bluuebunny/crossref_metadata_2025 huggingface dataset:
Executive Functions and Attention in Patients With Psychogenic Nonepileptic Seizures Compared With Healthy Controls: A Cross-Sectional Study
Authors: Hamouda Karim , Senf-Beckenbach Philine Anna , Gerhardt Carola , Irorutola Freddy , Rose Matthias , Hinkelmann Kim
Published: July 2021

Objective

Psychogenic nonepileptic seizures (PNESs) are considered functional neurological symptoms and are highly prevalent in specialized epilepsy clinics. The underlying mechanisms of PNES are not fully understood. Recent findings point toward possible alterations in attention and executive functions. This study aimed to extend the current knowledge of attention and executive function in patients with PNES and to assess possible relationships between seizures and dissociation, childhood trauma, and cognitive function.

Methods

We recruited 40 patients with PNES and 40 sex-, age-, and education-matched healthy controls (HCs) in this study. Participants completed self-report questionnaires to assess early life stress (Childhood Trauma Questionnaire [CTQ]), dissociation (the German version of the Dissociative Experience Scale, or Fragebogen zu dissoziativen Symptomen), and depression (Patient Health Questionnaire-9). Executive functions and attention were assessed with the Trail Making Test (TMT), Digit Span, and Attention Network Task.

Results

Compared with HCs, patients with PNES reported significantly higher levels of childhood trauma, depression, and dissociation. Patients with PNES also had reduced performance indices for Digit Span Forward (d = 0.62), Digit Span Backward (d = 0.62), and TMT (d = 0.67) but not Attention Network Task. CTQ scores positively correlated with TMT and Digit Span Backward performance in patients with PNES. Adjusting for CTQ scores attenuated the observed group difference in TMT performance. Depression and dissociation did not explain the observed findings.

Conclusions

These results contribute to the evidence of impaired executive functions in patients with PNES. Furthermore, childhood trauma scores, but not (trait) dissociation or depression scores, seem to drive group differences (HC versus patients with PNES).
Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder
Authors: Wittbrodt Matthew T. , Gurel Nil Z. , Nye Jonathon A. , Shandhi Md Mobashir H. , Gazi Asim H. , Shah Amit J. , Pearce Bradley D. , Murrah Nancy , Ko Yi-An , Shallenberger Lucy H. , Vaccarino Viola , Inan Omer T. , Bremner J. Douglas
Published: July 2021

Objective

Posttraumatic stress disorder (PTSD) is a disabling condition affecting a large segment of the population; however, current treatment options have limitations. New interventions that target the neurobiological alterations underlying symptoms of PTSD could be highly beneficial. Transcutaneous cervical (neck) vagal nerve stimulation (tcVNS) has the potential to represent such an intervention. The goal of this study was to determine the effects of tcVNS on neural responses to reminders of traumatic stress in PTSD.

Methods

Twenty-two participants were randomized to receive either sham (n = 11) or active (n = 11) tcVNS stimulation in conjunction with exposure to neutral and personalized traumatic stress scripts with high-resolution positron emission tomography scanning with radiolabeled water for brain blood flow measurements.

Results

Compared with sham, tcVNS increased brain activations during trauma scripts (p < .005) within the bilateral frontal and temporal lobes, left hippocampus, posterior cingulate, and anterior cingulate (dorsal and pregenual), and right postcentral gyrus. Greater deactivations (p < .005) with tcVNS were observed within the bilateral frontal and parietal lobes and left thalamus. Compared with tcVNS, sham elicited greater activations (p < .005) in the bilateral frontal lobe, left precentral gyrus, precuneus, and thalamus, and right temporal and parietal lobes, hippocampus, insula, and posterior cingulate. Greater (p < .005) deactivations were observed with sham in the right temporal lobe, posterior cingulate, hippocampus, left anterior cingulate, and bilateral cerebellum.

Conclusions

tcVNS increased anterior cingulate and hippocampus activation during trauma scripts, potentially indicating a reversal of neurobiological changes with PTSD consistent with improved autonomic control.

Trial Registration: No. NCT02992899.
Congenital Chagas disease: progress toward implementation of pregnancy-based screening
Authors: Edwards Morven S. , Montgomery Susan P.
Published: July 2021

Purpose of review

Lack of recognition of congenital Chagas disease in infants of mothers from endemic regions who are living in countries nonendemic for Trypanosoma cruzi infection suggests a high rate of underdiagnosis. Pregnancy is the optimal access point for identifying Chagas disease in at-risk mothers and their infants. In this review, we update progress toward implementation of pregnancy-based screening for congenital Chagas disease in nonendemic settings.

