bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards Assessing Subcortical “Deep Brain” Biomarkers of PTSD with Functional Near-Infrared Spectroscopy
Authors: Balters Stephanie , Schlichting Marc R. , Foland-Ross Lara , Brigadoi Sabrina , Miller Jonas G. , Kochenderfer Mykel J. , Garrett Amy S. , Reiss Allan L.
Published: June 2022

Assessment of brain function with functional near-infrared spectroscopy (fNIRS) is limited to the outer regions of the cortex. Previously, we demonstrated the feasibility of inferring activity in subcortical “deep brain” regions using cortical fMRI and fNIRS activity in healthy adults. Access to subcortical regions subserving emotion and arousal using affordable and portable fNIRS is likely to be transformative for clinical diagnostic and treatment planning. Here, we validate the feasibility of inferring activity in subcortical regions that are central to the pathophysiology of PTSD (i.e., amygdala and hippocampus) using cortical fMRI and simulated fNIRS activity in a sample of adolescents diagnosed with PTSD (N=20, mean age=15.3±1.9 years) and age-matched healthy controls (N=20, mean age=14.5±2.0 years) as they performed a facial expression task. We tested different prediction models, including linear regression, a multi-layer perceptron neural network, and a k-nearest neighbors model. Inference of subcortical fMRI activity with cortical fMRI showed high prediction performance for the amygdala (r>0.91) and hippocampus (r>0.95) in both groups. Using fNIRS simulated data, relatively high prediction performance for deep brain regions was maintained in healthy controls (r>0.79), as well as in youths with PTSD (r>0.75). The linear regression and neural network models provided the best predictions.
Clinical Holds in Early Oncology Drug Development
Authors: Snyder Alexandra , De Alwis Dinesh , Goonewardene Asthika , Hegde Priti S.
Published: June 2022

Clinical holds in oncology are necessary to safeguard patients. Researchers are alerted to holds by news sources, but a systematic evaluation of clinical holds in early oncology drug development is lacking. Analysis of publicly disclosed clinical holds in oncology from 2016-2021 identified 39 holds. The majority (n=29) were for toxicity-related reasons, with fewer for chemistry, manufacturing and controls (CMC) (n=7) or other reasons (n=3). Toxicity-related holds took a median of 74 days till resolution, whereas chemistry, manufacturing and controls (CMC)-related holds took a median of 108 days to resolve. Acknowledging the limited sample size and scope of stock market conditions, toxicity-related clinical holds impacted the market value of small/medium sized biotechs by a median of -15%, which is far more than large biopharma (median 0%). These data suggest that toxicity-related clinical holds are common in early oncology and can have a more detrimental impact on small/medium sized biotech sponsors, the latter of which could have substantial financial repercussions, particularly in “biotech bear markets” where public investing in the sector has fallen out of favor (as in 2021-2022).
Predictive steering: Integration of artificial motor signals in self-motion estimation
Authors: van Helvert Milou J.L. , Selen Luc P.J. , van Beers Robert J. , Medendorp W. Pieter
Published: June 2022

The brain’s computations for active and passive self-motion estimation can be unified with a single model that optimally combines vestibular and visual signals with sensory predictions based on motor efference copies. It is unknown whether this theoretical framework also applies to the integration of artificial motor signals, like the motor signals that occur when driving a car. Here, we examined if training humans to control a self-motion platform would lead to the construction of an accurate internal model of the mapping between the steering movement and the vestibular reafference. Participants (n = 15) were seated on a linear motion platform and actively controlled the platform’s velocity using a steering wheel to translate their body to a memorized visual target location (Motion condition). We compared their steering behavior to that of participants (n = 15) who remained stationary and instead aligned a non-visible line with the target (Stationary condition). To probe learning, the gain between the steering wheel angle and the platform velocity or line velocity changed abruptly twice during the experiment. These gain changes were virtually undetectable in the displacement error in the Motion condition, whereas clear deviations were observed in the Stationary condition. These results show that participants in the Motion condition made within-trial changes to their steering behavior immediately after the gain changes. This suggests that they continuously compared the vestibular reafference to internal predictions, and thus employed and updated an internal forward model of the mapping between the steering movement and the vestibular reafference.

New & Noteworthy

Perception of self-motion is known to depend on the integration of sensory signals and, when the motion is self-generated, the predicted sensory reafference based on motor efference copies. Here we show, using a closed-loop steering experiment with a direct coupling between the steering movement and the vestibular self-motion feedback, that humans are also able to integrate artificial motor signals, like the motor signals that occur when driving a car.
Rab11-FIP1C is dispensable for HIV-1 replication in primary CD4+T cells but its role is cell-type-dependent in immortalized human T-cell lines
Authors: de Céspedes Melissa V. , Hoffman Huxley K. , Carter Hannah , Simons Lacy M. , Naing Lwar , Ablan Sherimay D. , Hultquist Judd F. , van Engelenburg Schuyler B. , Freed Eric O.
Published: June 2022

