bluuebunny/crossref_metadata_2025 huggingface dataset:
Biventricular mechanical pattern of the athlete’s heart: comprehensive characterization using three-dimensional echocardiography
Authors: Fábián Alexandra , Ujvári Adrienn , Tokodi Márton , Lakatos Bálint Károly , Kiss Orsolya , Babity Máté , Zámodics Márk , Sydó Nóra , Csulak Emese , Vágó Hajnalka , Szabó Liliána , Kiss Anna Réka , Szűcs Andrea , Hizoh Istvan , Merkely Béla , Kovács Attila
Published: February 2022

Aims

While left ventricular (LV) adaptation to regular, intense exercise has been thoroughly studied, data concerning the right ventricular (RV) mechanical changes and their continuum with athletic performance are scarce. The aim of this study was to characterize biventricular morphology and function and their relation to sex, age, and sports classes in a large cohort of elite athletes using three-dimensional (3D) echocardiography.

Methods and results

Elite, competitive athletes (n = 422) and healthy, sedentary volunteers (n = 55) were enrolled. Left ventricular and RV end-diastolic volumes (EDVi) and ejection fractions (EFs) were measured. To characterize biventricular mechanics, LV and RV global longitudinal (GLS) and circumferential strains (GCS) were quantified. All subjects underwent cardiopulmonary exercise testing to determine peak oxygen uptake (VO2/kg). Athletes had significantly higher LV and RV EDVi compared with controls (athletes vs. controls; LV EDVi: 81 ± 13 vs. 62 ± 11 mL/m2, RV EDVi: 82 ± 14 vs. 63 ± 11 mL/m2; P < 0.001). Concerning biventricular systolic function, athletes had significantly lower resting LV and RV EF (LV EF: 57 ± 4 vs. 61 ± 5%; RV EF: 55 ± 5 vs. 59 ± 5%; P < 0.001). The exercise-induced relative decrease in LV GLS (9.5 ± 10.7%) and LV GCS (10.7 ± 9.8%) was similar; however, the decrement in RV GCS (14.8 ± 17.8%) was disproportionately larger compared with RV GLS (1.7 ± 15.4%, P < 0.01). Right ventricular EDVi was found to be the strongest independent predictor of VO2/kg by multivariable linear regression.

Conclusion

Resting LV mechanics of the athlete’s heart is characterized by a balanced decrement in GLS and GCS; however, RV GCS decreases disproportionately compared with RV GLS. Moreover, this mechanical pattern is associated with better exercise capacity.
Diversity, activity, and abundance of benthic microbes in the Southeastern Mediterranean Sea
Authors: Rubin-Blum Maxim , Sisma-Ventura Guy , Yudkovski Yana , Belkin Natalia , Kanari Mor , Herut Barak , Rahav Eyal
Published: February 2022

Benthic microbes are key organisms in the oligotrophic Southeastern Mediterranean Sea (SEMS), yet their abundance, activity, and diversity in this rapidly changing basin are not fully understood. We investigated the prokaryotic and microfungal communities throughout years 2018–2020 at 27 stations (6–1900 m water depths, down to 20 cm below the sediment surface), in two transects with distinct downslope transport regimes, and along the eutrophic coastline. We estimated microbial abundance with flow cytometry, secondary production as leucine assimilation, and sequenced marker genes (the 16S rRNA and internal transcribed spacer) to assess diversity indices. The highest abundance (0.21 × 108 cells gr–1 sediment) was estimated at slope stations where we assumed substantial transport rates and found an accumulation of organic carbon. Secondary production was the highest nearshore (12 ± 4 ng C gr–1 h–1), and markedly declined offshore (0.5 ± 0.9 ng C gr–1 h–1). Populations of archaea (dominant Nitrososphaeria and Nanoarchaeia) and diverse bacteria were stable over three years, and taxonomic composition was dictated mainly by depth gradients. Saprotrophic and pathotrophic microfungi Ascomycota (70% ± 23%) and Basidiomycota (16% ± 18%) were prevalent, whereas parasitic chytrids were abundant nearshore. Our results highlight the role of downslope transport, which enriched the typical deep-sea communities with anaerobic lineages, in shaping microbial populations near the continental slope.
Race Inequity in School Attendance Across the Jim Crow South and Its Implications for Black–White Disparities in Trajectories of Cognitive Function Among Older Adults
Authors: Walsemann Katrina M , Ureña Stephanie , Farina Mateo P , Ailshire Jennifer A
Published: February 2022

Objectives

Although education is a key determinant of cognitive function, its role in determining Black–White disparities in cognitive function is unclear. This may be due, in part, to data limitations that have made it difficult to account for systemic educational inequities in the Jim Crow South experienced by older cohorts, including differences in the number of days Black students attended school compared to their White counterparts or Black peers in better-funded southern states. We determine if accounting for differential rates of school attendance across race, years, and states in the Jim Crow South better illuminates Black–White disparities in trajectories of cognitive function.

Methods

We linked historical state-level data on school attendance from the 1919/1920 to 1953/1954 Biennial Surveys of Education to the Health and Retirement Study, a nationally representative, longitudinal study of U.S. adults older than age 50. We restricted our sample to Black and White older adults who attended school in the Jim Crow South and began primary school in/after 1919/1920 and completed primary/secondary school by 1953/1954 (n = 4,343). We used linear mixed models to estimate trajectories of total cognitive function, episodic memory, and working memory.

