Miracle-dz/UniFAR-FTUs huggingface dataset:
Treponema denticola Induces Interleukin-36γ Expression in Human Oral Gingival Keratinocytes via the Parallel Activation of NF-κB and Mitogen-Activated Protein Kinase Pathways

The oral epithelial barrier acts as both a physical barrier to the abundant oral microbiome and a sentry for the immune system that, in health, constrains the accumulation of the polymicrobial plaque biofilm. The immune homeostasis during gingivitis that is largely protective becomes dysregulated, unproductive, and destructive to gingival tissue as periodontal disease progresses to periodontitis. ABSTRACT The oral epithelial barrier acts as both a physical barrier to the abundant oral microbiome and a sentry for the immune system that, in health, constrains the accumulation of the polymicrobial plaque biofilm. The immune homeostasis during gingivitis that is largely protective becomes dysregulated, unproductive, and destructive to gingival tissue as periodontal disease progresses to periodontitis. The progression to periodontitis is associated with the dysbiosis of the oral microbiome, with increasing prevalences and abundances of periodontal pathogens such as Treponema denticola. Despite the association of T. denticola with a chronic inflammatory disease, relatively little is known about gingival epithelial cell responses to T. denticola infection. Here, we characterized the transcriptome of gingival keratinocytes following T. denticola challenge and identified interleukin-36γ (IL-36γ) as the most differentially expressed cytokine. IL-36γ expression is regulated by p65 NF-κB and the activation of both the Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways downstream of Toll-like receptor 2 (TLR2). Finally, we demonstrate for the first time that mitogen- and stress-activated kinase 1 (MSK1) contributes to IL-36γ expression and may link the activation of MAPK and NF-κB signaling. These findings suggest that the interactions of T. denticola with the gingival epithelium lead to elevated IL-36γ expression, which may be a critical inducer and amplifier of gingival inflammation and subsequent alveolar bone loss.
Covariant Bimodules Over Monoidal Hom-Hopf Algebras

Covariant Hom-bimodules are introduced and the structure theory of them in the Hom-setting is studied in a detailed way. The category of bicovariant Hom-bimodules is proved to be a (pre-)braided monoidal category. The notion of Yetter-Drinfel'd Hom-modules is presented and it is shown that the category of Yetter-Drinfel'd Hom-modules is a (pre-)braided tensor category as well. Finally, it is verified that these tensor categories are braided monoidal equivalent under certain conditions.
Smartphone overuse, depression & anxiety in medical students during the COVID-19 pandemic

Introduction Medical students have made particular use of smartphones during the COVID-19 pandemic. Although higher smartphone overuse has been observed, its effect on mental disorders is unclear. This study aimed to assess the association between smartphone overuse and mental disorders in Peruvian medical students during the COVID-19 pandemic. Methods A cross-sectional study was conducted in 370 students aged between 16 and 41 years (median age: 20) in three universities from July to October 2020. A survey including Smartphone Dependence and Addiction Scale, PHQ-9, and GAD-7 was applied. Prevalence ratios were estimated using generalized linear models. Results Smartphone overuse was a common feature among students (n = 291, 79%). Depressive symptoms were present in 290 (78%) students and anxiety symptoms in 255 (69%). Adjusted for confounders, addictive/dependent smartphone use was significantly associated with presence of depressive symptoms (PR = 1.29, 95% CI: 1.20–1.38 for dependent use; PR = 1.30, 95% CI: 1.12–1.50 for addictive use). Also, addictive/dependent smartphone use was significantly associated with presence of anxiety symptoms (PR = 1.59, 95% CI: 1.14–2.23 for dependent use; PR = 1.61, 95% CI: 1.07–2.41 for addictive use). Conclusions Our findings suggest that medical students exposed to smartphone overuse are vulnerable to mental disorders. Overuse may reflect an inappropriate way of finding emotional relief, which may significantly affect quality of life and academic performance. Findings would assist faculties to establish effective measures for prevention of smartphone overuse.
A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV

Orofaciodigital syndrome (OFD) is clinically heterogeneous and is characterized by abnormalities in the oral cavity, facial features, digits, and central nervous system. At least 18 subtypes of the condition have been described in the literature. OFD is caused by variants in several genes with overlapping phenotypes. We studied a consanguineous Pakistani family with two affected siblings with an atypical form of OFD type 4 (OFD4). In addition to the typical features of OFD4 that include limb defects and growth retardation, the siblings displayed rare features of scaphocephaly and seizures. Exome sequencing analysis revealed a novel homozygous splice site variant c.257‐1G>A in TCTN3 that segregated with disease. This homozygous splice site variant in TCTN3 is most likely the underlying cause of the atypical form of OFD4 observed in this family. Our results contribute to the phenotypic spectrum of TCTN3 associated ciliopathies and will facilitate better clinical diagnosis.
Editorial Perspective: Are treatments for childhood mental disorders helpful in the long run? An overview of systematic reviews