The HIV-1 envelope glycoprotein (Env) contains a long cytoplasmic tail harboring highly conserved motifs that direct Env trafficking and incorporation into virions and promote efficient virus spread. The cellular trafficking factor Rab11a family interacting protein 1C (FIP1C) has been implicated in the directed trafficking of Env to sites of viral assembly. In this study, we confirm that siRNA-mediated depletion of FIP1C in HeLa cells modestly reduces Env incorporation into virions. To determine whether FIP1C is required for Env incorporation and HIV-1 replication in physiologically relevant cells, CRISPR/Cas9 technology was used to knock out the expression of this protein in several human T-cell lines – Jurkat E6.1, SupT1 and H9 – and in primary human CD4+T cells.FIP1Cknock-out caused modest reductions in Env incorporation in SupT1 cells but did not inhibit virus replication in SupT1 or Jurkat E6.1 T-cell lines. In H9 cells,FIP1Cknock-out caused a cell-density-dependent defect in virus replication. In primary CD4+T cells,FIP1Cknock-out had no effect on HIV-1 replication. Furthermore, HTLV-I transformed cell lines that are permissive for HIV-1 replication do not express FIP1C. Mutation of an aromatic motif in the Env cytoplasmic tail – Y795W – implicated in FIP1C-mediated Env incorporation impaired virus replication independently of FIP1C expression in SupT1, Jurkat E6.1, H9, and primary T cells. Together, these results indicate that while FIP1C may contribute to HIV-1 Env incorporation in some contexts, additional and potentially redundant host factors are likely required for Env incorporation and virus dissemination in T cells.

Importance

The incorporation of the HIV-1 envelope (Env) glycoproteins, gp120 and gp41, into virus particles is critical for virus infectivity. Gp41 contains a long cytoplasmic tail that has been proposed to interact with host cell factors, including the trafficking factor Rab11a family interacting protein 1C (FIP1C). To investigate the role of FIP1C in relevant cell types – human T-cell lines and primary CD4+T cells – we used CRISPR/Cas9 to knock out FIP1C expression and examined the effect on HIV-1 Env incorporation and virus replication. We observed that in two of the T-cell lines examined (Jurkat E6.1 and SupT1) and in primary CD4+T cells, FIP1C knockout did not disrupt HIV-1 replication, whereas FIP1C knockout reduced Env expression and delayed replication in H9 cells. The results indicate that while FIP1C may contribute to Env incorporation in some cell lines, it is not an essential factor for efficient HIV-1 replication in primary CD4+ T cells.
Epstein-Barr Virus DNAemia and Post-Transplant Lymphoproliferative Disorder in Pediatric Solid Organ Transplant Recipients
Authors: Chang Yeh-Chung , Young Rebecca R. , Mavis Alisha M. , Chambers Eileen T. , Kirmani Sonya , Kelly Matthew S. , Kalu Ibukunoluwa C. , Smith Michael J. , Lugo Debra J.
Published: June 2022

Background

Pediatric solid organ transplant (SOT) recipients commonly have Epstein-Barr virus (EBV) DNAemia and are at risk of developing post-transplant lymphoproliferative disorder (PTLD). EBV DNAemia has not been analyzed on a continuous scale in this population.

Methods

All children ≤ 18 years of age who underwent SOT at a single center between January 1, 2007 and July 31, 2018 were included in this retrospective study. Transplant episodes in which PTLD occurred were compared to transplant episodes without PTLD. Multivariable logistic regression was used to identify factors associated with the development of EBV DNAemia and maximum height of EBV DNAemia. A Cox proportional hazards model was used to calculate hazard ratios for time to PTLD.

Results

Of 275 total transplant recipients and 294 transplant episodes, there were 14 episodes of PTLD. Intestinal and multivisceral transplant were strongly associated with PTLD (p=0.002). Risk factors for the development of EBV DNAemia include donor and recipient positive EBV serologies (p=0.001) and older age (p=0.001). Maximum level of EBV DNAemia was significantly associated with development of PTLD (p<0.0001). Every one log (log10) increase in the maximum level of EBV DNAemia was associated with a more than doubling of the hazard on developing PTLD (HR: 2.18, 95% CI 1.19-3.99).

Conclusions

Transplant type was strongly associated with development of PTLD in pediatric SOT recipients. EBV serologies and age were associated with the development of EBV DNAemia and height of DNAemia. High levels of EBV DNAemia were strongly associated with an increased hazard of PTLD.
Prevalence and determinants of chronic respiratory diseases in adults in Khartoum State, Sudan
Authors: Ahmed Rana , Osman Nada , Noory Bandar , Osman Rashid , ElHassan Hana , Eltigani Hind , Nightingale Rebecca , Amaral Andre FS , Patel Jaymini , Burney Peter G. , Mortimer Kevin , ElSony Asma
Published: June 2022

Background

Chronic respiratory diseases are considered a significant cause of morbidity and mortality worldwide, although data from Africa are limited. This study aimed to determine the prevalence and determinants of chronic respiratory diseases in Khartoum, Sudan.

Methods

Data was collected from 516 participants, aged≥40, who had completed a questionnaire and undertook pre- and post-bronchodilator spirometry testing. Trained field workers conducted questionnaires and spirometry. Survey-weighted prevalence of respiratory symptoms and spirometric abnormalities were estimated. Regression analysis models were used to identify risk factors for chronic lung diseases.

Results

Using the NHANESIII reference equations, the prevalence of Chronic Airflow Obstruction (CAO) was 10%. The main risk factor was older age 60-69 years (Odds ratio 3.16, 95% Confidence Interval 1.20 – 8.31). Lower education, high body mass index and a history of tuberculosis were also identified as significant risk factors. The prevalence of a low forced vital capacity (FVC) using NHANES III was 62.7% [SE 2.2] and 11.3% [SE 1.4] using locally derived values.

