), which we constructed to facilitate the wider utilisation of genomic data and evolution-related domain knowledge in flavivirid research.
Exosome-transmitted miR-769-5p confers cisplatin resistance and tumorigenesis in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53
Authors: Jing Xinming , Xie Mengyan , Ding Kun , Xu Tingting , Fang Yuan , Ma Pei , Shu Yongqian
Published: September 2021

Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism of cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participates in tumor metastasis and drug resistance. In this study, we discovered that cisplatin-resistant GC cells communicate with the tumor microenvironment by secreting microvesicles. The biologically active miR-769-5p can be integrated into exosomes and delivered to sensitive cells, thereby spreading cisplatin resistance. Mi769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. Mechanistically, miR-769-5p promotes cisplatin resistance by targeting CASP9 so as to inhibit the downstream caspase pathway and promote the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769 with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can be a key regulator of cisplatin resistance in GC. Therefore, exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.
A Data-Driven Framework for Identifying Intensive Care Unit Admissions Colonized with Multidrug-Resistant Organisms
Authors: Çağlayan Çağlar , Barnes Sean , Pineles Lisa L. , Klein Eili Y. , Harris Anthony D.
Published: September 2021

The rising prevalence of multi-drug resistant organisms (MDROs), such as Methicillin-resistantStaphylococcus aureus(MRSA), Vancomycin-resistantEnterococci(VRE), and Carbapenem-resistantEnterobacteriaceae(CRE), is an increasing concern in healthcare settings. Leveraging electronic healthcare record data, we developed a data-driven framework to predict MRSA, VRE, and CRE colonization upon intensive care unit admission (ICU), and identify the associated socio-demographic and clinical factors using logistic regression (LR), random forest (RF), and XGBoost algorithms. We performed threshold optimization for converting predicted probabilities into binary predictions and identified the cut-off maximizing the sum of sensitivity and specificity. We achieved the following sensitivity and specificity values with the best performing models: 80% and 66% for VRE with LR, 73% and 77% for CRE with XGBoost, 76% and 59% for MRSA with RF, and 82% and 83% for MDRO (i.e., VRE or CRE or MRSA) with RF. Further, we identified several predictors of MDRO colonization, including long-term care facility exposure, current diagnosis of skin/subcutaneous tissue or infectious/parasitic disease, and recent isolation precaution procedures before ICU admission. Our data-driven modeling framework can be used as a clinical decision support tool for timely predictions, identification of high-risk patients, and selective and timely use of infection control measures in ICUs.
Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, including early variants of concern: a test-negative design, British Columbia, Canada
Authors: Skowronski Danuta M , Setayeshgar Solmaz , Zou Macy , Prystajecky Natalie , Tyson John R , Sbihi Hind , Fjell Chris D , Galanis Eleni , Naus Monika , Patrick David M , Adam Shiraz El , Ahmed May , Kim Shinhye , Henry Bonnie , Hoang Linda M N , Sadarangani Manish , Jassem Agatha N , Krajden Mel
Published: September 2021

Introduction

In randomized controlled trials, single-dose efficacy against SARS-CoV-2 illness exceeded 90% for mRNA vaccines (BNT162b2 and mRNA-1273), and 75% for ChAdOx1. In British Columbia (BC), Canada second doses were deferred up to 16 weeks and ChAdOx1 was only initially recommended for adults 55 years of age and older. We compared single-dose vaccine effectiveness (VE) during the spring 2021 wave in BC when Alpha and Gamma variants of concern (VOC) predominated.

Methods

VE was estimated against infection and hospitalization by test-negative design: cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Adults 50-69 years old with specimen collection between April 4 and May 22 (weeks 14-20) were included. Variant-specific VE was estimated between weeks 17-20 when genetic characterization of all case viruses was performed, primarily through whole genome sequencing.