Mental disorders may have severe consequences for individuals across their entire lifespan, especially when they start in childhood. Effective treatments (both psychosocial and pharmacological) exist for the short‐term treatment of common mental disorders in young people. These could, at least theoretically, prevent future problems, including recurrence of the disorder, development of comorbidity, or problems in functioning. However, little is known about the actual effects of these treatments in the long run. In the current editorial perspective, we consider the available evidence for the long‐term (i.e., ≥2 years) effectiveness and safety of treatments for attention deficit hyperactivity disorder, behavior disorders, and anxiety and depressive disorders for children between 6 and 12 years old. After providing an overview of the literature, we reflect on two key issues, namely, methodological difficulties in establishing long‐term treatment effects, and the risk–benefit ratio of treatments for common childhood mental disorders. In addition, we discuss future research possibilities, clinical implications, and other approaches, specifically whole‐of‐society‐actions that could potentially reduce the burden of common childhood mental disorders.
Suppression of Ca2+ signaling enhances melanoma progression

The role of store‐operated Ca2+ entry (SOCE) in melanoma metastasis is highly controversial. To address this, we here examined UV‐dependent metastasis, revealing a critical role for SOCE suppression in melanoma progression. UV‐induced cholesterol biosynthesis was critical for UV‐induced SOCE suppression and subsequent metastasis, although SOCE suppression alone was both necessary and sufficient for metastasis to occur. Further, SOCE suppression was responsible for UV‐dependent differences in gene expression associated with both increased invasion and reduced glucose metabolism. Functional analyses further established that increased glucose uptake leads to a metabolic shift towards biosynthetic pathways critical for melanoma metastasis. Finally, examination of fresh surgically isolated human melanoma explants revealed cholesterol biosynthesis‐dependent reduced SOCE. Invasiveness could be reversed with either cholesterol biosynthesis inhibitors or pharmacological SOCE potentiation. Collectively, we provide evidence that, contrary to current thinking, Ca2+ signals can block invasive behavior, and suppression of these signals promotes invasion and metastasis.
The relation between sensory processing sensitivity and telomere length in adolescents

In the present study, we investigated the association between sensory processing sensitivity (SPS) and telomere length (TL), which is considered a biomarker of cellular aging. SPS is an individual characteristic describing increased perception and procession of inner or outer stimuli, and is positively related to self‐perceived stress.
Outer Membrane Vesicles of Actinobacillus pleuropneumoniae Exert Immunomodulatory Effects on Porcine Alveolar Macrophages

Owing to their built-in adjuvanticity and antigenicity, bacterial outer membrane vesicles (OMVs) are gaining increasing attention as potential vaccines for both human and animal use. OMVs released by Actinobacillus pleuropneumoniae, an important respiratory pathogen in pigs, have also been investigated for vaccine development. ABSTRACT Outer membrane vesicles (OMVs) are spontaneously released by Gram-negative bacteria, including Actinobacillus pleuropneumoniae, which causes contagious pleuropneumonia in pigs and leads to considerable economic losses in the swine industry worldwide. A. pleuropneumoniae OMVs have previously been demonstrated to contain Apx toxins and proteases, as well as antigenic proteins. Nevertheless, comprehensive characterizations of their contents and interactions with host immune cells have not been made. Understanding the protein compositions and immunomodulating ability of A. pleuropneumoniae OMVs could help illuminate their biological functions and facilitate the development of OMV-based applications. In the current investigation, we comprehensively characterized the proteome of native A. pleuropneumoniae OMVs. Moreover, we qualitatively and quantitatively compared the OMV proteomes of a wild-type strain and three mutant strains, in which relevant genes were disrupted to increase OMV production and/or produce OMVs devoid of superantigen PalA. Furthermore, the interaction between A. pleuropneumoniae OMVs and porcine alveolar macrophages was also characterized. Our results indicate that native OMVs spontaneously released by A. pleuropneumoniae MIDG2331 appeared to dampen the innate immune responses by porcine alveolar macrophages stimulated by either inactivated or live parent cells. The findings suggest that OMVs may play a role in manipulating the porcine defense during the initial phases of the A. pleuropneumoniae infection. IMPORTANCE Owing to their built-in adjuvanticity and antigenicity, bacterial outer membrane vesicles (OMVs) are gaining increasing attention as potential vaccines for both human and animal use. OMVs released by Actinobacillus pleuropneumoniae, an important respiratory pathogen in pigs, have also been investigated for vaccine development. Our previous studies have shown that A. pleuropneumoniae secretes OMVs containing multiple immunogenic proteins. However, immunization of pigs with these vesicles was not able to relieve the pig lung lesions induced by the challenge with A. pleuropneumoniae, implying the elusive roles that A. pleuropneumoniae OMVs play in host-pathogen interaction. Here, we showed that A. pleuropneumoniae secretes OMVs whose yield and protein content can be altered by the deletion of the nlpI and palA genes. Furthermore, we demonstrate that A. pleuropneumoniae OMVs dampen the immune responses in porcine alveolar macrophages stimulated by A. pleuropneumoniae cells, suggesting a novel mechanism that A. pleuropneumoniae might use to evade host defense.
Health practitioner beliefs regarding the impact of age-based stereotype threat on performance in the cognitive assessment of older adults

