Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus.

The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relies on the sequential binding to surface glycans and transmembrane serine protease 2 (TMPRSS2) for entry into target cells. TMPRSS2 is synthesized as a zymogen that undergoes autolytic activation to process its substrates. Several respiratory viruses, in particular coronaviruses, use TMPRSS2 for proteolytic priming of their surface spike protein to drive membrane fusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptor binding domain in complex with TMPRSS2, showing that it recognizes residues lining the catalytic groove. Combined mutagenesis of interface residues and comparison across species highlight positions 417 and 469 as determinants of HKU1-CoV host tropism. The structure of a receptor-blocking nanobody in complex with zymogen or activated TMPRSS2 further provides the structural basis of TMPRSS2 activating conformational change, which alters loops recognized by HKU1-CoV and dramatically increases binding affinity.

The origin of esterase activity of Parkinson's disease causative factor DJ-1 implied by evolutionary trace analysis of its prokaryotic homolog HchA.

DJ-1, a causative gene for hereditary recessive Parkinsonism, is evolutionarily conserved across eukaryotes and prokaryotes. Structural analyses of DJ-1 and its homologs suggested the 106th Cys is a nucleophilic cysteine functioning as the catalytic center of hydratase or hydrolase activity. Indeed, DJ-1 and its homologs can convert highly electrophilic α-oxoaldehydes such as methylglyoxal into α-hydroxy acids as hydratase in vitro, and oxidation-dependent ester hydrolase (esterase) activity has also been reported for DJ-1. The mechanism underlying such plural activities, however, has not been fully characterized. To address this knowledge gap, we conducted a series of biochemical assays assessing the enzymatic activity of DJ-1 and its homologs. We found no evidence for esterase activity in any of the Escherichia coli DJ-1 homologs. Furthermore, contrary to previous reports, we found that oxidation inactivated rather than facilitated DJ-1 esterase activity. The E. coli DJ-1 homolog HchA possesses phenylglyoxalase and methylglyoxalase activities but lacks esterase activity. Since evolutionary trace analysis identified the 186th H as a candidate residue involved in functional differentiation between HchA and DJ-1, we focused on H186 of HchA and found that an esterase activity was acquired by H186A mutation. Introduction of reverse mutations into the equivalent position in DJ-1 (A107H) selectively eliminated its esterase activity without compromising α-oxoaldehyde hydratase activity. The obtained results suggest that differences in the amino acid sequences near the active site contributed to acquisition of esterase activity in vitro and provide an important clue to the origin and significance of DJ-1 esterase activity.

Recent Advances in Pristine Iron Triad Metal-Organic Framework Cathodes for Alkali Metal-Ion Batteries.

Pristine iron triad metal-organic frameworks (MOFs), i.e., Fe-MOFs, Co-MOFs, Ni-MOFs, and heterometallic iron triad MOFs, are utilized as versatile and promising cathodes for alkali metal-ion batteries, owing to their distinctive structure characteristics, including modifiable and designable composition, multi-electron redox-active sites, exceptional porosity, and stable construction facilitating rapid ion diffusion. Notably, pristine iron triad MOFs cathodes have recently achieved significant milestones in electrochemical energy storage due to their exceptional electrochemical properties. Here, the recent advances in pristine iron triad MOFs cathodes for alkali metal-ion batteries are summarized. The redox reaction mechanisms and essential strategies to boost the electrochemical behaviors in associated electrochemical energy storage devices are also explored. Furthermore, insights into the future prospects related to pristine iron triad MOFs cathodes for lithium-ion, sodium-ion, and potassium-ion batteries are also delivered.

Characteristics of bone mineral density in patients with functional hypothalamic amenorrhoea and its association with reproductive hormones and body composition.