Conclusion

The prevalence of spirometric abnormality mainly (low FVC); was high suggesting that chronic respiratory disease is of substantial public health importance in urban Sudan. Strategies for the prevention and control of these problems are needed.
Modelling Lockdown Effects on Controlling the Spread of COVID-19
Authors: Chow W.K. , Chow C.L.
Published: June 2022

The COVID-19 variant omicron is spreading rapidly, infecting about 1.2 million people in 2 months in Hong Kong from early January 2022. Locking down the city at the beginning of outbreak for an adequate period is effective in mitigation and suppression of disease transmission. However, it is difficult to implement the locking down proposal without strong supporting argument because of the accompanied economic loss. An appropriate mathematical model to provide key predictive information on the local epidemic and evaluate the effects of lockdown is reported in this paper. The number of susceptible citizens, infection cases and recovery number under some assumption on isolating citizens are predicted by solving the ordinary differential equations analytically. Observed infected cases during the fifth wave of outbreak in Hong Kong is taken as an example to illustrate the concept. Three lockdown scenarios are proposed and assessed by the developed mathematical approach. Early lockdown is illustrated to keep infected cases low, therefore very effective in controlling the spread by isolating the citizens in their own units.
Relating neighborhood deprivation to childhood obesity in the ABCD Study®: evidence for theories of neuroinflammation and neuronal stress
Authors: Adise Shana , Marshall Andrew T. , Kan Eric , Gonzalez Marybel , Sowell Elizabeth R.
Published: June 2022

Objective

We evaluated whether the relationships between area deprivation (ADI), body mass index (BMI) and brain structure (e.g., cortical thickness, subcortical volume) during pre-adolescence supported the neuroinflammation (NI) and/or neuronal stress (NS) theories of overeating. The NI theory proposes that ADI causes structural alteration in the brain due to the neuroinflammatory effects of overeating unhealthy foods. The NS theory proposes that ADI-related stress negatively impacts brain structure, which causes stress-related overeating and subsequent obesity.

Methods

Data were gathered from the Adolescent Brain Cognitive DevelopmentSM Study® (9-12-years-old; n=2872, 51.3% female). Linear mixed-effects models identified brain regions that were associated with both ADI and BMI; longitudinal mediation models assessed potential causal pathways. The NI model included ADI and BMI at 9/10-years-old and brain data at 11/12-years-old. The NS model included ADI and brain data at 9/10-years-old and BMI at 11/12-years-old.

Results

In the NI model, BMI at 9/10-years-old positively mediated the relationship between AD and cortical thinning in the cuneus, lingual, and paracentral gyrus and larger volume of the Ventral DC at 11/12-years-old. In the NS model, cortical thinning in the lateral orbitofrontal cortex, lingual gyrus and larger volume of the Ventral DC at 9/10-years-old partially mediated the relationship between ADI and BMI at 11/12-years-old.

Conclusion

Greater area deprivation may indicate fewer access to resources that support healthy development, like nutritious food and non-stressful environments. Our findings provide evidence in support of the neuroinflammation and stress theories of overeating, specifically, with greater ADI influencing health outcomes of obesity via brain structure alterations.
Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection
Authors: Khoury David S , Schlub Timothy E , Cromer Deborah , Steain Megan , Fong Youyi , Gilbert Peter B , Subbarao Kanta , Triccas James A , Kent Stephen J , Davenport Miles P
Published: June 2022

Several studies show neutralizing antibody levels are an important correlate of immune protection from COVID-19 and have estimated the relationship between neutralizing antibodies and protection. However, a number of these studies appear to yield quite different estimates of the level of neutralizing antibodies required for protection. Here we show that after normalization of antibody titers current studies converge on a consistent relationship between antibody levels and protection from COVID-19.
Computer-assisted analysis of routine EEG to identify hidden biomarkers of epilepsy: protocol for a systematic review
Authors: Lemoine Émile , Briard Joel Neves , Rioux Bastien , Podbielski Renata , Nauche Bénédicte , Toffa Denahin , Keezer Mark , Lesage Frédéric , Nguyen Dang K. , Assi Elie Bou
Published: June 2022

Background

The diagnosis of epilepsy frequently relies on the visual interpretation of the electroencephalogram (EEG) by a neurologist. The hallmark of epilepsy on EEG is the interictal epileptiform discharge (IED). This marker lacks sensitivity: it is only captured in a small percentage of 30-minute routine EEGs in patients with epilepsy. In the past three decades, there has been growing interest in the use of computational methods to analyze the EEG without relying on the detection of IEDs, but none have made it to the clinical practice. We aim to review the diagnostic accuracy of quantitative methods applied to ambulatory EEG analysis to guide the diagnosis and management of epilepsy.

Methods

The protocol complies with the recommendations for systematic reviews of diagnostic test accuracy by Cochrane. We will search MEDLINE, EMBASE, EBM reviews, IEEE Explore along with grey literature for articles, conference papers and conference abstracts published after 1961. We will include observational studies that present a computational method to analyze the EEG for the diagnosis of epilepsy in adults or children without relying on the identification of IEDs or seizures. The reference standard is the diagnosis of epilepsy by a physician. We will report the estimated pooled sensitivity and specificity, and receiver operating characteristic area-under-the-curve (ROC AUC) for each marker. If possible, we will perform a meta-analysis of the sensitivity and specificity and ROC AUC for each individual marker. We will assess the risk of bias using an adapted QUADAS-2 tool. We will also describe the algorithms used for signal processing, feature extraction and predictive modeling, and comment on the reproducibility of the different studies.