Results

Self-reported years of schooling explained 28%–33% of the Black–White disparity in level of cognitive function, episodic memory, and working memory. Duration of school, a measure that accounted for differential rates of school attendance, explained 41%–55% of the Black–White disparity in these outcomes.

Discussion

Our study highlights the importance of using a more refined measure of schooling for understanding the education–cognitive health relationship.
A mixed, unified forward/inverse framework for earthquake problems: fault implementation and coseismic slip estimate
Authors: Puel S , Khattatov E , Villa U , Liu D , Ghattas O , Becker T W
Published: February 2022

We introduce a new finite-element (FE) based computational framework to solve forward and inverse elastic deformation problems for earthquake faulting via the adjoint method. Based on two advanced computational libraries, FEniCS and hIPPYlib for the forward and inverse problems, respectively, this framework is flexible, transparent and easily extensible. We represent a fault discontinuity through a mixed FE elasticity formulation, which approximates the stress with higher order accuracy and exposes the prescribed slip explicitly in the variational form without using conventional split node and decomposition discrete approaches. This also allows the first order optimality condition, that is the vanishing of the gradient, to be expressed in continuous form, which leads to consistent discretizations of all field variables, including the slip. We show comparisons with the standard, pure displacement formulation and a model containing an in-plane mode II crack, whose slip is prescribed via the split node technique. We demonstrate the potential of this new computational framework by performing a linear coseismic slip inversion through adjoint-based optimization methods, without requiring computation of elastic Green’s functions. Specifically, we consider a penalized least squares formulation, which in a Bayesian setting—under the assumption of Gaussian noise and prior—reflects the negative log of the posterior distribution. The comparison of the inversion results with a standard, linear inverse theory approach based on Okada’s solutions shows analogous results. Preliminary uncertainties are estimated via eigenvalue analysis of the Hessian of the penalized least squares objective function. Our implementation is fully open-source and Jupyter notebooks to reproduce our results are provided. The extension to a fully Bayesian framework for detailed uncertainty quantification and non-linear inversions, including for heterogeneous media earthquake problems, will be analysed in a forthcoming paper.
A comparative policy analysis of the adoption and implementation of sugar-sweetened beverage taxes (2016–19) in 16 countries
Authors: Mulcahy Georgina , Boelsen-Robinson Tara , Hart Ashleigh Chanel , Pesantes Maria Amalia , Sameeha Mohd Jamil , Phulkerd Sirinya , Alsukait Reem F , Thow Anne Marie
Published: February 2022

Taxes on sugar-sweetened beverages (SSBs) are recommended as part of comprehensive policy action to prevent diet-related non-communicable diseases (NCDs), but have been adopted by only one quarter of World Health Organization (WHO) Member States. This paper presents a comparative policy analysis of recent SSB taxes (2016–19) in 16 countries. This study aimed to analyse the characteristics and patterns of factors influencing adoption and implementation of SSB taxes and policy learning between countries, to draw lessons for future SSB taxes. The data collection and analysis were informed by an analytical framework that drew on ‘diffusion of innovation’ and theories of policy learning. Qualitative data were collected from policy documents and media, in addition to national statistics. Qualitative data were thematically analysed and a narrative synthesis approach was used for integrated case study analysis. We found adaptation and heterogeneity in the approaches used for SSB taxation with a majority of countries adopting excise taxes, and consistent health framing in media and policy documents. Common public frames supporting the taxes included reducing obesity/NCDs and raising revenue (government actors) and subsequent health system savings (non-government actors). Opposing frames focused on regressivity and incoherence with other economic policy (government actors) and posited that taxes have limited health benefits and negative economic impacts on the food industry (industry). Evident ‘diffusion networks’ included the WHO, predominantly in middle-income countries, and some regional economic bodies. We found indications of policy learning in the form of reference to other countries’ taxes, particularly countries with membership in the same economic bodies and with shared borders. The study suggests that adoption of SSB taxation could be enhanced through strategic engagement by health actors with the policy-making process, consideration of the economic context, use of consistent health frames by cross-sector coalitions, and robust evaluation and reporting of SSB taxation.
Association between low-density lipoprotein cholesterol and cardiovascular mortality in statin non-users: a prospective cohort study in 14.9 million Korean adults
Authors: Yi Sang-Wook , An Sang Joon , Park Hyung Bok , Yi Jee-Jeon , Ohrr Heechoul
Published: February 2022

Background

Limited information is available on detailed sex/age-specific associations between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) mortality and ‘the optimal range’ associated with the lowest CVD mortality in the general population.

Methods

Korean adults (N = 14 884 975) who received routine health screenings during 2009–2010 were followed until 2018 for CVD mortality.