Recent findings

International organizations have updated recommendations for diagnosis, treatment and prevention of congenital Chagas disease. Reports of successful implementation of pregnancy-based screening at some centers provide a model for optimizing diagnosis of congenital Chagas disease. Screening family members of index patients may identify additional T. cruzi-infected persons. Promising tests to augment current diagnostic modalities for maternal and congenital Chagas disease are in development. Universal or risk-based screening would be cost-effective. More healthcare providers are now aware that treatment of congenital Chagas disease is curative and are promoting efforts to make pregnancy-based screening for congenital Chagas disease a standard of care.

Ongoing efforts to implement routine pregnancy-based screening for congenital Chagas disease in nonendemic regions will mutually benefit infants, their mothers and family members and can prevent potentially fatal Chagas cardiomyopathy.
Low-Field Magnetic Resonance Imaging
Authors: Hori Masaaki , Hagiwara Akifumi , Goto Masami , Wada Akihiko , Aoki Shigeki
Published: July 2021

Low-field magnetic resonance imaging (MRI) systems have seen a renaissance recently due to improvements in technology (both hardware and software). Originally, the performance of low-field MRI systems was rated lower than their actual clinical usefulness, and they were viewed as low-cost but poorly performing systems. However, various applications similar to high-field MRI systems (1.5 T and 3 T) have gradually become possible, culminating with high-performance low-field MRI systems and their adaptations now being proposed that have unique advantages over high-field MRI systems in various aspects. This review article describes the physical characteristics of low-field MRI systems and presents both their advantages and disadvantages for clinical use (past to present), along with their cutting-edge clinical applications.
Handball-Related Head and Neck Trauma: An Analysis of the 2000–2019 National Electronic Injury Surveillance System (NEISS) Database
Authors: Stanbouly Dani , Murphy Richard , Lee Kevin C. , Halepas Steve , Koch Alia
Published: July 2021

Purpose:

The purpose of this study was to report on the characteristics of head and neck injuries secondary to the sport of Handball in the United States.

Materials and Methods:

This is a 20-year cross-sectional study that was conducted using the National Electronic Injury Surveillance System. Handball injuries were included in the study if they involved the head, face, eyeball, mouth, ear, or neck. The primary study predictor was age group. The study outcome was the type of injury (diagnosis) and the location of injury. Chi-squared testing (χ2) was performed to compare categorical variables.

Results:

Males composed more than three-fourths of the sample of patients (76.2%). White patients (38.7%) composed the most common racial group. The most common anatomical location injured was the head (45.9%). The most common primary diagnoses were contusion/abrasion (22.5%). Children were most likely to injure their head (P < 0.01) among all the anatomic regions. Young adults were least likely to injure their eyeball (P < 0.05). In contrast to children, adults were least likely to injure their head (P < 0.01). In contrast to young adults, adults were most likely to injure their eyeball (P < 0.01). With regards to types of injuries, Children were least likely to incur lacerations (P < 0.01). In contrast, young adults were most likely to incur lacerations (P < 0.01); however, young adults were least likely to suffer from contusions/abrasions (P < 0.01). In contrast to young adults, adults were most likely to suffer from contusions/abrasions (P < 0.01).

Conclusions:

Contusions/abrasions and brain damage were the two most common injuries in this sport. The head was the most commonly injured anatomical region. Both the type of injury and the anatomical location of injury that occur during the practice of handball significantly vary depending on the age group involved in the game.
Cognitive-behavioral and related therapies for obsessive–compulsive and related disorders
Authors: Reddy Y.C. Janardhan , Arumugham Shyam Sundar , Balachander Srinivas
Published: July 2021

Purpose of review

Cognitive behavioral therapy (CBT) with exposure and response prevention is the first-line treatment for obsessive–compulsive disorder (OCD) and related disorders such as body dysmorphic disorder (BDD). We review here recent developments in CBT and related therapies in treating OCD and related disorders.

Recent findings

Superiority of CBT over medications in treating OCD is being questioned by some recent meta-analyses, nonetheless CBT continues to be the mainstay of treatment. Web-based therapies have been shown to be beneficial in treating at least mild-to-moderately ill patients. Mindfulness-based CBT, intensive residential treatment and Bergen 4-day concentrated exposure are also proving to be useful in treating OCD. Large well designed studies have demonstrated the efficacy CBT over supportive therapy in treating BDD. Research on the efficacy of CBT in treating hoarding disorder is accumulating.