Results

VE analyses included 7,116 (10%) cases and 60,958 controls. Three-quarters of vaccinated participants received mRNA vaccine (60% BNT162b2, 15% mRNA-1273) and 25% received ChAdOx1. Half of genetically characterized viruses were Alpha, with 38% Gamma, 4% Delta and 8% non-VOCs. Single-dose VE against any infection was 75% (95%CI: 72-78) for BNT162b2, 82% (95%CI: 76-87) for mRNA-1273 and 61% (95%CI: 54-66) for ChAdOx1. VE against hospitalization was 83% (95%CI: 76-89), 85% (95%CI: 63-94) and 96% (95%CI: 86-99), respectively. VE against Alpha vs. Gamma infections did not differ among mRNA (78%;95%CI: 73-82 and 80%;95%CI: 74-85) or ChAdOx1 (66%;95%CI: 57-74 and 60%;95%CI: 48-69) recipients.

Conclusions

A single dose of mRNA vaccine reduced the SARS-CoV-2 infection risk by at least 75%, including infections due to early VOC. Although effectiveness of a single dose of ChAdOx1 was lower at 60% against infection, just one dose of any vaccine reduced the hospitalization risk by more than 80%. In the context of constrained vaccine supplies, these findings have implications for global vaccine deployment to reduce the overall burden of infections and hospitalizations due to SARS-CoV-2.
Polygenic signals of sexually antagonistic selection in contemporary human genomes
Authors: Ruzicka Filip , Holman Luke , Connallon Tim
Published: September 2021

Mutations that increase fitness in one sex may decrease fitness in the other. Such “sexually antagonistic” (SA) genetic variants can constrain adaptation and increase variability for fitness components (e.g., survival, fertility, and disease susceptibility). However, detecting SA selection in genomes is immensely challenging, as it requires prohibitively large datasets that combine genomic sequences with individual fitness measurements. Here, we use genotypic and reproductive success data from ∼250,000 UK Biobank individuals to comprehensively assess the extent of SA genetic variation in humans. We first develop new theoretical models for signals of SA selection spanning a full generational life cycle—including SA polymorphisms affecting survival, reproductive success and overall fitness. Comparing our models with UK Biobank data, we uncover multiple empirical signals of polygenic SA selection, including sex-differential effects of genetic variants on each fitness component, and positive correlations between sex-differential effects and minor allele frequencies. We show that these signals cannot be explained by simple models of sex differences in purifying selection, or by potential confounders such as population structure and sequence mapping errors. We further show that candidate SA sites disproportionately affect functional genomic regions, including polymorphisms associated with quantitative traits and disease. Finally, we examine historical evolutionary processes affecting candidate SA sites, which are consistent with the drift-dominated dynamics predicted by previous theory. Overall, our results support SA genomic variation in humans and highlight its broader functional and evolutionary consequences.
Imaging Sensitive and Drug-Resistant Bacterial Infection with [11C]-TMP: In Vitro and First-in-Human Evaluation
Authors: Lee Iris K. , Jacome Daniel A. , Cho Joshua K. , Tu Vincent , Young Anthony , Dominguez Tiffany , Northrup Justin D. , Etersque Jean M. , Lee Hsiaoju , Ruff Andrew , Aklilu Ouniol , Bittinger Kyle , Glaser Laurel , Dorgan Daniel , Hadjiliadis Denis , Kohli Rahul M. , Mach Robert H. , Mankoff David A. , Doot Robert , Sellmyer Mark A.
Published: September 2021