Results

During 8.8 years (mean) of follow-up, 94 344 individuals died from CVD. LDL-C had U-curve associations with mortality from CVD and its subtypes, except haemorrhagic stroke. Optimal range was 90–149 mg/dL for CVD; 70–114 for ischaemic heart disease; 85–129 for ischaemic stroke; ≥85 for subarachnoid haemorrhage; ≥130 for intracerebral haemorrhage; 115–159 for hypertension and heart failure; and 100–144 for sudden cardiac death. Assuming linear associations between 100 and 300 mg/dL, LDL-C was positively associated with CVD mortality [hazard ratio (HR) per 39-mg/dL (1-mmol/L) higher LDL-C = 1.10], largely due to ischaemic heart disease (HR = 1.26), followed by sudden cardiac death (HR = 1.13), ischaemic stroke (HR = 1.11) and heart failure (HR = 1.05). Intracerebral haemorrhage (HR = 0.90), but not subarachnoid haemorrhage, had inverse associations. Women and older adults had weaker positive associations than men and younger adults (Pinteraction < 0.001 for both sex and age). Individuals aged 75–84 years had modest positive associations with CVD mortality, especially ischaemic heart disease and ischaemic stroke.

Conclusion

LDL-C had U-curve associations for CVD mortality. The associations and optimal ranges differed across CVD subtypes. Women and older adults had weaker positive associations than men and younger adults. Positive associations with ischaemic heart disease and ischaemic stroke were maintained in adults aged 75–84 years.
Community pharmacy practice related to the COVID-19 pandemic: barriers and facilitators
Authors: Bahlol Mohamed , Tran Van De , Dewey Rebecca Susan
Published: February 2022

Background

Community pharmacies provide an important healthcare service. Their significant value has been further highlighted during the COVID-19 pandemic crisis.

Objectives

To identify and categorize potential barriers and facilitators to the role of community pharmacists during the pandemic and their association with demographic factors.

Methods

A cross-sectional survey of community pharmacists was conducted using a self-administered questionnaire during April 2020 across all regions of Egypt.

Key findings

Respondents (n = 1018; 98.4% response rate) revealed practical and psychological barriers, including inadequate levels of pandemic preparedness (mean 61.43%; ±SD 0.47), inadequate working environments (mean 56.23%; ±SD 0.49) and uncooperative behaviour from stakeholders (mean 65.3%; ±SD 0.47).The majority of respondents emphasized the universal, region-independent necessity for facilitators, including the availability of timely (94.9%) guidance (97.4%) published by the Egyptian healthcare authority (94.6%), in electronic format (82.1%), through smartphone application (80.0%) and the provision of a dedicated telephone hotline (89.5%). Furthermore, authorities must use the media to manage public perceptions (97.2%) and increase public trust (94.8%) towards the pharmacist.

Conclusions

The barriers and facilitators identified herein could improve service provision in an integrated manner by overcoming the reported inadequate level of preparedness (barrier) through the provision of electronic guidance (facilitator), and the use of the media in managing public perceptions and trust (facilitators) to reduce the panic that negatively affects the working environment (barrier) for pharmacy staff. The varied level of healthcare authority cooperation reported in many regions requires further investigation.
A Joint Model for the Term Structure of Interest Rates and Realized Volatility
Authors: Hansen Anne Lundgaard
Published: February 2022

This paper presents a term structure model for no-arbitrage bond yields and realized bond market volatility. Based on well-known results, realized yield curve covariation is linked to generalized autoregressive conditional heteroskedasticity (GARCH)-type conditional covariation. The model is tractable and its latent state variables can be filtered using an exact algorithm. In an empirical study of U.S. Treasury bond data, the model shows that conditional yield curve covariation is priced in long-term yields. Moreover, the model proves useful for multi-step ahead forecasting of realized covariation. Finally, I use the model to quantify interest-rate risk and risk compensation.
GLTSCR1 coordinates alternative splicing and transcription elongation of ZO1 to regulate colorectal cancer progression
Authors: Han Fengyan , Yang Beibei , Zhou Mingyue , Huang Qiong , Mai Minglang , Huang Zhaohui , Lai Maode , Xu Enping , Zhang Honghe
Published: February 2022

Alternative splicing (AS) and transcription elongation are vital biological processes, and their dysregulation causes multiple diseases, including tumors. However, the coregulatory mechanism of AS and transcription elongation in tumors remains unclear. This study demonstrates a novel AS pattern of tight junction protein 1 (ZO1) regulated by the RNA polymerase II elongation rate in colorectal cancer (CRC). Glioma tumor suppressor candidate region gene 1 (GLTSCR1) decreases the transcription elongation rate of ZO1 to provide a time window for binding of the splicing factor HuR to the specific motif in intron 22 of ZO1 and spliceosome recognition of the weak 3′ and 5′ splice sites in exon 23 to promote exon 23 inclusion. Since exon 23 inclusion in ZO1 suppresses migration and invasion of CRC cells, our findings suggest a novel potential therapeutic target for CRC.
AGN impact on the molecular gas in galactic centres as probed by CO lines
Authors: Esposito Federico , Vallini Livia , Pozzi Francesca , Casasola Viviana , Mingozzi Matilde , Vignali Cristian , Gruppioni Carlotta , Salvestrini Francesco
Published: February 2022