Efficacy of web-based CBT has a potential public health importance in that CBT may now become accessible to all and benefit at least mild-to-moderately ill patients who form most of the clinically ill sample. Similarly, efficacy of Bergen 4-day concentrated exposure will have a huge public health implication if the findings can be replicated in other centers across the world.
Contemporary psychological perspectives of personality disorders
Authors: Marčinko Darko , Jakšić Nenad , Šimunović Filipčić Ivona , Mustač Filip
Published: July 2021

Purpose of review

The aim of this study was to review the recent literature on contemporary psychological perspectives of personality disorders, including novel psychotherapeutic interventions aimed at these vulnerable individuals.

Recent findings

Among the various psychological theories and models of personality disorders, still the most popular and researched are psychodynamic, cognitive and interpersonal perspectives. More specifically, object relations theory, cognitive schema conceptualization and interpersonal circumplex model have produced the most empirical investigations of personality disorders in recent years. Latest work has suggested that all three perspectives have contributed to and are compatible with the dimensional personality disorders framework in DSM-5-AMPD and ICD-11 (including level of personality functioning and personality traits). These models have yielded specific psychological treatments of personality disorders; although most psychotherapies have been constructed for patients with borderline personality disorder (BPD), there is an increasing number of treatment modalities aimed at individuals with other forms of personality disorder, such as those with narcissistic or antisocial traits/disorders. More research into their effectiveness and long-term benefits is necessary.

Novel research keeps updating our knowledge on the cause, manifestations and psychological treatments of personality disorders, particularly from psychodynamic, cognitive and interpersonal perspectives.
Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia
Authors: Stölzel Friedrich , Fordham Sarah E. , Lin Wei-Yu , Blair Helen , Elstob Claire , Nandana Devi , Mohr Brigitte , Ruhnke Leo , Kunadt Desiree , Dill Claudia , Allsop Daniel , Piddock Rachel , Soura Emmanouela-Niki , Park Catherine , Fadly Mohd , Rahman Thahira , Alharbi Abrar , Wobus Manja , Altmann Heidi , Röllig Christoph , Wagenführ Lisa , Jones Gail L. , Menne Tobias , Jackson Graham H. , Marr Helen J. , Fitzgibbon Jude , Onel Kenan , Meggendorfer Manja , Heidenreich Olaf , Haferlach Torsten , Villar Sara , Ariceta Beñat , Diaz Rosa Ayala , Prosper Felipe , Montesinos Pau , Martinez-Lopez Joaquin , Bornhäuser Martin , Allan James M.
Published: July 2021

Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutation (focal deletion and nonsense mutation) in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine, but acutely sensitive to 5’-azacitidine (5’-Aza) hypomethylating monotherapy, resulting in long-term morphological remission (overall survival (OS) 850 days). Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5’-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5’-Aza compared to cells with monoallelic mutation. We subsequently identified 29 additional patients from the Study Alliance Leukemia biobank with chromosome 4 abnormalities and identified two further patients with complex biallelic TET2 mutations, including one with trisomy 4, homozygosity across the long arm and an inactivating point mutation. We also screened patients recruited to the PETHEMA FLUGAZA phase 3 clinical trial and identified three patients with biallelic TET2 mutations, two of whom had responded very well to single agent 5’-Aza (OS 767 and 579 days) despite having adverse risk AML and poor performance status. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.

Key Points

Mutant TET2 allele dosage affects response to 5’-azacitidine in acute myeloid leukemia in vitro and in a xenograft model.

Our data highlight the importance for screening of biallelic mutations to predict response to therapy in acute myeloid leukemia.
Powerful gene-based testing by integrating long-range chromatin interactions and knockoff genotypes
Authors: Ma Shiyang , Dalgleish James L. , Lee Justin , Wang Chen , Liu Linxi , Gill Richard , Buxbaum Joseph D. , Chung Wendy , Aschard Hugues , Silverman Edwin K. , Cho Michael H. , He Zihuai , Ionita-Laza Iuliana
Published: July 2021

Gene-based tests are valuable techniques for identifying genetic factors in complex traits. Here we propose a novel gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to GWAS and whole-genome sequencing data for multiple diseases and traits we show that the proposed test increases the power over state-of-the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrow focus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion.

