Miracle-dz/UniFAR-FTUs huggingface dataset:
Boar spermadhesin AWN: novel insights in its binding behavior and localization on sperm

Abstract As a major spermadhesin first found in the seminal plasma (SP) of boars, AWN is described to fulfil a variety of reproduction related tasks. Although being the best investigated boar spermadhesin, information about its interaction with membranes is inconsistent. In this regard, previous reports locate AWN either inside or on the surface of sperm cells and at different regions, depending on the method and antibody used. Here, we localize native AWN (natAWN) in/on epididymal, ejaculated, capacitated, and acrosome-reacted boar sperm using epifluorescence and electron microscopy as well as an analysis of potential lipid-binding partners of natAWN and recombinant AWN (recAWN). By applying a custom-made anti-AWN antibody, localization of AWN in the equatorial segment (EQS) of ejaculated, capacitated, and acrosome-reacted boar sperm was discovered. Electron microscopy showed that AWN is localized both on the sperm surface and on the cytoplasmic side of the plasma membrane and in close vicinity to the nuclear and both acrosomal membranes of sperm. Analysis of epididymal sperm indicated migration of AWN from the retral postacrosomal part to the EQS during the epididymal passage. In contrast to hypotheses claiming a specific association of AWN to phosphatidylethanolamine (PE) and in line with our previous study describing an interaction with phosphatidic acid (PA), the current results show a rather electrostatically driven binding mechanism of AWN to negative lipids. In conclusion, this work provides new insights into the arrangement of AWN in the EQS, which suggest a possible role in sperm–oocyte fusion. Summary Sentence Spermadhesin AWN is highly associated with the equatorial segment of boar sperm, and its binding behavior is electrostatically driven.
Outcomes after hybrid minimally invasive treatment of Boerhaave syndrome: a single-institution experience

Abstract Background Spontaneous esophageal perforation or Boerhaave syndrome is a life-threatening emergency, associated with significant morbidity and mortality. In this retrospective series we describe our single-center experience with a hybrid minimally invasive treatment approach for the treatment of Boerhaave syndrome. Methods Clinical data of all patients who presented with spontaneous esophageal rupture between January 2009 and December 2019 were analyzed. All patients underwent esophageal endoscopic stenting to seal the perforation and debridement of the contaminated mediastinal and pleural cavity through video-assisted thoracoscopic surgery (VATS). Primary outcome measure was defined as in-hospital death and 30-day mortality. Results Twelve patients were included with a median age of 63 years (interquartile range [IQR] 51–74 years) of whom 58% (n = 7) were male. The median Pittsburg perforation severity score was 6.5 (IQR 6–9). Endoscopic reintervention was required in 8 patients (67%), primarily due to stent dislocation. In addition, 5 patients (42%) required re-VATS due to empyema formation. Thirty-day mortality and in-hospital mortality were respectively 17% (n = 2) and 25% (n = 3). Conclusion Endoscopic stenting in combination with thoracoscopic debridement is an effective and safe minimally invasive hybrid approach for the treatment of Boerhaave syndrome. This is depicted by the relatively low mortality rates, even among patients with high perforation severity scores. The relatively low mortality rates may be attributed to the combined approach of rapidly sealing the defect and decontamination of the thorax. Future studies should aim to corroborate this evidence which is limited by its sample size and retrospective nature.
Coping Strategies Utilized by Emergency Department Providers During the COVID-19 Pandemic.

INTRODUCTION COVID-19 has exposed health care workers to new stressors; emergency department providers are at risk of increased stress. It is unknown how coping strategies are utilized by this group during a pandemic. METHODS A cross-sectional survey incorporating the Brief COPE inventory was deployed to residents, fellows, faculty, and physician assistants at a single US academic emergency department in the spring (April 2020 - May 2020) and winter (December 2020 - January 2021). Scores for 14 individual coping strategies, as well as approach (positive) and avoidant (negative) coping categories, were measured, and utilization of these coping strategies was compared with respect to the provider's role, sex, the number of people living at home, presence of pets and/or children at home, and stress level. RESULTS The response rate was 58/103 (56.3%) and 50/109 (45.9%) for the spring and winter distributions, respectively. In the spring, 70.6% of responders reported increased stress vs 66% in the winter. Overall utilization of coping strategies increased slightly between spring and winter for approach coping (32.22 to 32.64) and avoidant coping (20.95 to 21.73). Resident physicians utilized less approach coping and more avoidant coping when compared to faculty/fellows. Substance use overall had a relatively low score, which increased slightly between spring and winter distributions (2.93 to 3.04). CONCLUSIONS Approach coping was frequently utilized among ED providers during the COVID-19 pandemic study period. Resident physicians had higher utilization of avoidant coping strategies compared to faculty/fellows and could benefit from targeted wellness interventions during times of increased stress.
Associations between social determinants of health and interpersonal violence-related injury in Cameroon: a cross-sectional study