OBJECTIVE: Bone mineral density (BMD) is typically reduced in patients with female athlete triad (FAT) and anorexia nervosa (AN). However, bone health in most patients with functional hypothalamic amenorrhoea (FHA), who may not suffer from severe energy deficiency, has not received adequate attention in clinical practice. This study aimed to investigate BMD and its association with clinical and endocrine features in individuals with FHA and to provide clinical evidence for improving bone loss and preventing osteoporosis in FHA. DESIGN: To assess the bone status of patients with FHA and investigate its association with various clinical and endocrinological characteristics. PATIENTS: We retrospectively analysed 80 patients with FHA who attended the Obstetrics and Gynecology Hospital of Fudan University from January 2022 to March 2023. MEASUREMENTS: The levels of reproductive hormones, including luteinising hormone (LH), follicle-stimulating hormone, oestradiol (E2 ) and total testosterone (TT), were examined at the time of initial diagnosis, and a body composition analyser was used to measure body fat percentage (BF%), lean body mass (LBM) and segmental muscle/fat. Dual-emission X-ray absorptiometry was used to measure lumbar spine BMD and femoral neck BMD in patients with FHA, and the Z score was calculated. RESULTS: The study cohort consisted of 80 female patients with FHA. The average age of the patients was 24.64 ± 6.02 years, and their body mass index (BMI) was 19.47 ± 2.86 kg/m2 . The duration of weight loss was 12 (6, 24) months, while the duration of oligo/amenorrhoea was 12 (4.5, 24) months. The mean degree of weight loss was 18.39 ± 9.53%. Low BMD were present in 15% of patients with FHA at the lumbar spine and/or femoral neck; 12.5% and 10% had low bone mass at the lumbar spine and femoral neck, respectively. The low bone mass group experienced a longer period of weight loss than the normal group [24 (16.5, 60) vs. 12 (4.5, 24) months, p = .037]. In addition, the abnormal group had a lower BMR (basal metabolic rate, BMR) [1158 ± 85 vs. 1231 ± 91 kcal/day, p = .011] and lower bone mineral content [2.15 ± 0.26 vs. 2.43 ± 0.31 kg, p = .009] than the normal group. Both LBMD and femoral neck BMD (Fn BMD) were positively correlated with BMI, BF%, LBM, and regional muscle/fat mass (all p < .05). There was also a positive correlation between LBMD and basal LH levels (p = .009) and waist-to-hip ratio (p = .034), whereas Fn BMD was positively correlated with TT levels (p = .029). Multiple linear regression analysis showed that LBM was positively associated with LBMD (ß = .007, 95% confidence interval [CI] = 0.004-0.009, p < .001), while trunk muscle mass was positively associated with Fn BMD (ß = .046, 95% CI = 0.013-0.080, p = .008). CONCLUSION: Fifteen percent of the patients with FHA exhibited low bone mass, a condition associated with prolonged weight loss. The basal LH and TT levels showed positive correlations with LBMD and Fn BMD, respectively. Meanwhile, BMR levels, BMI, BF%, and muscle mass were all positively correlated with LBMD and Fn BMD. Clinically, we should be attentive to suboptimal bone health in patients with FHA and take early screening, diagnosis and intervention measures, especially appropriate muscle mass gain, to prevent the onset of osteoporosis and fragility fractures in the long term.

Synthesis, Structure and Reactivity of a Mononuclear N,N,O-Bound Fe(II) α-Keto-Acid Complex.

A bulky, tridentate phenolate ligand (ImPh2 NNOtBu ) was used to synthesise the first example of a mononuclear, facial, N,N,O-bound iron(II) benzoylformate complex, [Fe(ImPh2 NNOtBu )(BF)] (2). The X-ray crystal structure of 2 reveals that the iron centre is pentacoordinate (τ=0.5), with a vacant site located cis to the bidentate BF ligand. The Mössbauer parameters of 2 are consistent with high-spin iron(II), and are very close to those reported for α-ketoglutarate-bound non-heme iron enzyme active sites. According to NMR and UV-vis spectroscopies, the structural integrity of 2 is retained in both coordinating and non-coordinating solvents. Cyclic voltammetry studies show that the iron centre has a very low oxidation potential and is more prone to electrochemical oxidation than the redox-active phenolate ligand. Complex 2 reacts with NO to form a S=3 /2 {FeNO}7 adduct in which NO binds directly to the iron centre, according to EPR, UV-vis, IR spectroscopies and DFT analysis. Upon O2 exposure, 2 undergoes oxidative decarboxylation to form a diiron(III) benzoate complex, [Fe2 (ImPh2 NNOtBu )2 (µ2 -OBz)(µ2 -OH)2 ]+ (3). A small amount of hydroxylated ligand was also observed by ESI-MS, hinting at the formation of a high-valent iron(IV)-oxo intermediate. Initial reactivity studies show that 2 is capable of oxygen atom transfer reactivity with O2 , converting methyl(p-tolyl)sulfide to sulfoxide.