Abstract Objectives Health practitioners’ understanding of the impact of age-based stereotype threat (ABST) on the cognitive test performance of older adults is not well understood. This study aimed to investigate health practitioners’ ability to recognize the influence of ABST in the cognitive assessment of older adults and their perceptions of its impact in practice. Methods One-hundred and twenty-nine health practitioners (86% female; M age = 39.75, SD = 11.50) with experience in conducting cognitive assessments with older adults (mainly psychologists and occupational therapists) completed an online survey assessing demographic and practice characteristics, aging beliefs, a hypothetical cognitive assessment scenario, and perceived impact of ABST on practice. Results Overall, health practitioners rated ABST factors in the assessment scenario as less detrimental to cognitive performance than internal and external factors. In a hierarchical regression model, lower recognition of ABST and negative aging beliefs significantly accounted for lower perceived impact of ABST on older adults’ cognitive test performance in practice (R 2 = .37, p < .001). Conclusion Health practitioners may not recognize the influence of ABST on assessment findings, especially if they hold negative aging beliefs. The findings highlight the need to improve health practitioners’ knowledge of ABST to increase the validity of cognitive testing in older adults.
Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic

Abstract Background Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK). Methods We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016–20. All centres studied children and adolescents (age range 8–20 years), except the UK centre which involved 26–27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum. Results Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37–2.94) with lower odds in the LMICs: Brazil (0.73, 0.42–1.27), Ecuador (0.40, 0.24–0.66) and Uganda (0.62, 0.37–1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda. Conclusions This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.
The psychometric properties of the Spanish version of the Morningness-Eveningness Stability Scale improved (MESSi) in adolescents

ABSTRACT The aim of the present study was to adapt the Morningness-Eveningness-Stability Scale improved (MESSi) to the Spanish adolescent population, testing its factor structure and construct validity. The participants were 725 adolescents (52.9% girls; M = 14.8, SD = 1.99) who completed the MESSi, the Morningness Eveningness Scale of Children (MESC), questions about sleep habits adapted from the School Sleep Habits Survey, and self-reported academic performance. The psychometric results support a three-factor model with the factors of morning affect, eveningness, and distinctness, which show good internal consistency. The pattern of correlations between MESSi and the other measures was in the expected direction. The MESC correlated positively with morning affect and negatively with eveningness, whereas distinctness was uncorrelated. Boys reported higher morningness, whereas girls reported higher distinctness. Eveningness was negatively related to academic performance. Overall, the results support the validity and reliability of the Spanish adolescent version of the MESSi.
Allele-specific silencing of the gain-of-function mutation in Huntington’s disease using CRISPR/Cas9

Dominant gain-of-function mechanisms in Huntington’s disease (HD) suggest that selective silencing of mutant HTT produces robust therapeutic benefits. Here, capitalizing on exonic protospacer adjacent motif–altering (PAM-altering) SNP (PAS), we developed an allele-specific CRISPR/Cas9 strategy to permanently inactivate mutant HTT through nonsense-mediated decay (NMD). Comprehensive sequence/haplotype analysis identified SNP-generated NGG PAM sites on exons of common HTT haplotypes in HD subjects, revealing a clinically relevant PAS-based mutant-specific CRISPR/Cas9 strategy. Alternative allele of rs363099 (29th exon) eliminates the NGG PAM site on the most frequent normal HTT haplotype in HD, permitting mutant-specific CRISPR/Cas9 therapeutics in a predicted ~20% of HD subjects with European ancestry. Our rs363099-based CRISPR/Cas9 showed perfect allele specificity and good targeting efficiencies in patient-derived cells. Dramatically reduced mutant HTT mRNA and complete loss of mutant protein suggest that our allele-specific CRISPR/Cas9 strategy inactivates mutant HTT through NMD. In addition, GUIDE-Seq analysis and subsequent validation experiments support high levels of on-target gene specificity. Our data demonstrate a significant target population, complete mutant specificity, decent targeting efficiency in patient-derived cells, and minimal off-target effects on protein-coding genes, proving the concept of PAS-based allele-specific NMD-CRISPR/Cas9 and supporting its therapeutic potential in HD.
Effects of sleep deprivation on coronary heart disease