Significance

Gene-based tests are important tools for elucidating the genetic basis of complex traits. Despite substantial recent efforts in this direction, the existing tests are still limited owing to low power and detection of false positive signals due to the confounding effects of linkage disequilibrium. In this paper we describe a novel gene-based test that attempts to address these limitations by incorporating data on long-range chromatin interactions, several recent technical advances for region-based testing, and the knockoff framework for synthetic genotype generation. Through extensive simulations and applications to multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests and provides a narrower focus on the possible causal genes involved at a locus.
Lives saved and hospitalizations averted by COVID-19 vaccination in New York City
Authors: Shoukat Affan , Vilches Thomas N. , Moghadas Seyed M. , Sah Pratha , Schneider Eric C. , Shaff Jaimie , Zucker Jane , Quinn Celia , Chokshi Dave A. , Galvani Alison P.
Published: July 2021

Despite the emergence of highly transmissible variants, the number of cases in NYC has fallen from over 5,500 average daily cases in January, 2020 to less than 350 average daily cases in July, 2021. The impact of vaccination in saving lives and averting hospitalizations in NYC has not been formally investigated yet. We used an age-stratified agent-based model calibrated to COVID-19 transmission and vaccination in NYC to evaluate the impact of the vaccination campaign in suppressing the COVID-19 burden. We found that the vaccination campaign has prevented over 250,000 COVID-19 cases, 44,000 hospitalizations and 8,300 deaths from COVID-19 infection since the start of vaccination through July 1, 2021. Notably, the swift vaccine rollout suppressed another wave of COVID-19 that would have led to sustained increase in cases, hospitalizations and deaths during spring triggered by highly transmissible variants. As the Delta variant sweeps across the city, the findings of this study underscore the urgent need to accelerate vaccination and close the vaccine coverage gaps across the city.
The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepaticTransthyretinexpression
Authors: Pathak Gita A. , De Lillo Antonella , Wendt Frank R. , De Angelis Flavio , Koller Dora , Mendoza Brenda Cabrera , Jacoby Daniel , Miller Edward J. , Buxbaum Joel N. , Polimanti Renato
Published: July 2021

Background

Transthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targetingTTRhepatic transcription have been shown to reduce TTR amyloid formation. The goal of our study was to investigate the role of genetic regulation ofTTRtranscriptomic variation in human traits and diseases.

Methods and Findings

We leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the GTEx (Genotype-Tissue Expression) project to test the association of genetically regulatedTTRgene expression with 7,149 traits assessed in 420,531 individuals. We conducted a joint multi-tissue analysis ofTTRtranscription regulation and identified an association with a specific operational procedure related to secondary open reduction of fracture of bone (p=5.46×10−6, false discovery rate q=0.039). Using tissue-specificTTR cisexpression quantitative trait loci, we demonstrated that the association is driven by the genetic regulation ofTTRhepatic expression (odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.85-6.44, p = 9.51×10−5). Although there is an established relationship of retinol and thyroxine abnormalities with bone loss and the risk of bone fracture, this is the first evidence of a possible effect ofTTRtranscriptomic regulation. Investigating the UK Biobank electronic health records available, we investigated the comorbidities affecting individuals undergoing the specific surgical procedure. Excluding medical codes related to bone fracture events, we identified a pattern of health outcomes that have been previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, 95%CI=1.93-4.25, p=9.18×10−8), carpal tunnel syndrome (OR=2.15, 95%CI=1.33-3.48, p=0.002), and a history of gastrointestinal diseases (OR=2.01, 95%CI=1.33-3.01, p=8.07×10−4).

Conclusions

The present study supports the notion thatTTRhepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. Our findings highlight how the integration of omics information and electronic health records can successfully dissect the complexity of multi-function proteins such as TTR.
Benefit-finding and self-compassion promote psychological well-being in caregivers of individuals with mental illness: a cross-sectional study
Authors: Tan Edina Yi-Qin , Yip Vania T. , Rolles-Abraham Kim Lian
Published: July 2021

Background

Resilience factors that promote psychological well-being amongst caregivers of individuals with a mental illness are understudied. Coping strategies (problem-focused coping, emotion-focused coping and benefit-finding) have been found to influence the relation between stress and psychological outcomes, but their relative contribution to psychological well-being has not been tested. Self-compassion reduces caregiver burden in caregivers, yet no research has examined its contribution to psychological well-being nor the mechanisms via which it could do so. The aim of this study was to examine benefit-finding and self-compassion as resilience factors that could promote psychological well-being amongst caregivers of individuals with mental illnesses.

Methods

This cross-sectional study was conducted between June 2019 to October 2019 in Singapore. 107 informal caregivers of individuals with various diagnosed mental illnesses completed an online questionnaire. COPE, General Benefit Finding Scale (GBFS), Self-Compassion Scale -Short (SCS-SF), Psychological Well-Being Scale -Brief (PWBS-B), and Hospital Anxiety and Depression Scale (HADS) were used. Hierarchical multiple regression and mediation analyses were conducted.