Introduction Risk factors for interpersonal violence-related injury (IPVRI) in low-income and middle-income countries (LMICs) remain poorly defined. We describe associations between IPVRI and select social determinants of health (SDH) in Cameroon. Methods We conducted a cross-sectional analysis of prospective trauma registry data collected from injured patients >15 years old between October 2017 and January 2020 at four Cameroonian hospitals. Our primary outcome was IPVRI, compared with unintentional injury. Explanatory SDH variables included education level, employment status, household socioeconomic status (SES) and alcohol use. The EconomicClusters model grouped patients into household SES clusters: rural, urban poor, urban middle-class (MC) homeowners, urban MC tenants and urban wealthy. Results were stratified by sex. Categorical variables were compared via Pearson’s χ2 statistic. Associations with IPVRI were estimated using adjusted odds ratios (aOR) with 95% confidence intervals (95%CI). Results Among 7605 patients, 5488 (72.2%) were men. Unemployment was associated with increased odds of IPVRI for men (aOR 2.44 (95% CI 1.95 to 3.06), p<0.001) and women (aOR 2.53 (95% CI 1.35 to 4.72), p=0.004), as was alcohol use (men: aOR 2.33 (95% CI 1.91 to 2.83), p<0.001; women: aOR 3.71 (95% CI 2.41 to 5.72), p<0.001). Male patients from rural (aOR 1.45 (95% CI 1.04 to 2.03), p=0.028) or urban poor (aOR 2.08 (95% CI 1.27 to 3.41), p=0.004) compared with urban wealthy households had increased odds of IPVRI, as did female patients with primary-level/no formal (aOR 1.78 (95% CI 1.10 to 2.87), p=0.019) or secondary-level (aOR 1.54 (95% CI 1.03 to 2.32), p=0.037) compared with tertiary-level education. Conclusion Lower educational attainment, unemployment, lower household SES and alcohol use are risk factors for IPVRI in Cameroon. Future research should explore LMIC-appropriate interventions to address SDH risk factors for IPVRI.
Human Cytomegalovirus Hijacks WD Repeat Domain 11 for Virion Assembly Compartment Formation and Virion Morphogenesis

During the late phase of human cytomegalovirus (HCMV) infection, the endomembrane system is dramatically reorganized, resulting in the formation of a unique structure termed the virion assembly compartment (vAC), which is critical for the assembly of infectious virions. The mechanism of HCMV-induced vAC formation is still not fully understood. ABSTRACT Human cytomegalovirus (HCMV) has a large (∼235 kb) genome with more than 200 predicted open reading frames that exploits numerous cellular factors to facilitate its replication. A key feature of HCMV-infected cells is the emergence of a distinctive membranous cytoplasmic compartment termed the virion assembly compartment (vAC). Here, we report that host protein WD repeat domain 11 (WDR11) plays a key role in vAC formation and virion morphogenesis. We found that WDR11 was upregulated at both mRNA and protein levels during HCMV infection. At the late stage of HCMV replication, WDR11 relocated to the vAC and colocalized with markers of the trans-Golgi network (TGN) and vAC. Depletion of WDR11 hindered HCMV-induced membrane reorganization of the Golgi and TGN, altered vAC formation, and impaired HCMV secondary envelopment and virion morphogenesis. Further, motifs critical for the localization of WDR11 in TGN were identified by alanine-scanning mutagenesis. Mutation of these motifs led to WDR11 mislocation outside the TGN and loss of vAC formation. Taken together, these data indicate that host protein WDR11 is required for efficient viral replication at the stage of virion assembly, possibly by facilitating the remodeling of the endomembrane system for vAC formation and virion morphogenesis. IMPORTANCE During the late phase of human cytomegalovirus (HCMV) infection, the endomembrane system is dramatically reorganized, resulting in the formation of a unique structure termed the virion assembly compartment (vAC), which is critical for the assembly of infectious virions. The mechanism of HCMV-induced vAC formation is still not fully understood. In this report, we identified a host factor, WDR11, that plays an important role in vAC formation. Our findings argue that WDR11 contributes to the relocation of the Golgi and trans-Golgi network to the vAC, a membrane reorganization process that appears to be required for efficient virion maturation. The present work provides new insights into the vAC formation and HCMV virion morphogenesis and a potential novel target for antiviral treatment.
Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19

Background The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. Objectives We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. Methods This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1β, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni’s adjustment, were used for testing all outcomes. Results The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni’s adjustment was not significant. No significant effects were observed for the other outcomes. Conclusions The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. This trial was registered at clinicaltrials.gov as NCT04449718.
Androgen downregulates desmocollin‐2 in association with induction of mesenchymal transition of breast MDA‐MB‐453 cancer cells