Discussion

Despite the promise to unveil epileptiform patterns that cannot be seen by the naked eye, computational analysis of ambulatory EEG has not yet been successfully translated to the clinical setting. We hope to produce recommendations for future studies on computer-assisted EEG interpretation for the diagnosis and management of epilepsy.

Systematic review registration

PROSPERO #292261
Pathogen-Host Adhesion between SARS-CoV-2 Spike Proteins from Different Variants and Human ACE2 Probed at Single-Molecule and Single-Cell Levels
Authors: Zhang Xiaoxu , Chen Jialin , Hong Bixia , Xu Haifeng , Pei Pengfei , Chen Long , Tong Yigang , Luo Shi-Zhong , Fan Huahao , He Chengzhi
Published: June 2022

Pathogen-Host adhesion is considered the first step of infection for many pathogens such as bacteria and virus. The binding of the receptor binding domain (RBD) of SARS-CoV-2 Spike protein (S protein) onto human angiotensin-converting enzyme 2 (ACE2) is considered as the first step for the SARS-CoV-2 to adhere onto the host cells during the infection. Within three years, a number of variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been found all around the world. Here, we investigated the adhesion of S Proteins from different variants and ACE2 using atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) and single-cell force spectroscopy (SCFS). We found that the unbinding force and binding probability of the S protein from Delta variant to the ACE2 was the highest among the variants tested in our study at both single-molecule and single-cell levels. Molecular dynamics simulation showed that ACE2-RBD (Omicron) complex is destabilized by the E484A and Y505H mutations and stabilized by S477N and N501Y mutations, when compared with Delta variant. In addition, a neutralizing antibody, produced by immunization with wild type RBD of S protein, could effectively inhibit the binding of S proteins from wild type, Delta and Omicron variants onto ACE2. Our results provide new insight for the molecular mechanism of the adhesive interactions between S protein and ACE2 and suggest that effective monoclonal antibody can be prepared using wild type S protein against the different variants.
Trans-Radial Electrical Bioimpedance Velocimetry: A Novel Method for Detecting Cardiac Contractility
Authors: Stump Alexandra I. , Dundon Neil M. , Babenko Viktoriya , Macy Alan , Grafton Scott T.
Published: June 2022

Increasing insight into the complex human response to external states can be captured by measuring event-related cardiac sympathetic activity. However existing assays are either confounded by influence from other branches of the autonomic system, or require preprocessing steps that eliminate moment-to-moment capture of fluctuation. We accordingly tested a novel device (TREV) that measures cardiac impedance directly from the radial and ulnar arteries of the human forearm, while healthy human participants performed a small number of trials of a task known to elicit sympathetic drive, a maximum-strength grip task. TREV recorded robust estimates of contractility at each heartbeat, that allowed fully automated beatwise estimations. TREV further reliably described credible group-level departures from baseline aligned with each individual grip in the task. We conclude that the device can be a useful addition to a broadening field exploring event-related sympathetic perturbations.
Measuring circadian rhythms in patients with dementia: protocol for a scoping review
Authors: Gabb Victoria G. , Ince Louise M. , Rudd Sarah , Coulthard Elizabeth
Published: June 2022

Introduction

Most physiological processes are under circadian regulation. Disturbances to circadian rhythms are common and often early symptoms in dementia. There is a gap in the literature regarding how and which circadian functions have been, or could optimally be, measured in patients with dementia. This protocol outlines a scoping review to identify which and how circadian variables have been studied in patients with dementia and mild cognitive impairment, and examine whether feasibility, acceptability, appropriateness, and utility in clinical practice has been considered.

Methods and analysis

The scoping review will be conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews and will be reported in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). We will systematically search five electronic bibliographic databases (MEDLINE, CINAHL, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo). There will be no restriction on date of publication or language; corresponding authors will be contacted where relevant non-English articles are identified to request a translation. Search results will be merged using reference management software and duplicates will be removed. To ensure consistency in applying eligibility criteria, 10% of retrieved articles will be checked by each reviewer in the team at the title and abstract screening stage and full texts will be reviewed by at least 2 reviewers. Data from eligible articles will be extracted using a standardised form. Where study outcomes (e.g., patient and public involvement, adherence) have not been described in the article, authors will be contacted in case relevant data is available to share but was omitted from the main report. Results will be presented as a narrative synthesis as study and population heterogeneity will likely prohibit meta-analysis.