Recently, several molecular imaging strategies have developed to image bacterial infections in humans. Nuclear approaches, specifically positron emission tomography (PET), affords sensitive detection and the ability to non-invasively locate infections deep within the body. Two key radiotracer classes have arisen: metabolic approaches targeting bacterial specific biochemical transformations, and antibiotic-based approaches that have inherent selectivity for bacteria over mammalian cells. A critical question for clinical application of antibiotic radiotracers is whether resistance to the template antibiotic abrogates specific uptake, thus diminishing the predictive value of the diagnostic test. We recently developed small-molecule PET radiotracers based on the antibiotic trimethoprim (TMP), including [11C]-TMP, and have shown their selectivity for imaging bacteria in preclinical models. Here, we measure the in vitro uptake of [11C]-TMP in pathogenic susceptible and drug-resistant bacterial strains. Both resistant and susceptible bacteria showed similar in vitro uptake, which led us to perform whole genome sequencing of these isolates to identify the mechanisms of TMP resistance that permit retained radiotracer binding. By interrogating these isolate genomes and a broad panel of previously sequenced strains, we reveal mechanisms where uptake or binding of TMP radiotracers can potentially be maintained despite the annotation of genes conferring antimicrobial resistance. Finally, we present several examples of patients with both TMP-sensitive and drug-resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of an antibiotic radiotracer to image bacterial infection in patients, which may allow insights into human bacterial pathogenesis, infection diagnosis, and antimicrobial response monitoring.

One Sentence Summary

The PET radiotracer [11C]-trimethoprim shows high uptake in both TMP-sensitive and -resistant bacteria in vitro, the potential for imaging many different pathogenic strains, and uptake in patients with active infections.
Viral loads and profile of the patients infected with SARS-CoV-2 Delta, Alpha or R.1 variants in Tokyo
Authors: Tani-Sassa Chihiro , Iwasaki Yumi , Ichimura Naoya , Nagano Katsutoshi , Takatsuki Yuna , Yuasa Sonoka , Takahashi Yuta , Nakajima Jun , Sonobe Kazunari , Nukui Yoko , Takeuchi Hiroaki , Tanimoto Kousuke , Tanaka Yukie , Kimura Akinori , Tohda Shuji
Published: September 2021

The rapid spread of the Delta variant of SARS-CoV-2 became a serious concern worldwide in summer 2021. We examined the copy number and variant types of all SARS-CoV-2-positive patients who visited our hospital from February to August 2021 using PCR tests. Whole genome sequencing was performed for some samples. The R.1 variant (B.1.1.316) was responsible for most infections in March, replacing the previous variant (B.1.1.214); the Alpha (B.1.1.7) variant caused most infections in April and May; and the Delta variant (B.1.617.2) was the most prevalent in July and August. There was no significant difference in copy numbers among the previous variant cases (n=29, median 3.0×104 copies/μL), R.1 variant cases (n=28, 2.1×105 copies/μL), Alpha variant cases (n=125, 4.1×105 copies/μL), and Delta variant cases (n=106, 2.4×105 copies/μL). Patients with Delta variant infection were significantly younger than those infected with R.1 and the previous variants, possibly because many elderly individuals in Tokyo were vaccinated between May and August. There was no significant difference in mortality among the four groups. Our results suggest that the increased infectivity of Delta variant may be caused by factors other than the higher viral loads. Clarifying these factors is important to control the spread of Delta variant infection.
Linking rattiness, geography and environmental degradation to spillover Leptospira infections in marginalised urban settings: an eco-epidemiological community-based cohort study in Brazil
Authors: Eyre Max T. , Souza Fábio N. , Carvalho-Pereira Ticiana S. A. , Nery Nivison , de Oliveira Daiana , Cruz Jaqueline S , Sacramento Gielson A. , Khalil Hussein , Wunder Elsio A. , Hacker Kathryn P. , Childs James E. , Reis Mitermayer G. , Begon Mike , Diggle Peter J. , Ko Albert I. , Giorgi Emanuele , Costa Federico
Published: September 2021

Background

Zoonotic spillover from animal reservoirs is responsible for a significant global public health burden, but the processes that promote spillover events are poorly understood in complex urban settings. Endemic transmission of Leptospira, the agent of leptospirosis, in marginalised urban communities occurs through human exposure to an environment contaminated by bacteria shed in the urine of the rat reservoir. However, it is unclear to what extent transmission is driven by variation in the distribution of rats or by the dispersal of bacteria in rainwater runoff and overflow from open sewer systems.