Results

Benefit-finding was a more important predictor of psychological well-being compared to problem-focused and emotion-focused coping. Self-compassion was positively associated with psychological well-being amongst caregivers, and this is partially due to an increased use of problem-focused coping strategies.

Conclusions

Future interventions should cultivate caregivers’ benefit-finding and self-compassion and consider using psychological well-being as an additional outcome measure.
microRNAs Over-expressed in Diabetic Foot Ulcers Healing - Computational Modeling of Molecular Structure
Authors: de Oliveira Andrade Luis Jesuino , Vinhaes Bittencourt Alcina Maria , Matos de Oliveira Luís , Matos de Oliveira Gabriela Correia
Published: July 2021

Background

Vasculopathy associated with diabetic neuropathy are important risk factors for the diabetic foot ulcers development. Diabetic foot ulcers is severe complication that occur in about 15% of people with diabetes, being able require hospitalization and amputation in its treatment.

Objective

Design in silico the molecular structure of micro-ribonucleic acid (miRNA) overexpressed in diabetic foot ulcers healing.

Method

We performed a careful search of the nucleotide sequence of 8 miRNAs over-expressed in diabetic foot ulcers, designing in silico the molecular structure of following miRNAs: miRNA-146a, miRNA-155, miRNA-132, miRNA-191, miRNA-21, miRNA-203a, miRNA-203b, and miRNA-210. The nucleotides were taken from GenBank of National Center for Biotechnology Information genetic sequence database. The sequences acquired were aligned with the Clustal W multiple alignment algorithms. The molecular modeling of structures was built using the RNAstructure, an automated miRNAs structure modelling server.

Results

We showed a search for nucleotide sequence and the design of the molecular structure of following miRNA over-expressed in diabetic foot ulcers healing: miRNA-146a, miRNA-155, miRNA-132, miRNA-191, miRNA-21, miRNA-203a, miRNA-203b, and miRNA-210. We produced a tutorial on a molecular model of the 8 miRNAs overexpressed in the diabetic foot by processing in silico projection of their molecular structures.

Conclusion

We show in silico secondary structures design of selected of 8 miRNAs over-expressed in diabetic foot ulcers healing by means of computational biology.
TREM2 impacts brain microglia, oligodendrocytes and endothelial co-expression modules revealing genes and pathways important in Alzheimer’s disease
Authors: Carbajosa Guillermo , Malki Karim , Lawless Nathan , Wang Hong , Ryder John W. , Wozniak Eva , Wood Kristie , Mein Charles A. , Hodgkinson Alan , Dobson Richard J.B. , Collier David A. , O’Neill Michael J. , Newhouse Stephen J. , Hodges Angela K.
Published: July 2021

A microglia response to pathogenic signals in diseases such as Alzheimer’s disease (AD) has long been recognised, but recent genetic findings have cemented their direct causal contribution to AD and thus the potential to target them or their effector pathways as a possible treatment strategy. TREM2 is a highly penetrant microglia risk gene for AD, which appears central to the coordination of the damage response by microglia in AD. Its absence has a negative impact on Tau and amyloid symptoms and pathologies. Full knowledge of its pathway and relationships with other brain cells in AD has not been fully characterised, but will be essential to fully evaluate the impact of manipulating this pathway for treatment development and to establish the best targets for achieving this. We used whole genome RNA sequencing of hippocampus and cortical brain samples from control, AD, and AD TREM2 risk carriers to identify TREM2-dependent genes driving changes in pathways, processes and cell types in AD. Through highly influential intra and intermodular hub genes and overall changes in the levels of gene expression, TREM2-DAP12 was found to strongly influence a number of other microglia, oligodendrocyte and endothelial genes, notably those involved in complement and Fcγ receptor function, microglia-associated ribosomal genes and oligodendrocyte genes, particularly proteosomal subunits. These strong TREM2 centred co-expression relationships were significantly disrupted in AD cases with a TREM2 risk variant, revealing for the first time genes and pathways directly impacted by TREM2 in the brains of AD patients. Consistent with its function as a lipid sensor, our data supports a role for TREM2 in mediating oligodendrocyte and/or myelin clearance in AD which may be essential not only for preserving healthy tissue homeostasis but may also serve to minimise the persistence of antigenic peptides and lipids which may lead to detrimental pro-inflammatory sequelae. Further work should expand our knowledge of TREM2 on complement and Fcγ receptor function and its impact on oligodendcrotye and myelin integrity and further evaluate the genes and pathways we have identified as possible treatment targets for AD.
Quantification ofMyxococcus xanthusAggregation and Rippling Behaviors: Deep-learning Transformation of Phase-contrast into Fluorescence Microscopy Images
Authors: Zhang Jiangguo , Comstock Jessica A. , Cotter Christopher R. , Murphy Patrick A. , Nie Weili , Welch Roy D. , Patel Ankit B. , Igoshin Oleg A.
Published: July 2021