Ethics and dissemination

Ethical approval is not required as the scoping review methodology does not involve human or animal participants. This review will provide an extensive overview of established and emerging trends in measurement of circadian rhythms in dementia and identify gaps in the research to inform future clinical and research practice. The review will also highlight whether patient and public involvement, participant burden, and clinical usefulness of methods have been considered in developing protocols. Results will be disseminated in a peer-reviewed publication.
The impact of surgical mask-wearing, contact tracing program, and vaccination on COVID-19 transmission in Taiwan from January 2020 to March 2022: a modelling study
Authors: Filonets Tatiana , Solovchuk Maxim , Gao Wayne
Published: June 2022

The effectiveness of interventions such as public mask-wearing, contact tracing, and vaccination presents an important lesson for control of the further COVID-19 outbreaks without of whole country lockdowns and the restriction of individual movement. We simulated different scenarios of COVID-19 waves in Taiwan from 2020 to the beginning of March 2022 and considered the following interventions: travel restrictions, quarantine of infected individuals, contact tracing, mask-wearing, vaccination, and mass gathering restrictions. We propose an epidemiological compartmental model modified from the susceptible-exposed-infectious-removed (SEIR) model and derive a formula for the basic reproduction number (R0) describing its dependence on all investigated parameters. The simulation results are fitted with the official Taiwanese COVID-19 data. Thus, the results demonstrate that the fast introduction of the interventions and maintaining them at a high level are able the outbreak control without strict lockdowns. By estimation of the R0, it was shown that it is necessary to maintain on high implementation level of both non- and pharmaceutical intervention types to control the COVID-19 transmission. Our results can be useful as advice or recommendation for public health policies, and our model can be applied for other epidemiological simulation studies.
Cross-Cultural Adaptation and Validation of the 5C Scale to Identify Factors Associated With COVID-19 and Influenza Vaccine Hesitancy Among Healthcare Workers in Cape Town, South Africa – A Protocol
Authors: Alobwede Samuel M , Katoto Patrick DMC , Cooper Sara , Lumngwena Evelyn N , Kidzeru Elvis B , Goliath Rene , Jackson Amanda , Wiysonge Charles S , Shey Muki S
Published: June 2022

Background

Healthcare workers are at an increased risk of acquiring vaccine-preventable diseases and are known to be reliable source of information for the patients and their relatives. Knowledge and attitudes of Healthcare workers about vaccines are thus important determinants of their own vaccination uptake and their intention to recommend vaccinations to their patients. However, culturally adapted tools and studies to address vaccine uptake and hesitancy as well as related behaviours among Healthcare workers in the Global South are limited.

Methods

We propose a mixed methods project to understand the extent and determinants of vaccination hesitancy among Healthcare workers and construct a validated scale to measure this complex and context-specific phenomenon in Cape Town. We will summarise responses as counts and percentages for categorical variables and means with standard deviations (or median with inter quartile ranges) for continuous variables. We will run the Shapiro-Wilks test to assess the normality. Analysis of the variance, chi-square tests, and equivalents will be conducted as appropriate for group comparisons. Logistic regression models will also be performed to assess association between variables.

We will focus on the seasonal influenza and COVID-19 vaccine. We will use an existing tool developed and validated in Germany and the United States of America to measure five psychological determinants of vaccination (referred to as the 5C scale), as the basis to develop and validate a scale to measure the scope and determinants of vaccine hesitancy and acceptance among Healthcare workers in Cape Town.

Discussion and conclusion

Through this study, we hope to expand the scientific evidence based on vaccination acceptance and demand among Healthcare workers in South Africa and build resources to enable better understanding of, detection, and response to vaccination hesitancy in Cape Town.
TTN truncating variants in hiPSI exons show high penetrance for cardiomyopathy in carriers with atrial fibrillation
Authors: Schiabor Barrett Kelly M. , Cirulli Elizabeth T. , Bolze Alexandre , Rowan Chris , Elhanan Gai , Grzymski Joseph J. , Lee William , Washington Nicole L.
Published: June 2022

Background

Truncating variants in TTN (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCM). At the population level, even when limited to TTNtvs in cardiac-specific exons (hiPSI TTNtvs) penetrance estimates for DCM are low. Recent work shows that individuals harboring TTNtvs have a high prevalence of other cardiac conditions aside from heart failure, in particular, atrial fibrillation (Afib).

Objectives

Pinpoint the genetic footprint TTN-related diagnoses aside from DCM, such as Afib, and determine if vetting additional significantly-associated phenotypes better stratifies cardiomyopathy risk across TTN carriers.

Methods

We leverage longitudinal EHR and exome sequencing data from two cohorts to determine the penetrance of TTNtvs using multiple gene expression models against Afib, CM, and other cardiac diagnoses.

Results

Controlling for CM and Afib, related cardio phenotypes retain only nominal association with TTNtvs. An unbiased sliding window analysis of TTNtvs across the locus confirms the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in lowPSI exons nor improvements from LOFTEE designations. We find 34% of hiPSI TTNtv carriers with early Afib have a CM diagnosis – a 5-fold increase in risk over non-carriers with early Afib and 47-fold increase over population controls.

Conclusion

CM and Afib are often coincident in hiPSI TTNtv carriers, which represent varying and progressive manifestations of structurally-based heart failure. We provide statistical support for a hiPSI variant interpretation model for TTNtvs and evidence for the first population-level screening method with clinical utility for cardiomyopathies, especially in relation to an Afib finding.
Hospitalization, death, and probable reinfection in Peruvian healthcare workers infected with SARS-CoV-2: a national retrospective cohort study
Authors: Ramos Willy , Guerrero Nadia , Saldaña Omar Napanga , Medina José , Loayza Manuel , De La Cruz-Vargas Jhony A. , Vargas María , Ordóñez Luis , Seclén Yovana , Álvarez-Antonio Carlos , Arrasco Juan
Published: June 2022

OBJECTIVE

To determine if occupation is a risk factor for probable reinfection, hospitalization, and death from COVID-19 in Peruvian healthcare workers infected with SARS-CoV-2.