We present a detailed analysis of the X-ray, infrared, and carbon monoxide (CO) emission for a sample of 35 local (z ≤ 0.15), active (LX ≥ 1042 erg s−1) galaxies. Our goal is to infer the contribution of far-ultraviolet (FUV) radiation from star formation (SF), and X-ray radiation from the active galactic nuclei (AGNs), respectively, producing photodissociation regions (PDRs) and X-ray-dominated regions (XDRs), to the molecular gas heating. To this aim, we exploit the CO spectral line energy distribution (CO SLED) as traced by Herschel, complemented with data from single-dish telescopes for the low-J lines, and high-resolution ALMA images of the mid-J CO emitting region. By comparing our results to the Schmidt–Kennicutt relation, we find no evidence for AGN influence on the cold and low-density gas on kpc-scales. On nuclear (r = 250 pc) scales, we find weak correlations between the CO line ratios and either the FUV or X-ray fluxes: this may indicate that neither SF nor AGN radiation dominates the gas excitation, at least at r = 250 pc. From a comparison of the CO line ratios with PDR and XDR models, we find that PDRs can reproduce observations only in presence of extremely high gas densities (n > 105 cm−3). In the XDR case, instead, the models suggest moderate densities (n ≈ 102−4 cm−3). We conclude that a mix of the two mechanisms (PDR for the mid-J, XDR, or possibly shocks for the high-J) is necessary to explain the observed CO excitation in active galaxies.
Cotranscriptional RNA strand exchange underlies the gene regulation mechanism in a purine-sensing transcriptional riboswitch
Authors: Cheng Luyi , White Elise N , Brandt Naomi L , Yu Angela M , Chen Alan A , Lucks Julius B
Published: February 2022

RNA folds cotranscriptionally to traverse out-of-equilibrium intermediate structures that are important for RNA function in the context of gene regulation. To investigate this process, here we study the structure and function of the Bacillus subtilis yxjA purine riboswitch, a transcriptional riboswitch that downregulates a nucleoside transporter in response to binding guanine. Although the aptamer and expression platform domain sequences of the yxjA riboswitch do not completely overlap, we hypothesized that a strand exchange process triggers its structural switching in response to ligand binding. In vivo fluorescence assays, structural chemical probing data and experimentally informed secondary structure modeling suggest the presence of a nascent intermediate central helix. The formation of this central helix in the absence of ligand appears to compete with both the aptamer’s P1 helix and the expression platform’s transcriptional terminator. All-atom molecular dynamics simulations support the hypothesis that ligand binding stabilizes the aptamer P1 helix against central helix strand invasion, thus allowing the terminator to form. These results present a potential model mechanism to explain how ligand binding can induce downstream conformational changes by influencing local strand displacement processes of intermediate folds that could be at play in multiple riboswitch classes.
Humoral and cellular response to COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases under real-life conditions
Authors: Krasselt Marco , Wagner Ulf , Nguyen Phuong , Pietsch Corinna , Boldt Andreas , Baerwald Christoph , Pierer Matthias , Seifert Olga
Published: February 2022

Objectives

Successful vaccination is key to overcoming the COVID-19 pandemic. Immunosuppressive medication is known to potentially compromise vaccination responses, and expansion of our knowledge on vaccination efficacy in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is therefore of utmost importance.

Methods

We conducted a single-centre observational study and evaluated the efficacy of approved COVID-19 vaccines in 303 adult AIIRD patients. Serum levels of IgG antibodies against the S1 subunit of SARS-CoV-2 spike proteins (anti-S IgG) were measured at least two weeks after vaccination. In a subgroup of patients without humoral response, T-cell responses were determined using an interferon-γ gamma release assay.

Results

Overall seropositivity rate was 78.5% and was significantly lower in patients under immunosuppressive therapy (75.7 vs 93.2%, P = 0.009). No difference regarding the vaccination type was observed. Glucocorticoids, mycophenolate-mofetil, TNF inhibitors, tocilizumab, abatacept and rituximab were all associated with non-response after proper vaccination. The risk was highest under RTX therapy (OR 0.004, 95% CI 0.001, 0.023, P < 0.0001). A strong negative correlation was observed between time since vaccination with an mRNA vaccine and anti-S antibody levels (r=–0.6149, P < 0.0001). In patients without humoral response, a T-cell response was found in 50%.

Conclusions

COVID-19 vaccination in patients with AIIRD is effective using any approved vaccine. Humoral response might be impaired depending on the individual immunosuppressive medication. The risk of non-response is highest under rituximab therapy. Anti-S IgG antibody levels wane over time after mRNA vaccination. Importantly, 50% of humoral non-responders showed a T-cellular response, suggesting T-cell-mediated protection to a certain extent.
Stem xylem traits and wood formation affect sex-specific responses to drought and rewatering inPopulus cathayana
Authors: Liu Miao , Zhao Yang , Wang Yuting , Korpelainen Helena , Li Chunyang
Published: February 2022

The increased frequency and intensity of drought pose great threats to the survival of trees, especially in dioecious tree species with sexual differences in mortality and biased sex ratios. The sex-specific mechanisms underlying stem xylem anatomy and function and carbon metabolism in drought resistance and recovery were investigated in dioecious Populus cathayana Rehder. The sex-specific drought resistance and subsequent recovery were linked to the xylem anatomy and carbon metabolism. Females had a greater xylem vessel area per vessel, biomass and theoretically hydraulic efficiency under well-watered conditions. Conversely, males had a lower xylem lumen area, but greater vessel numbers, and a higher cell wall thickness, suggesting a theoretically conservative water-use strategy and drought resistance. The recovery of photosynthetic ability after drought in males was largely dependent on the recovery of xylem function and the regulation of the xylem carbohydrate metabolism. Additionally, the number of upregulated genes related to xylem cell wall biogenesis was greater in males relative to females under drought stress and subsequent rewatering, which facilitated drought resistance and xylem function restoration in males. These results suggested that sex-specific drought resistance and restoration were related to xylem anatomy and function, carbohydrate metabolism and cell turgor maintenance.
Recognizing elder abuse
Authors: Hammond Lori , Harris Shonna
Published: February 2022