Methods

We conducted an eco-epidemiological study in a high-risk community in Salvador, Brazil, by prospectively following a cohort of 1,401 residents to ascertain serological evidence for leptospiral infections. A concurrent rat ecology study was used to collect information on the fine-scale spatial distribution of ‘rattiness’, our proxy for rat abundance and exposure of interest. We developed and applied a novel geostatistical framework for joint spatial modelling of multiple indices of disease reservoir abundance and human infection risk.

Results

The estimated infection rate was 51.4 (95%CI 40.4, 64.2) infections per 1,000 follow-up events. Infection risk increased with age until 30 years of age and was associated with male gender. Rattiness was positively associated with infection risk for residents across the entire study area, but this effect was stronger in higher elevation areas (OR 3.27 95%CI 1.68, 19.07) than in lower elevation areas (OR 1.14 95%CI 1.05, 1.53).

Conclusions

These findings suggest that, while frequent flooding events may disperse bacteria in regions of low elevation, environmental risk in higher elevation areas is more localised and directly driven by the distribution of local rat populations. The modelling framework developed may have broad applications in delineating complex animal-environment-human interactions during zoonotic spillover and identifying opportunities for public health intervention.

Funding

This work was supported by the Oswaldo Cruz Foundation and Secretariat of Health Surveillance, Brazilian Ministry of Health, the National Institutes of Health of the United States (grant numbers F31 AI114245, R01 AI052473, U01 AI088752, R01 TW009504 and R25 TW009338); the Wellcome Trust (102330/Z/13/Z), and by the Fundacção de Amparo à Pesquisa do Estado da Bahia (FAPES-B/JCB0020/2016). M.T.E is supported by an MRC doctorate studentship. F.N.S. participated in this study under a FAPESB doctorate scholarship.
LM-GVP: A Generalizable Deep Learning Framework for Protein Property Prediction from Sequence and Structure
Authors: Wang Zichen , Combs Steven A. , Brand Ryan , Calvo Miguel Romero , Xu Panpan , Price George , Golovach Nataliya , Salawu Emmanuel O. , Wise Colby J. , Ponnapalli Sri Priya , Clark Peter M.
Published: September 2021

Proteins perform many essential functions in biological systems and can be successfully developed as bio-therapeutics. It is invaluable to be able to predict their properties based on a proposed sequence and structure. In this study, we developed a novel generalizable deep learning framework, LM-GVP, composed of a protein Language Model (LM) and Graph Neural Network (GNN) to leverage information from both 1D amino acid sequences and 3D structures of proteins. Our approach outperformed the state-of-the-art protein LMs on a variety of property prediction tasks including fluorescence, protease stability, and protein functions from Gene Ontology (GO). We also illustrated insights into how a GNN prediction head can guide the protein LM to better leverage structural information. We envision that our deep learning framework will be generalizable to many protein property prediction problems to greatly accelerate protein engineering and drug development.
Brain I3 Binding Protein regulates K-Ras4B membrane localization and signaling
Authors: McCabe Ian , Zhang Huanqing , Cooper Jonathan A. , Turner David L. , Vojtek Anne B.
Published: September 2021

Membrane localization of Ras proteins is necessary for their biological functions and oncogenic activity. We report here on the identification of Brain I3 Binding Protein (BRI3BP) as a novel binding partner for Ras. We show that K-Ras4B plasma membrane localization and biological function are reduced in the absence of BRI3BP. BRI3BP interacts with K-Ras4B and K-Ras4A and our data suggest that BRI3BP operates within the recycling endosomal compartment to regulate K-Ras localization to the plasma membrane. This study uncovers a new regulatory protein for Ras membrane localization.
Ligand binding remodels protein side chain conformational heterogeneity
Authors: Wankowicz Stephanie A. , de Oliveira Saulo H.P. , Hogan Daniel W. , van den Bedem Henry , Fraser James S.
Published: September 2021

While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decrease and relative hydrophobicity increases. Across a series of 13 inhibitor bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from NMR studies suggesting that residual side chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.