MATERIAL AND METHODS

Retrospective cohort study. Healthcare workers who presented SARS-CoV-2 infection between March 1, 2020 and August 9, 2021 were included. Occupational cohorts were reconstructed from the following sources of information: the National Epidemiological Surveillance System, molecular tests (NETLAB), results of serology and antigen tests (SICOVID-19), National Registry of Health Personnel (INFORHUS) and National Information System of Deaths (SINADEF). The incidence of probable reinfection, hospitalization, and death from COVID-19 was obtained in the cohorts of health auxiliaries and technicians, nursing staff, obstetricians, physicians, and other healthcare workers. We evaluated whether occupation was a risk factor for probable reinfection, hospitalization, and death from COVID-19 using a log-binomial generalized linear model, obtaining the adjusted relative risk (RR AJ).

RESULTS

90,672 healthcare workers were included. 8.1% required hospitalization, 1.7% died from COVID-19, and 2.0% had probable reinfection. A similar incidence of probable reinfection was found in the 5 cohorts (1.9%-2.2%). Physicians had a higher incidence of hospitalization (13.2%) and death (2.6%); however, they were also those who presented greater susceptibility linked to non-occupational variables such as age and comorbidities. The multivariate analysis found that physicians (RR=1.691; CI 95: 1.556–1.837) had a higher risk of hospitalization and that the occupation of health technician and assistant was the only one that constituted a risk factor for mortality from COVID-19 (RR =1.240; 95% CI: 1.052–1.463).

CONCLUSIONS

Peruvian health technicians and auxiliaries have a higher risk of death from COVID-19 linked to their occupation, while doctors have higher mortality due to non-occupational factors. Physicians had a higher risk of hospitalization independent of the presence of comorbidities and age; likewise, all occupations had a similar risk of probable reinfection.
YAP/TAZ mediate TGFβ2-induced Schlemm’s canal cell dysfunction
Authors: Li Haiyan , Singh Ayushi , Perkumas Kristin M. , Stamer W. Daniel , Ganapathy Preethi S. , Herberg Samuel
Published: June 2022

Purpose

Elevated transforming growth factor beta2 (TGFβ2) levels in the aqueous humor have been linked to glaucomatous outflow tissue dysfunction. Potential mediators of dysfunction are the transcriptional co-activators, Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ). However, the molecular underpinnings of YAP/TAZ modulation in Schlemm’s Canal (SC) cells under glaucomatous conditions are not well understood. Here, we investigate how TGFβ2 regulates YAP/TAZ activity in human SC (HSC) cells using biomimetic extracellular matrix (ECM) hydrogels, and examine whether pharmacologic YAP/TAZ inhibition would attenuate TGFβ2-induced HSC cell dysfunction.

Methods

Primary HSC cells were seeded atop photocrosslinked ECM hydrogels, made of collagen type I, elastin-like polypeptide and hyaluronic acid, or encapsulated within the hydrogels. HSC cells were induced with TGFβ2 in the absence or presence of concurrent actin destabilization or pharmacologic YAP/TAZ inhibition. Changes in actin cytoskeletal organization, YAP/TAZ activity, ECM production, phospho-myosin light chain levels, and hydrogel contraction were assessed.

Results

TGFβ2 significantly increased YAP/TAZ nuclear localization in HSC cells, which was prevented by either filamentous (F)-actin relaxation or depolymerization. Pharmacologic YAP/TAZ inhibition using verteporfin without light stimulation decreased fibronectin expression and reduced actomyosin cytoskeletal rearrangement in HSC cells induced by TGFβ2. Similarly, verteporfin significantly attenuated TGFβ2-induced HSC cell-encapsulated hydrogel contraction.

Conclusions

Our data provide evidence for a pathologic role of aberrant YAP/TAZ signaling in HSC cells under simulated glaucomatous conditions, and suggest that pharmacologic YAP/TAZ inhibition has promising potential to improve outflow tissue dysfunction.
Adaptation to starvation requires a flexible circadian clockwork inNeurospora crassa
Authors: Szőke Anita , Sárkány Orsolya , Schermann Géza , Kapuy Orsolya , Diernfellner Axel C. R. , Brunner Michael , Gyöngyösi Norbert , Káldi Krisztina
Published: June 2022

The circadian clock governs rhythmic cellular functions by driving expression of a substantial fraction of the genome and thereby significantly contributes to the adaptation to changing environmental conditions. Using the circadian model organismNeurospora crassa,we show that molecular timekeeping is robust even under severe limitation of carbon sources, however, stoichiometry, phosphorylation and subcellular distribution of the key clock components display drastic alterations. Protein kinase A, protein phosphatase 2A and glycogen synthase kinase are involved in the molecular reorganization of the clock. RNA-seq analysis reveals that the transcriptomic response of metabolism to starvation is highly dependent on the positive clock component WC-1. Moreover, our molecular and phenotypic data indicate that a functional clock facilitates recovery from starvation. We suggest that the molecular clock is a flexible network that allows the organism to maintain a rhythmic physiology and preserve fitness even under long-term nutritional stress.
Superinfection exclusion creates spatially distinct influenza virus populations
Authors: Sims Anna , Tornaletti Laura Burgess , Jasim Seema , Pirillo Chiara , Devlin Ryan , Hirst Jack , Loney Colin , Wojtus Joanna , Sloan Elizabeth , Thorley Luke , Boutell Chris , Roberts Edward , Hutchinson Edward
Published: June 2022