Diligent assessment of older adults who may be experiencing abuse can improve a living situation, promote well-being and happiness, and even save a life.
Challenges in Diagnosis of Crimean-Congo Hemorrhagic Fever
Authors: Almayahi Zayid K. , Al Kindi Hanan , Al Jabri Ishaq , Al Shaqsi Nasser , Al Hattali Noaman , Al Hattali Azza , Al Quyoodhi Badriya , Al Dhuhli Khalid
Published: February 2022

Crimean-Congo hemorrhagic fever is a serious and fatal disease. Since the disease was first identified in the first half of the last century, it has caused hundreds of fatalities worldwide. Although it is believed that the prognosis for each patient increases with early detection and management, some patients present in the late stage, whereas others may not be detected at all. The risk of disease transmission has increased in many countries in the Middle East, Eastern Europe, and Africa for many reasons, especially the existing challenges of the surveillance and control in the human and animal population, the limited testing and diagnostic capacity, increased trading of infected animals, low level of awareness and adherence to preventive measures in some communities, and the climatic changes and other risk factors, which have possibly affected the vector and reservoir activity. Therefore, to have better control of this disease, there should be a lot of effort in close surveillance to the animals and ticks that transmit the disease and to apply stringent preventive measures. This case report reflects how the patients themselves could help save their own lives through possible self-detection or self-diagnosis. The diagnosis of the disease in the 30-year-old male patient reported here was unfortunately missed by 3 health institutions, despite the patient providing a clear history of tick bite, which was followed by typical symptoms. When the patient referred himself for the fourth time, to rule out Crimean-Congo hemorrhagic fever, the diagnosis was made. It is proposed that raising the population's knowledge and awareness about the disease would help individuals and the community at large. Self-detection or self-diagnosis of Crimean-Congo hemorrhagic fever is not impossible when patients are aware about the disease symptoms and risk factors.
Undergraduate Nursing Students' Readiness to Practice
Authors: AlMekkawi Mohamad , Khalil Rouwida El
Published: February 2022

Background:

Nursing literature identifies difficulties facing new graduates in managing their responsibilities as registered nurses. The ability of new graduates to be practice-ready upon entry to the workplace remains a challenging concern for nurse educators.

Purpose:

This study investigated the perceptions of senior students toward their readiness to practice safely and independently and perform registered nurses' job-specific requirements upon graduation.

Methods:

A descriptive design using quantitative and qualitative methods was used to conduct the study. Data were collected from a sample of 117 senior nursing students in the United Arab Emirates using the Casey-Fink Readiness to Practice Survey.

Results:

Senior students felt confident to manage the care of 2 to 3 patients, communicate with patients and interdisciplinary teams, solve clinical problems, prioritize patients' care, and recognize significant changes in patient conditions. Areas of concern were their ability to care for more than 3 patients, among others, such as caring for dying patients and performing catheter insertion/irrigation.

Conclusion:

Students need better learning opportunities and closer guidance, support, and on-time feedback in clinical settings.
Nursing Faculty and Students' Satisfaction With Telepresence Robots During the COVID-19 Pandemic
Authors: Abuatiq Alham , Brown Robin , Plemmons Christina , Walstrom Beth , Hultman Cassy , Currier Danielle , Schmit Marie , Kvigne Valborg , Horsley Leann , Mennenga Heidi
Published: February 2022

Background:

Telepresence robots provide real-time audio, video, and mobility features, allowing faculty and students to engage in learning experiences without being physically present.

Problem:

With multiple students and faculty members needing to quarantine due to the COVID-19 pandemic, a flexible learning environment was essential.

Approach:

The telepresence robots were used as an innovative approach for both faculty and students to engage in learning experiences offered in a variety of settings.

Outcome:

Feedback was obtained from faculty and students about the use of and satisfaction with telepresence robots. The robots were easy to use and posed only a few technological challenges, which were easily overcome.

Conclusions:

Telepresence robots were effective tools in overcoming teaching and learning barriers caused by the COVID-19 pandemic. The telepresence robots have many applications, including use in clinical and community settings.
Postoperative Urinary Incontinence in Diabetic Patients Undergoing Pelvic Reconstructive Surgery
Authors: Siddique Moiuri , Ringel Nancy E. , de Winter K. Lauren , Marczak Tara , Kisby Cassandra , Rutledge Emily , Soriano Alex , Samimi Parisa , Schroeder Michelle , Handler Stephanie , Chou Jiling , Gutman Robert E.
Published: February 2022

Importance

Diabetes is an independent risk factor for urinary incontinence, and its impact on rates of postoperative incontinence after pelvic reconstructive surgery remains unexplored.