The presence of artificial light enables humans to be active 24 h a day. Many people across the globe live in a social culture that encourages staying up late to meet the demands of various activities, such as work and school. Sleep deprivation (SD) is a severe health problem in modern society. Meanwhile, as with cardiometabolic disease, there was an obvious tendency that coronary heart disease (CHD) to become a global epidemic chronic disease. Specifically, SD can significantly increase the morbidity and mortality of CHD. However, the underlying mechanisms responsible for the effects of SD on CHD are multilayered and complex. Inflammatory response, lipid metabolism, oxidative stress, and endothelial function all contribute to cardiovascular lesions. In this review, the effects of SD on CHD development are summarized, and SD-related pathogenesis of coronary artery lesions is discussed. In general, early assessment of SD played a vital role in preventing the harmful consequences of CHD.
Factors Associated With Mechanical Ventilation Duration in Pediatric Burn Patients in a Regional Burn Center in the United States*

Objectives: Among burned children who arrive at a burn center and require invasive mechanical ventilation (IMV), some may have prolonged IMV needs. This has implications for patient-centered outcomes as well as triage and resource allocation decisions. Our objective was to identify factors associated with the duration of mechanical ventilation in pediatric patients with acute burn injury in this setting. Design: Single-center, retrospective cohort study. Setting: Registry data from a regional, pediatric burn center in the United States. Patients: Children less than or equal to 18 years old admitted with acute burn injury who received IMV between January 2005 and December 2020. Interventions: None. Measurements and Main Results: Ventilator days were defined as any full or partial day having received IMV via an endotracheal tube or tracheostomy, not inclusive of time spent ventilated for procedures. Of 5,766 admissions for acute burn care, 4.3% (n = 249) required IMV with a median duration of 10 days. A multivariable model for freedom from mechanical ventilation showed that the presence of inhalational injury (subhazard ratio [sHR], 0.62; 95% CI, 0.46–0.85) and burns to the head and neck region (sHR, 0.94; 95% CI, 0.90–0.98) were associated with increased risk of remaining mechanically ventilated at any time point. Older (sHR, 1.03; 95% CI, 1.01–1.04) and male children (sHR, 1.39; 95% CI, 1.05–1.84) were more likely to discontinue mechanical ventilation. A majority of children (94.8%) survived to hospital discharge. Conclusions: The presence of inhalational injury and burns to the head and neck region were associated with a longer duration of mechanical ventilation. Older age and male gender were associated with a shorter duration of mechanical ventilation. These factors should help clinicians better estimate a burned child’s expected trajectory and resource-intensive needs upon arrival to a burn center.
Metformin-associated lactic acidosis and factors associated with 30-day mortality

Background Metformin-associated lactic acidosis (MALA) is a rare event but underrecognition may lead to unfavorable outcomes in type 2 diabetes patients. While many risk factors of MALA have been identified, how to reduce mortality from MALA is a matter of debate. This study aimed to explore the factors associated with 30-day mortality amongst MALA patients. Methods An observational study enrolled patients diagnosed with MALA between January 2014 and December 2017. MALA was defined by a history of metformin administration, metabolic acidosis (arterial blood gas pH <7.35 or HCO3 <15 mmol/L), and elevated plasma lactate level (>5 mmol/L). We examined risk factors including age, sex, underlying diseases, current medications, blood tests, disease severity, and dialysis data. Mortality status was identified from medical records or report on telephone. Results We included 105 MALA patients. Most patients (95.2%) were diagnosed acute kidney injury stage 3 according to KDIGO 2012 definition. The 30-day mortality rate was 36.2% and dialysis rate was 85.7%. The survivors had higher proportions of underlying chronic kidney disease, presence of metabolic acidosis, receiving renal replacement therapy within 6 hours, and haemodialysis, whereas the non-survivors had higher percentage of hypertension and disease severity. Lower APACHE II score (HR = 0.95; 95%CI, 0.91–0.99; p = 0.038), time to dialysis < 6 hours (0.31; 0.14–0.69; 0.004), and haemodialysis (0.20;0.06–0.67; 0.010) were associated with lower 30-day mortality, using multivariate Cox-regression analysis. Conclusions Mortality rate amongst patients with MALA was high. Early dialysis treatment within 6 hours after admission and haemodialysis were independently associated with lower 30-day mortality. The large scale, well-designed studies need to confirm these encouraging results.