Influenza viruses can interact during coinfections, allowing viral fitness to be altered by genome complementation and competition, and increasing population diversity through reassortment. However, opportunities for these interactions are limited, as coinfection is blocked shortly after primary infection by a process known as superinfection exclusion (SIE). We asked whether SIE, which occurs at the level of individual cells, could limit within-host interactions between populations of influenza viruses as they spread across regions of cells. We first created a simplified model of within-host spread by infecting monolayers of cells with two isogenic influenza A viruses, each encoding a different fluorophore, and measuring the proportion of coinfected cells. In this system SIE begins within 2-4 hours of primary infection, with the kinetics of onset defined by the dose of primary virus. We then asked how SIE controls opportunities for coinfection as viruses spread across a monolayer of cells. We observed that viruses spreading from a single coinfected focus continued to coinfect cells as they spread, as all new infections were of cells that had not yet established SIE. In contrast, viruses spreading towards each other from separately infected foci could only establish minimal regions of coinfection before SIE blocked further coinfection. This patterning was recapitulated in the lungs of infected mice and is likely to apply to other viruses that exhibit SIE. It suggests that the kinetics of SIE onset separate a spreading infection into discrete regions, within which interactions between virus populations can occur freely, and between which they are blocked.

Importance

Viral fitness and diversity are altered by genome interactions, which occur when multiple viruses coinfect a cell. This has been extensively studied for influenza A viruses (IAV), which use genome reassortment to adapt to new hosts and create pandemic strains, and whose replication can be compromised by the acquisition of defective-interfering RNAs. Coinfection of an individual cell by IAV is restricted by the gradual onset of superinfection exclusion (SIE). Replication of IAVs within host organisms involve the asynchronous replication of viruses as they spread to infect multiple cells. We found that under these circumstances, SIE creates spatially separated sub-populations of IAV, between which there are limited opportunities for genome interactions. Our work suggests SIE will cause many viruses to segregate into distinct subpopulations within their hosts, constraining the effects of genome interactions on their fitness and evolution.
The performance of deep generative models for learning joint embeddings of single-cell multi-omics data
Authors: Brombacher Eva , Hackenberg Maren , Kreutz Clemens , Binder Harald , Treppner Martin
Published: June 2022

Recent extensions of single-cell studies to multiple data modalities raise new questions regarding experimental design. For example, the challenge of sparsity in single-omics data might be partly resolved by compensating for missing information across modalities. In particular, deep learning approaches, such as deep generative models (DGMs), can potentially uncover complex patterns via a joint embedding. Yet, this also raises the question of sample size requirements for identifying such patterns from single-cell multi-omics data. Here, we empirically examine the quality of DGM-based integrations for varying sample sizes. We first review the existing literature and give a short overview of deep learning methods for multi-omics integration. Next, we consider eight popular tools in more detail and examine their robustness to different cell numbers, covering two of the most common multi-omics types currently favored. Specifically, we use data featuring simultaneous gene expression measurements at the RNA level and protein abundance measurements for cell surface proteins (CITE-seq), as well as data where chromatin accessibility and RNA expression are measured in thousands of cells (10x Multiome). We examine the ability of the methods to learn joint embeddings based on biological and technical metrics. Finally, we provide recommendations for the design of multi-omics experiments and discuss potential future developments.
In-silico identification of potential antigenic proteins in Bartonella bacilliformis for the serological diagnosis of Carrions’ disease
Authors: Jimenez-Vasquez Victor , Calvay-Sanchez Karen , Zarate-Sulca Yanina , Ruiz Joaquim , Mendoza-Mujica Giovanna
Published: June 2022

The current methods for inferring antigenic, pathogenic or virulence factors in bacteria include in-silico or computational tools. Bartonella bacilliformis, the causal agent of Carriońs disease (CD) is a Gram-negative microorganism transmitted by the sand fly Lutzomya verrucarum mainly in Peruvian Inter-Andean valleys. A better understanding of the pathogenicity of B. bacilliformis, the implementation of serological diagnostic methods and the development of candidate vaccines for the control of CD could be facilitated by the identification of outer membrane exposed proteins such as outer-membrane beta-barrels (OMBB) and outer-membrane lipoproteins (OMLPP). In this study we present the in-silico identification of OMBBs and OMLPPs in B. bacilliformis. The present analysis identified 32 OMBBs and 9 OMLPPs, of which 15 and 4 are reported for the first time as potential antigenic, pathogenic and virulence-related proteins, respectively. Future implications of this study are discussed and compared with proteins validated by experimental assays.
Interpretable XGBoost-SHAP model predicts the nanoparticles delivery and reveals its interaction with tumor genomic profiles
Authors: Tang Yuxia , Ma Xingqun , Wang Shouju
Published: June 2022