Objective

The aim of the study was to compare the incidence of postoperative stress urinary incontinence (SUI), urgency urinary incontinence (UUI), and mixed urinary incontinence in patients with diabetes mellitus undergoing surgery for pelvic organ prolapse (POP) with or without SUI surgery.

Study Design

This is a secondary analysis of a multicenter retrospective cohort study involving 10 diverse medical centers that identified a cohort of women with diabetes who had prolapse and/or anti-incontinence surgery. We compared rates of postoperative urinary incontinence among patients who had surgery for prolapse and incontinence versus surgery for prolapse only.

Results

Three hundred five patients had surgery for prolapse and incontinence, 330 had surgery for prolapse only, and 189 had anti-incontinence surgery only. De novo UUI was higher among those who underwent surgery for POP and SUI compared with surgery for POP alone (26.4% vs 14.1%, P < 0.01). Rates of persistent SUI (21% vs 4.9%, P < 0.01) and mixed urinary incontinence (15.9% vs 2.7%, P < 0.01) were higher for those who underwent prolapse surgery alone versus prolapse and an incontinence procedure. No differences were seen in hemoglobin A1C levels between those who did and did not report postoperative UI.

Conclusions

We found that postoperative de novo UUI rates were high among patients with diabetes after pelvic reconstructive surgery, with the incidence being significantly higher for those who had surgery for prolapse and incontinence compared with surgery for prolapse only.
Frequency of FLCN Loss of Function Variants and Birt-Hogg-Dubé-Associated Phenotypes in a Healthcare System Population
Authors: Savatt Juliann M. , Shimelis Hermela , Moreno-De-Luca Andres , Strande Natasha T. , Oetjens Matthew T. , Ledbetter David H. , Martin Christa Lese , Myers Scott M. , Finucane Brenda M.
Published: February 2022

Purpose

Current penetrance estimates of Birt-Hogg-Dubé (BHD)-associated cutaneous, pulmonary, and renal manifestations are based on clinically ascertained families. In a healthcare system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) variants in the FLCN gene, which cause BHD, and the penetrance of BHD-related phenotypes.

Methods

Exomes from 135,990 patient-participants in Geisinger’s MyCode® cohort were assessed for P/LP FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between FLCN P/LP variants and BHD-related phenotypes were assessed by Firth’s logistic regression.

Results

P/LP FLCN variants were identified in 35 (1 in 3,234) individuals, 68.6% of whom had BHD-related phenotype(s) including: cystic lung disease (65.7%); pneumothoraces (17.1%); cutaneous manifestations (8.6%); and renal cancer (2.9%). Only four (11.4%) were clinically diagnosed with BHD.

Conclusion

In this healthcare population, the frequency of P/LP FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes in the EHR, a minority were clinically diagnosed with BHD, likely because cutaneous manifestations, pneumothoraces, and renal cancer were observed at lower frequencies than clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.
6S RNA-dependent antibiotic susceptibility
Authors: Esberard Marick , Hallier Marc , Liu Wenfeng , Morvan Claire , Bossi Lionello , Figueroa-Bossi Nara , Felden Brice , Bouloc Philippe
Published: February 2022

Bacterial small RNAs (sRNAs) contribute to a variety of regulatory mechanisms that modulate wide ranging pathways, including metabolism, virulence, and antibiotic resistance. We investigated the involvement of sRNAs in rifampicin resistance in the opportunistic pathogenStaphylococcus aureus. Using a competition assay with an sRNA mutant library, we identified 6S RNA as being required for protection against low concentrations of rifampicin, an RNA polymerase (RNAP) inhibitor. This effect applied to rifabutin and fidaxomicin, two other RNAP-targeting antibiotics. 6S RNA is highly conserved in bacteria and its absence in two other major pathogens,Salmonella entericaandClostridioides difficile, also impaired susceptibility to RNAP inhibitors. InS. aureus, 6S RNA is produced from an autonomous gene and accumulates in stationary phase. In contrast to what was reported inEscherichia coli, S. aureus6S RNA does not appear to play a critical role in the transition from exponential to stationary phase, but affects σB-regulated expression in prolonged stationary phase. Nevertheless, its protective effect against rifampicin is independent of alternative sigma factor σBactivity. Our results suggest that 6S RNA helps maintain RNAP-σAintegrity inS. aureus, which could in turn help bacteria withstand low concentrations of RNAP inhibitors.
The impact of multigenerational high-fat diet feeding on the gut microbiome and host metabolism
Authors: Wibowo Marsha C. , Yang Zhen , Chavkin Theodore A. , Nguyen Brian , Pham Loc-Duyen , Huang Tian Lian , Lynes Matthew D. , Tseng Yu-Hua , Kostic Aleksandar D.
Published: February 2022