Myxococcus xanthusbacteria are a model system for understanding pattern formation and collective cell behaviors. When starving, cells aggregate into fruiting bodies to form metabolically inert spores. During predation, cells self-organize into traveling cell-density waves termed ripples. Both phase-contrast and fluorescence microscopy are used to observe these patterns but each has its limitations. Phase-contrast images have higher contrast, but the resulting image intensities lose their correlation with cell density. The intensities of fluorescence microscopy images, on the other hand, are well correlated with cell density, enabling better segmentation of aggregates and better visualization of streaming patterns in between aggregates. However, fluorescence microscopy requires the engineering of cells to express fluorescent proteins and can be phototoxic to the cells. To combine the advantages of both imaging methodologies, we develop a generative adversarial network that converts phase-contrast into fluorescent images. By including an additional histogram-equalized output to the state-of-art pix2pixHD algorithm, our model generates accurate images of aggregates and streams, enabling the estimation of aggregate positions and sizes, but with small shifts of their boundaries. Further training on ripple patterns enables accurate estimation of the rippling wavelength. Our methods are thus applicable for many other phenotypic behaviors and pattern formation studies.
Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host directed antivirals
Authors: Fang Jingru , Pietzsch Colette , Witwit Haydar , Tsaprailis George , Crynen Gogce , Cho Kelvin Frank , Ting Alice Y. , Bukreyev Alexander , Saphire Erica Ollmann , de la Torre Juan Carlos
Published: July 2021

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells, under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed an siRNA screen to identify those interactors that have functional roles in authentic LASV infection. As proof-of-principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet to be defined, host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.

Significance Statement

Lassa virus (LASV), the causative agent of Lassa fever (LF), represents an important public health problem in Western Africa. There is no FDA-approved therapeutic intervention to treat LF. Due to its limited genome coding capacity, LASV proteins are often multifunctional and orchestrate complex interactions with cellular factors to execute steps required to complete the viral life cycle. LASV polymerase is essential for replication and expression of the viral genome, and thus is an attractive target for antiviral intervention. Here we present the first host interactome of the LASV polymerase, which can guide identification of novel druggable host cellular targets for the development of cost-effective antiviral therapies for LF.
Identification of leptospiral protein antigens recognized by WC1+γδ T cell subsets as target for development of recombinant vaccines
Authors: Teixeira Aline F. , Gillespie Alexandria , Yirsaw Alehegne , Britton Emily , Telfer Janice C. , do Nascimento Ana Lucia , Baldwin Cynthia L.
Published: July 2021

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.
A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses
Authors: Talbot-Cooper Callum , Pantelejevs Teodors , Shannon John P. , Cherry Christian R. , Au Marcus T. , Hyvönen Marko , Hickman Heather D. , Smith Geoffrey L.
Published: July 2021

The induction of interferon-stimulated genes by signal transducer and activator of transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, a highly expressed poxvirus protein 018 is shown to inhibit IFN-induced signalling by binding the SH2 domain of STAT1 to prevent STAT1 association with an activated IFN receptor. Despite the presence of additional inhibitors of IFN-induced signalling, a poxvirus lacking 018 was attenuated in mice. The 2.0 Å crystal structure of the 018:STAT1 complex reveals a mechanism for a high-affinity, pTyr-independent mode of binding to an SH2 domain. Furthermore, the STAT1 binding motif of 018 shows sequence similarity to the STAT1-binding proteins from Nipah virus, which like 018, block the association of STAT1 with an IFN receptor. Taken together, these results provide detailed mechanistic insight into a potent mode of STAT1 antagonism, found to exist in genetically diverse virus families.
Deep deconvolution of the hematopoietic stem cell regulatory microenvironment reveals a high degree of specialization and conservation between mouse and human
Authors: Ye Jin , Calvo Isabel A. , Cenzano Itziar , Vilas Amaia , Martinez-de-Morentin Xabier , Lasaga Miren , Alignani Diego , Paiva Bruno , Viñado Ana C. , Martin-Uriz Patxi San , Romero Juan P. , Agreda Delia Quilez , Barrios Marta Miñana , González Ignacio Sancho , Todisco Gabriele , Malcovati Luca , Planell Nuria , Saez Borja , Tegner Jesper , Prosper Felipe , Gomez-Cabrero David
Published: July 2021

Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggests a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows to infer conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology are a steppingstone towards a comprehensive cell atlas of the BM microenvironment.
A subcellular biochemical model for T6SS dynamics reveals winning competitive strategies
Authors: Lin Yuexia Luna , Smith Stephanie N. , Kanso Eva , Septer Alecia N. , Rycroft Chris H.
Published: July 2021

The Type VI secretion system (T6SS) is a broadly distributed interbacterial weapon that can be used to eliminate competing bacterial populations. Although unarmed target populations are typically used to study T6SS function, bacteria most likely encounter other T6SS-armed competitors in nature. The outcome of such battles is not well understood, neither is the connection between the outcomes with the subcellular details of the T6SS. Here, we incorporated new biological data derived from natural competitors of Vibrio fischeri light organ symbionts to build a biochemical model for T6SS function at the single cell level. The model accounts for activation of structure formation, structure assembly, and deployment. By developing an integrated agent-based model (IABM) that incorporates strain-specific T6SS parameters, we replicated outcomes of biological competitions, validating our approach. We used the IABM to isolate and manipulate strain-specific physiological differences between competitors, in a way that is not possible using biological samples, to identify winning strategies for T6SS-armed populations. We found that a tipping point exists where the cost of building more T6SS weapons outweighs their protective ability. Furthermore, we found that competitions between a T6SS-armed population and a unarmed target had different outcomes dependent on the geometry of the battlefield: target cells survived at the edges of a range expansion scenario where unlimited territory could be claimed, while competitions within a confined space, much like the light organ crypts where natural V. fischeri compete, resulted in the rapid elimination of the unarmed competitor.
The adaptation front equation explains diversification hotspots and living-fossilization
Authors: Ito Hiroshi C. , Sasaki Akira
Published: July 2021

Taxonomic turnovers are common in the evolutionary histories of biological communities. Such turnovers are often associated with the emergence and diversification of groups that have achieved fundamental innovations beneficial in various ecological niches. In the present study, we show that such innovation-driven turnovers could be analyzed using an equation that describes the dynamics of zero-fitness isoclines in a two-dimensional trait space comprising a “fundamental trait” (describing fundamental innovation) and a “niche trait” (describing niche position) or with its higher-dimensional extensions. Our equation allows analytical prediction of evolutionary source–sink dynamics along the niche axis for an arbitrary unimodal (or multimodal with weak separation) carrying capacity distribution. The prediction was confirmed by numerical simulation under different assumptions for resource competition, reproduction, and mutation. In the simulated evolution, biodiversity sources are the central niches having higher carrying capacities than the outer niches, allowing species there the faster evolutionary advancement in fundamental traits and their repeated diversification into outer niches, which outcompete the indigenous less advanced species. The outcompeted species go extinct or evolve directionally toward the far outer niches of the far slower advancement because of the far lower carrying capacities. In consequence of this globally acting process over niches, species occupying peripheral (i.e., the outermost) niches can have significantly primitive fundamental traits and deep divergence times from their closest relatives, and thus, they correspond to living fossils. The extension of this analysis for multiple geographic regions showed that living fossils are also expected in geographically peripheral regions for the focal species group.

Significance Statement

We developed a new equation for analyzing the long-term coevolution of many species through their directional evolution, evolutionary branching, and extinction in an arbitrary trait space comprising traits describing niche positions and traits describing fundamental innovations. This equation describes the many coevolving species as a fluid, as in the study of galaxy dynamics in astronomical physics. This equation may be used to explain how innovation-driven taxonomic turnovers generate diversification hotspots and coldspots among niches or geographical regions, accompanied by continuous production of “living fossil” species in peripheries, in a logic equivalent to that deduced by Darwin and Darlington from empirical observations.
Single-dose mRNA vaccine effectiveness against SARS-CoV-2 in healthcare workers extending 16 weeks post-vaccination: a test-negative design from Quebec, Canada
Authors: Carazo Sara , Talbot Denis , Boulianne Nicole , Brisson Marc , Gilca Rodica , Deceuninck Geneviève , Brousseau Nicholas , Drolet Mélanie , Ouakki Manale , Sauvageau Chantal , Barkati Sapha , Fortin Elise , Carignan Alex , De Wals Philippe , Skowronski Danuta M. , De Serres Gaston
Published: July 2021

Introduction

In Canada, first and second doses of mRNA vaccines against SARS-CoV-2 were uniquely spaced 16 weeks apart, but the duration of single-dose protection remains uncertain. We estimated one- and two-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Quebec, Canada including protection against varying outcome severity, variants of concern (VOC), and the stability of single-dose protection out to 16 weeks post-vaccination.