Desmosomes are cellular structures that are critical in cell–cell adhesion and in maintaining tissue architecture. Changes in the expression of desmocollin‐2 (DSC2) have been noted during tumor progression into an invasive phenotype and as cells undergo epithelial‐mesenchymal transition. We have previously reported that breast MDA‐MB‐453 cancer cells, a luminal androgen receptor (AR) model of triple‐negative breast cancer, acquire mesenchymal features when treated with the AR agonist, dihydrotestosterone (DHT). We have therefore investigated androgen regulation of the expression and cellular localization of DSC2 in MDA‐MB‐453 cells. Treatment of the cells with DHT resulted in a dose‐dependent reduction in DSC2 protein levels and dispersion of its membrane localization concomitant with AR‐ and β‐catenin‐mediated mesenchymal transition of cells. A significant correlation was revealed between decreased expression of AR and increased expression of DSC2 in patient samples. In addition, whereas lower expression of AR was associated with a reduced overall and recurrence‐free survival of breast cancer patients, higher expression of DSC2 was found in invasive breast tumors than in normal breast cells and was correlated with lower patient survival. Upon knocking down DSC2, the cells became elongated, mesenchymal‐like, and slightly, but insignificantly, more migratory. The addition of DHT further stimulated cell elongation and migration. DSC2 siRNA‐transfected cells reverted to a normal epithelial morphology upon inhibition of β‐catenin. These results highlight the role of DSC2 in maintaining the epithelial morphology of MDA‐MB‐453 cells and the negative regulation of the desmosomal protein by DHT during stimulation of the androgen‐induced, β‐catenin‐mediated mesenchymal transition of the cells.
Concentration and heritability of immunoglobulin G and natural antibody immunoglobulin M in dairy and beef colostrum along with serum total protein in their calves

Abstract Immunoglobulin (Ig) G and natural antibody (NAb) IgM are passively transferred to the neonatal calf through bovine colostrum. Maternal IgG provides pathogen- or vaccine-specific protection and comprises about 85% of colostral Ig. NAb-IgM is less abundant but provides broad and nonspecific reactivity, potentially contributing to protection against the dissemination of pathogens in the blood (septicemia) in a calf’s first days of life. In the dairy and beef industries, failure of passive transfer (FPT) of colostral Ig (serum total protein [STP] <5.2 g/dL) is still a common concern. The objectives of this study were to: (1) compare colostral IgG concentrations and NAb-IgM titers between dairy and beef cows; (2) assess the effect of beef breed on colostral IgG; (3) compare passive transfer of colostral Ig in dairy and beef calves; and (4) estimate the heritability of colostral IgG and NAb-IgM. Colostrum was collected from Holstein dairy (n = 282) and crossbred beef (n = 168) cows at the University of Guelph dairy and beef research centers. Colostral IgG was quantified by radial immunodiffusion and NAb-IgM was quantified by an enzyme-linked immunosorbent assay. In dairy (n = 308) and beef (n = 169) calves, STP was estimated by digital refractometry. Beef cows had significantly greater colostral IgG (146.5 ± 9.5 standard error of the mean [SEM] g/L) than dairy cows (92.4 ± 5.2 g/L, P <0.01). Beef cows with a higher proportion of Angus ancestry had significantly lower colostral IgG (125.5 ± 5.8 g/L) than cows grouped as “Other” (142.5 ± 4.9 g/L, P = 0.02). Using the FPT cutoff, 13% of dairy and 16% of beef calves had FPT; still, beef calves had a significantly larger proportion with excellent passive transfer (STP ≥6.2 g/dL, P <0.01). The heritability of colostral IgG was 0.04 (±0.14) in dairy and 0.14 (±0.32) in beef. Colostral NAb-IgM titers in dairy (12.12 ± 0.22, log2 [reciprocal of titer]) and beef cows (12.03 ± 0.19) did not differ significantly (P = 0.71). The range of NAb-IgM titers was 9.18–14.60, equivalent to a 42-fold range in antibody concentration. The heritability of colostral NAb was 0.24 (±0.16) in dairy and 0.11 (±0.19) in beef cows. This study is the first to compare colostral NAb-IgM between dairy and beef cows. Based on the range in NAb-IgM titers and the heritability, selective breeding may improve colostrum quality and protection for neonatal calves in the early days of life.
Comparative Analysis of Proteomes and Phosphoproteomes in Patients with Prostate Cancer Using Different Surgical Conditions