Understanding the complex interaction between nanoparticles (NPs) and tumors in vivo and how it dominates the delivery efficacy of NPs is critical for the translation of nanomedicine. Herein, we proposed an interpretable XGBoost-SHAP model by integrating the information of NPs physicochemical properties and tumor genomic profile to predict the delivery efficacy. The correlation coefficients were > 0.99 for all training sets, and 0.830, 0.839, and 0.741 for the prediction of maximum delivery efficacy (DEmax), delivery efficacy at 24 h (DE24), and delivery efficacy at 168 (DE168) for test sets. The analysis of the feature importance revealed that the tumor genomic mutations and their interaction with NPs properties played an important role in the delivery of NPs. The functional profile of the NP-delivery-related genes was further explored through gene ontology enrichment analysis. Our work provides a method to accurately predict the delivery efficacy of NPs to heterogeneous tumors and highlights the power of simultaneously using omics data and interpretable machine learning algorithms for discovering the interaction between NPs and tumors, which is important for the development of precision nanomedicine.
Estimating causality between smoking and abdominal obesity by Mendelian randomization
Authors: Carrasquilla Germán D. , García-Ureña Mario , Romero Lado María José , Kilpeläinen Tuomas O.
Published: June 2022

Background and Aims

Smokers tend to have a lower body weight than non-smokers, but also more abdominal fat. It remains unclear whether the relationship between smoking and abdominal obesity is causal. Previous Mendelian randomization studies have investigated this relationship by relying on a single genetic variant for smoking heaviness. This approach is sensitive to pleiotropic effects and may produce imprecise causal estimates. We aimed to assess causality between smoking and abdominal obesity using multiple genetic instruments.

Methods

We used GWAS results for smoking initiation (n=1,232,091), lifetime smoking (n=462,690) and smoking heaviness (n=337,334) as exposure traits, and waist-hip ratio (WHR) and waist and hip circumferences (WC and HC) (n up to 697,734), with and without adjustment for body mass index (adjBMI), as outcome traits. We implemented Mendelian randomization using the CAUSE and LHC-MR methods that instrument smoking using genome-wide data.

Results

Both CAUSE and LHC-MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95%CI 0.10, 0.16] and 0.49 [0.41, 0.57], respectively) and WHRadjBMI(0.07 [0.03, 0.10] and 0.31 [0.26, 0.37]). Similarly, they indicated a positive causal effect of lifetime smoking on WHR (0.35 [0.29, 0.41] and 0.44 [0.38, 0.51]) and WHRadjBMI(0.18 [0.13, 0.24] and 0.26 [0.20, 0.31]). In follow-up analyses, smoking particularly increased visceral fat. There was no evidence of a mediating role by cortisol or sex hormones.

Conclusions

Smoking initiation and higher lifetime smoking may lead to abdominal fat distribution. The increase in abdominal fat due to smoking was characterized by an increase in visceral fat. Thus, efforts to prevent and cease smoking can have the added benefit of reducing abdominal fat.
Ifit2 regulates murine-coronavirus spread to the spinal cord white matter and its associated myelin pathology
Authors: Sharma Madhav , Chakravarty Debanjana , Zalavadia Ajay , Burrows Amy , Rayman Patricia , Sharma Nikhil , Kenyon Lawrence C. , Bergmann Cornelia , Sen Ganes C. , Sarma Jayasri Das
Published: June 2022

Ifit2, an interferon-induced protein with tetratricopeptide repeats 2, plays a critical role in restricting neurotropic murine β-coronavirus RSA59 infection. RSA59 intracranial injection of Ifit2 deficient (-/-) compared to wild type (WT) mice results in impaired acute microglial activation, associated with reduced CX3CR1 expression, which consecutively limits migration of peripheral lymphocytes into the brain, leading to impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence on demyelination during the chronic phase of RSA59 infection. Our current study demonstrates that Ifit2 deficiency causes extensive RSA59 viral spread throughout both the spinal cord grey and white matter and is associated with impaired CD4+ T cell infiltration. Cervical lymph nodes of RSA59 infected Ifit2-/- mice showed reduced activation of CD4+ T cells and impaired IFNγ expression during acute encephalomyelitis. Furthermore, blood-brain-barrier integrity was preserved in the absence of Ifit2 as evidenced by integral, tight junction protein ZO-1 expression surrounding the meninges and blood vessels and decreased Texas red dye uptake. In contrast to WT mice exhibiting only sparse myelin loss, the chronic disease phase in Ifit2-/- mice was associated with severe demyelination and persistent viral load, even at low infection doses. Overall, our study highlights that Ifit2 provides antiviral functions by promoting acute neuroinflammation and thereby aiding virus control and limiting severe demyelination.

Author Summary

The role of interferons in providing protective immunity against viral spread and pathogenesis is well known. Interferons execute their function by inducing certain genes collectively called as interferon stimulated genes (ISGs) among which Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is known for restricting neurotropic viral replication and spread in the brain. So far, not much has been investigated about its role in viral spread to the spinal cord and its associated myelin pathology. Towards this our study using neurotropic murine-β-coronavirus and Ifit2 deficient mice demonstrate that Ifit2 deficiency causes extensive viral spread throughout grey and white matter of spinal cord accompanied by impaired microglial activation and CD4+ T cell infiltration. Furthermore, infected Ifit2 deficient mice showed impaired activation of T cells in cervical lymph node and Blood-Brain-Barrier was relatively intact. Ifit2 deficient mice developed viral induced severe chronic neuroinflammatory demyelination accompanied by the presence of ameboid shaped phagocytotic microglia/macrophages.