Methods

A test-negative design compared vaccination among SARS-CoV-2 test-positive and weekly-matched (10:1), randomly-sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by one dose ≥14 days or two doses ≥7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression.

Results

Primary analysis included 5,316 cases and 53,160 controls. Single-dose VE was 70% (95%CI: 68-73) against SARS-CoV-2 infection, 73% (95%CI: 71-75) against COVID-19 illness and 97% (95%CI: 92-99) against associated hospitalization. Two-dose VE was 86% (95%CI: 81-90) and 93% (95%CI: 89-95), respectively, with no associated hospitalizations. VE was higher for non-VOC than VOC (73% Alpha) among single-dose (77%, 95%CI: 73-81 versus 63%, 95%CI: 57-67) but not two-dose recipients (87%, 95%CI: 57-96 versus 94%, 95%CI: 89-96). Across 16 weeks, no decline in single-dose VE was observed with appropriate stratification based upon prioritized vaccination determined by higher versus lower likelihood of direct patient contact.

Conclusion

One mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least four months post-vaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy to consider.
Predicting future ocular Chlamydia trachomatis infection prevalence using serological, clinical, molecular, and geospatial data
Authors: Tedijanto Christine , Aragie Solomon , Tadesse Zerihun , Haile Mahteme , Zeru Taye , Nash Scott D. , Wittberg Dionna M. , Gwyn Sarah , Martin Diana L. , Sturrock Hugh J.W. , Lietman Thomas M. , Keenan Jeremy D. , Arnold Benjamin F.
Published: July 2021

Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. District-level estimates of clinical disease are currently used to guide control programs. However, clinical trachoma is a subjective indicator. Serological markers present an objective, scalable alternative for monitoring and targeting of more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. Among 40 communities in the hyperendemic Amhara region of Ethiopia, median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment to 29% at month 36. Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be a promising programmatic tool for identifying communities with high levels of active ocular Ct infections, but accurate, future prediction in the context of changing transmission remains a challenge.
Re-emergence of respiratory syncytial virus following the COVID-19 pandemic in the United States: a modeling study
Authors: Zheng Zhe , Pitzer Virginia E. , Shapiro Eugene D. , Bont Louis J. , Weinberger Daniel M.
Published: July 2021

Importance

Respiratory syncytial virus (RSV) is a leading cause of hospitalizations in young children. RSV largely disappeared in 2020 due to precautions taken because of the COVID-19 pandemic. Projecting the timing and intensity of the re-emergence of RSV and the age groups affected is crucial for planning for the administration of prophylactic antibodies and anticipating hospital capacity.

Objective

To project the potential timing and intensity of re-emergent RSV epidemics in different age groups.

Design, Setting, Participants

Mathematical models were used to reproduce the annual RSV epidemics before the COVID-19 pandemic in New York and California. These models were modified to project the trajectory of RSV epidemics in 2020-2025 under different scenarios with varying stringency of mitigation measures for SARS-CoV-2: 1) constant low RSV transmission rate from March 2020 to March 2021; 2) an immediate decrease in RSV transmission in March 2020 followed by a gradual increase in transmission until April 2021; 3) a decrease in non-household contacts from April to July 2020. Simulations also evaluated factors likely to impact the re-emergence of RSV epidemics, including introduction of virus from out-of-state sources and decreased transplacentally-acquired immunity in infants.

Main Outcomes and Measures

The primary outcome of this study was defined as the predicted number of RSV hospitalizations each month in the entire population. Secondary outcomes included the age distribution of hospitalizations among children <5 years of age, incidence of any RSV infection, and incidence of RSV lower respiratory tract infection (LRI).

Results

In the 2021-2022 RSV season, we expect that the lifting of mitigation measures and build-up of susceptibility will lead to a larger-than-normal RSV outbreak. We predict an earlier-than-usual onset in the upcoming RSV season if there is substantial external introduction of RSV. Among children 1-4 years of age, the incidence of RSV infections could be twice that of a typical RSV season, with infants <6 months of age having the greatest seasonal increase in the incidence of both severe RSV LRIs and hospitalizations.

Conclusions and Relevance

Pediatric departments, including pediatric intensive care units, should be alert to large RSV outbreaks. Enhanced surveillance is required for both prophylaxis administration and hospital capacity management.