Purpose To establish the standard of procedure in preparing benign and cancerous prostate tissues and evaluate the quality of proteomics and phosphoproteomics during transurethral resection of the prostate (TUR-P) with different surgical conditions. Materials and Methods TUR-P tissue samples from three patients, two diagnosed with prostate cancer and one with benign prostatic hyperplasia, were each analyzed under three different conditions, based on differences in energy values, tissue locations, and surgical techniques. Global- and phosphorylated proteomic profiles of prostate tissues were analyzed by liquid chromatography-tandem mass spectrometry. Results A total of 6,019 global proteins and 4,280 phosphorylated peptides were identified in the nine tissues. The quantitative distributions of proteins and phosphorylation in tissues from the same patient were not affected by changes in the surgical conditions, but indirect relative comparisons differed among patients. Phosphorylation levels, especially of proteins involved in the androgen receptor pathway, important in prostate cancer, were preserved in each patient. Conclusions Proteomic profiles of prostate tissue collected by TUR-P were not significantly affected by energy levels, tissue location, or surgical technique. In addition, since protein denaturation of samples through TUR-P is rarely confirmed in this study, we think that it will be an important guide for tissue samples in castration resistant prostate cancer patients, where it is difficult to obtain tissue. This result is the first report about proteomic and phosphoproteomic results with TUR-P samples in prostate cancer and will be theoretical basis in protein analysis research with prostate cancer tissues.
Epidemiology of hereditary transthyretin amyloidosis in the northernmost region of Sweden: a retrospective cohort study

Abstract Introduction Epidemiological data on hereditary transthyretin (ATTRv) amyloidosis from the northernmost region of Sweden (Norrbotten) are sparse. Methods We reviewed the medical records of all incident cases of ATTRv amyloidosis in Norrbotten between 2006 and 2018. Official population and mortality statistics were used to estimate incidence rates and standardised mortality ratios (SMRs). Results Ninety-three patients were diagnosed with ATTRv amyloidosis between 2006 and 2018 (median age, 72.8 years; 68.8% men; 95.7% Val30Met [p.Val50Met] mutation). The incidence rate per 100,000 persons and year increased from 1.50 (95% confidence interval [CI], 0.84–2.47) cases in 2006–2009 to 4.92 (95%CI, 3.46–6.78) cases in 2016–2018. The SMR in the ATTRv amyloidosis cohort was 2.64 times higher than in the general population in 2006–2018 (95%CI, 1.78–3.77). However, there were indications of lower SMRs over time (2006–2012, 2.96 [95%CI, 1.73–4.74]; 2013–2018, 2.32 [95%CI, 1.23–3.96]) and by use of disease-modifying drugs (no, 3.21 [95%CI, 1.87–5.13]; yes, 2.09 [95%CI, 1.08–3.64]). Conclusion The incidence of ATTRv amyloidosis increased 3-fold in Norrbotten between 2006 and 2018, most likely due to a previous underdiagnosis – with suggestions of lowered mortality during later years, possibly due to the introduction of disease-modifying drugs.
Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications.

The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.
Efficacy and Safety of Dextroamphetamine Transdermal System for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results from a Pivotal Phase 2 Study

Objectives: To assess efficacy and safety of the new Dextroamphetamine Transdermal System (d-ATS) to treat children and adolescents (aged 6–17 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: In this phase 2, randomized, placebo-controlled study, 4 d-ATS patches of differing doses (5, 10, 15, and 20 mg) were evaluated. Patients began a 5-week, open-label, stepwise dose-optimization period in which they received a 5-mg d-ATS patch (applied to hip) for 9 hours. During weekly visits, patients were evaluated for possible adjustments to the next dose level based on efficacy and safety. Once at the optimal dose, that dose was maintained during a 2-week, crossover double-blind treatment period. Primary endpoint was to assess efficacy of d-ATS versus placebo as measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) total score; key secondary endpoints included assessing onset and duration of efficacy by SKAMP total score, and additional secondary endpoints included Permanent Product Measure of Performance (PERMP) scores. Safety was assessed throughout. Results: d-ATS treatment resulted in significant improvements versus placebo in ADHD symptoms as measured by SKAMP total score, with overall least-squares mean difference (95% confidence interval) versus placebo of −5.87 (6.76, −4.97; p < 0.001) over the 12-hour assessment period. Onset of efficacy was observed at 2 hours postdose (p < 0.001), and duration of effect continued through 12 hours (patch removed at 9 hours), with significant differences between d-ATS and placebo at all time points from 2 hours onward (all p ≤ 0.003). Significant improvements versus placebo in PERMP-A and PERMP-C scores were also observed from 2 to 12 hours postdose with d-ATS treatment. d-ATS was safe and well-tolerated, with a systemic safety profile similar to that observed with oral amphetamines. Conclusions: This study demonstrates that d-ATS is an effective and well-tolerated treatment for children and adolescents with ADHD. These data indicate that d-ATS can deliver sustained levels of efficacy along with the advantages of transdermal drug delivery, making it a beneficial new treatment option. Clinical Trial Registration no.: NCT01711021.