Although human genetics partially explain the heritability of obesity and type 2 diabetes (T2D), the human gut microbiome also plays a significant role. While changes in human genetics at the population level occur only after many generations, the gut microbiome evolves over a shorter time span. The gut microbiome is also vertically transmitted across generations, therefore, changes in one generation can be passed on to subsequent generations. However, it is unknown whether the gut microbiome influences natural selection of its host under obesogenic pressure. Here, we show that C57BL/6 mice fed a high-fat diet (60% fat, HFD) over four generations develop resistance to obesity and the metabolic syndrome (MetS). Unexpectedly, the mice were increasingly leaner as well as more glucose tolerant and insulin sensitive across generations. This phenomenon was attributed to the most obese mice not yielding progenies, whereas the leanest mice successfully reproduced, and their offspring were also resistant to obesity. In other words, a population bottleneck was observed. Because all the mice were nearly genetically identical inbred C57BL/6J mice, the large variation in body weight gain in response to HFD feeding was likely independent of genetics. We explored whether microbial factors enriched in obesity-resistant mice promote healthier host metabolic phenotypes under HFD feeding, thereby contributing to the heterogeneity in body weight gain and providing an adaptive advantage to the host. Pearson correlation analysis revealed that body weight gain was positively correlated with Lactococcus lactis, as well as negatively correlated with Lactobacillus johnsonii and pathways for coenzyme A biosynthesis, amino acid biosynthesis (lysine, isoleucine, valine), and nucleotide biosynthesis (adenosine, guanosine). Overall, we observed multigenerational adaptation in the gut microbiome correlated with improved metabolism, yet further studies are needed to validate that these adaptations drive metabolic health.
Maternal transfer and long-term population effects of PCBs in Baltic grey seals using a new toxicokinetic-toxicodynamic population model
Authors: Mauritsson Karl , Desforges Jean-Pierre , Harding Karin C.
Published: February 2022

Empirical evidence has shown that historical exposure of polychlorinated biphenyls (PCBs) to Baltic grey seals not only severely affected individual fitness, but also population growth rates and most likely caused the retarded recovery rate of the depleted population for decades. We construct a new model which we term a toxicokinetic-toxicodynamic (TKTD) population model to quantify these effects. The toxicokinetic sub model describes in detail the bioaccumulation, elimination, and vertical transfer from mother to offspring of PCBs, and was linked to a toxicodynamic model for estimation of PCB-related damage, hazard, and stress impacts on fertility and survival rates. Both sub-models were then linked to a Leslie matrix population model to calculate changes in population growth rate and age structure given different rates of PCB exposure. Toxicodynamic model parameters related to reproductive organ lesions were calibrated using published historical data on observed pregnancy rates in Baltic grey seal females. Our model showed that increased PCB exposure caused reduced fertility, decreased vertical transfer, and increased biomagnification. Compared to empirical data, the TKTD population model described well the age-specific bioaccumulation pattern of PCBs in Baltic grey seals, and thus, the toxicokinetic parameters, deduced from literature, are believed to be reliable. The model also captured well the general effects of PCBs on historical population growth rates. The developed model can be used to perform population viability analyses of Baltic grey seals with multiple stressors, also including by-catches and different hunting regimes. The model can also be extended to other marine mammals and other contaminants than PCB by adjustments of model parameter values and thus provides a test bed in silico for new substances.
Positive and relaxed selective pressures have both strongly influenced the evolution of cryonotothenioid fishes during their radiation in the freezing Southern Ocean
Authors: Bilyk Kevin T. , Zhuang Xuan , Papetti Chiara
Published: February 2022

Evolution in the chronic cold of the Southern Ocean has had a profound influence on the physiology of cryonotothenioid fishes. However, the suite of genetic changes underlying the physiological gains and losses in these fishes is still poorly surveyed. Using molecular evolution techniques, this study aimed to identify which functional classes of genes changed during the cryonotothenioid radiation in a polar ocean. The influences of both positive and relaxed selective pressures were isolated following two major physiological transitions: the onset of freezing temperatures, and the loss of hemoproteins. Looking at the influence of cold temperatures, positive selective pressure was most prominently found to act on biosynthetic processes (the machinery of transcription and translation) as well as on protein polymerization, cell adhesion, and cell cycle progression, suggesting these are key challenges to life in freezing waters. Relaxation of selective pressure produced a more complex pattern of change, affecting several homeostatic processes, suggesting their attenuation in cold-stable and oxygen-rich waters, but also seemingly acting as a route to key genetic change behind the morphological and ecological diversification seen in the clade. Finally, while chronic cold-water temperatures appear to have instigated clear genetic change, the loss of hemoproteins led to little observable change relative to their red-blooded relatives. Combined, the influence of positive and relaxed selection show that long-term exposure to cold has led to profound changes in cryonotothenioid genomes, which may make it challenging for them to respond to unpredictable heat waves and to adapt to a rapidly changing climate.
Dissociable Roles of FEF Neurons in Initiating Saccades
Authors: Shams-Ahmar Mohammad , Thier Peter , Merrikhi Yaser
Published: February 2022

The frontal eye field (FEF) plays a key role in initiating saccades. To explain how single neurons in this region may enable the initiation of saccades, Jeffery Schall proposed the “variable rate model” (Hanes and Schall, 1996) which assumes that the discharge of a neuron must reach a fixed activation threshold for a saccade to be evoked. However, the validity of this model has been questioned as results from later work testing saccades in different behavioral contexts seemed to require the assumption of variable thresholds. Moreover, even when sticking to the original behavioral context, not all types of frontal eye field neurons seemed to behave according to a variable rate model. In an attempt to reconsider the viability of the variable rate model avoiding limitations of previous research, we studied single neurons recorded from the FEF of two rhesus monkeys while they performed a memory-guided saccade task. We evaluated the degree to which each type of FEF neurons complied with the variable rate model by quantifying how precisely their discharge predicted an imminent saccade based on their immediate presaccadic activity. In addition, we asked whether there might be a hierarchical relation between visuomotor and motor neurons with only the latter responsible for the release of saccades and therefore satisfying the assumption of the variable rate model. We show that decoders trained on single motor neurons’ presaccadic activity performed better than decoders trained on visuomotor neurons in predicting an imminent saccade, in line with the assumption of a top position in a putative processing hierarchy. While this position might have suggested significant resilience to perturbation of the visual input to the FEF, we found quite the opposite that motor neurons but not visuomotor neurons were susceptible to perturbation. As a matter of fact, they lost the ability to predict the initiation of a saccade based on their immediate pressacadic discharge rate. Our results support the notion that motor neurons and visuomotor neurons have dissociable functions in information processing for saccades with motor neurons more closely related to saccade initiation, in line with the tenets of the variable rate model. Yet, they also clearly indicate that even these supposedly top layer neurons exhibit an unexpected degree of dependence on afferent input questions the viability of the assumption of a simple processing hierarchy.
CLEC5A and TLR2 are critical in SARS-CoV-2-induced NET formation and lung inflammation
Authors: Sung Pei-Shan , Yang Shao-Ping , Peng Yu-Chun , Sun Cheng-Pu , Tao Mi-Hwa , Hsieh Shie-Liang
Published: February 2022

Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory distress syndrome (ARDS). Autopsy demonstrates the presence of thrombosis and microangiopathy in the small vessels and capillaries. Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS. It has been shown that sera from individuals with COVID-19 triggered NET release in vitro, and spleen tyrosine kinase (Syk) inhibitor R406 inhibited NETosis caused by COVID-19 plasma. However, the serum components responsible for NET formation are still unknown. In this study, we found that virus-free extracellular vesicles (EVs) from COVID-19 patients (COVID-19 EVs) induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A). Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation and lung fibrosis were attenuated dramatically in clec5a-/-/tlr2-/- mice. These results suggest that COVID-19 EVs play critical roles in SARS-CoV-2-induced immunothrombosis, and blockade of CLEC5A and TLR2 is a promising strategy to inhibit SARS-CoV-2-induced intravascular coagulopathy and reduce the risk of ARDS in COVID-19 patients.
Expanded transcriptomic analysis of human hepatic stellate cells links novel coding and noncoding products to human liver fibrosis
Authors: Mahpour Amin , Mullen Alan
Published: February 2022

End stage liver disease and liver failure occur primarily as a consequence of progressive fibrosis resulting from chronic liver injury. Hepatic stellate cells (HSCs) are the primary cell type responsible for production of the extracellular matrix (ECM) that forms the fibrotic scar. While the essential role of HSCs is understood, there remain no treatments that target HSCs to inhibit the development or progression of fibrosis. We have performed analysis of the transcriptome of human HSCs to define the long noncoding (lnc) RNAs expressed in this cell type, including many not previously annotated. Through analysis of full-length RNA transcripts, we identified additional lncRNAs that were not assembled by short reads. We also discovered new isoforms of proteincoding genes that encode amino acid sequences that are not present in annotated isoforms. Analysis of non-polyadenylated RNAs did not identify additional genes encoding long noncoding RNA transcripts, but did reveal the presence of hundreds of circular (circ) RNAs, including those with potential for translation. Incorporating these transcripts and genes into analysis of a published dataset of human liver fibrosis revealed the induction of lncRNAs, novel protein isoforms, and circRNAs associated with development of disease. These results identify RNAs and amino acid sequences expressed in HSCs and associated with human liver disease that may serve as therapeutic targets to inhibit fibrosis or biomarkers to benchmark progression of disease.
Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission
Authors: Lach Ryan S. , Qiu Chongxu , Kajbaf Erfan Zeyaei , Baxter Naomi , Han Dasol , Wang Alex , Lock Hannah , Chirikian Orlando , Pruitt Beth , Wilson Maxwell Z.
Published: February 2022

Wnt signal transduction is mediated by a protein assembly called the Destruction Complex (DC) made from scaffold proteins and kinases that are essential for transducing extracellular Wnt ligand concentrations to changes in nuclear β-catenin, the pathway’s transcriptional effector. Recently, DC scaffold proteins have been shown to undergo liquid-liquid phase separation in vivo and in vitro providing evidence for a mesoscale organization of the DC. However, the mesoscale organization of DC at endogenous expression levels and how that organization could play a role in β-catenin processing is unknown. Here we find that the native mesoscale structure is a dynamic biomolecular condensate nucleated by the centrosome. Through a combination of advanced microscopy, CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools, that allow for independent manipulation of the biophysical parameters that drive condensate formation, we find that a function of DC nucleation by the centrosome is to drive efficient processing of β-catenin by co-localizing DC components to a single reaction hub. We demonstrate that simply increasing the concentration of a single DC kinase onto the centrosome controls β-catenin processing. This simple change in localization completely alters the fate of the Wnt-driven human embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in dynamically controlling the activities of biomolecular condensates and suggest a tight integration between cell cycle progression and Wnt signal transduction.