Acute cholecystitis, obesity, and steatohepatitis constitute the lethal triad for bile duct injury (BDI) during laparoscopic cholecystectomy.

OBJECTIVE: The most feared complication during laparoscopic cholecystectomy remains a bile duct injury (BDI). Accurately risk-stratifying patients for a BDI remains difficult and imprecise. This study evaluated if the lethal triad of acute cholecystitis, obesity, and steatohepatitis is a prognostic measure for BDI. METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) registry was performed. All laparoscopic cholecystectomy cases within the main NSQIP database for 2012-2019 were queried. Two study cohorts were constructed. One with the lethal triad of acute cholecystitis, BMI ≥ 30, and steatohepatitis. The other cohort did not have the full triad present. Multivariate analysis was performed via logistic regression modeling with calculation of odds ratios (OR) to identify independent factors for BDI. An uncontrolled and controlled propensity score match analysis was performed. RESULTS: A total of 387,501 cases were analyzed. 36,887 cases contained the lethal triad, the remaining 350,614 cases did not have the full triad. 860 BDIs were identified resulting in an overall incidence rate 0.22%. There were 541 BDIs within the lethal triad group with 319 BDIs in the other cohort and an incidence rate of 1.49% vs 0.09% (P < 0.001). Multivariate analysis identified the lethal triad as an independent risk factor for a BDI by over 15-fold (OR 16.35, 95%CI 14.28-18.78, P < 0.0001) on the uncontrolled analysis. For the controlled propensity score match there were 29,803 equivalent pairs identified between the cohorts. The BDI incidence rate remained significantly higher with lethal triad cases at 1.65% vs 0.04% (P < 0.001). The lethal triad was an even more significant independent risk factor for BDI on the controlled analysis (OR 40.13, 95%CI 7.05-356.59, P < 0.0001). CONCLUSIONS: The lethal triad of acute cholecystitis, obesity, and steatohepatitis significantly increases the risk of a BDI. This prognostic measure can help better counsel patients and potentially alter management.

Sex and Sexual Orientation Differences in Dark Triad Traits, Sexual Excitation/Inhibition, and Sociosexuality.

The present study sought to investigate sex and sexual orientation differences in several traits related to sexuality and sexual behavior. Examining sexual orientation differences alongside basic sex differences to help identify correlates of sexual orientation diversity, and whether individuals with varying degrees of same-sex attraction show concurrent sex-atypical shifts in other domains. Males tend to score higher than females in the Dark Triad (DT) traits of sub-clinical narcissism, psychopathy, and Machiavellianism. Similarly, females tend to be more cautious than males in their attitudes and desires toward casual sex activity (i.e., sociosexuality). These sex differences may be related to the propensity for individuals to become easily sexually excited, which is higher in males, or to instead inhibit sexual arousal, which is higher in females. In a large undergraduate sample (N = 2047), we replicated expected sex differences in DT traits, sociosexuality, and sexual excitation/inhibition. We found that non-heterosexual females were "male-shifted" in some of these traits, but these shifts tended to be strongest among mostly heterosexual and bisexual individuals. Furthermore, we found that within-sex variation in sociosexuality, sexual excitation, and sexual inhibition was not related to sexual orientation in a linear fashion. Instead, sociosexuality and sexual excitation were related to sexual orientation in a curvilinear (inverted-U) fashion, especially among females. The fact that traits correlated with bisexuality and homosexuality were somewhat distinct is consistent with the idea that different developmental pathways may lead to these discrete sexual attraction patterns.

Towards agreement amongst parents, teachers and children on perceived psychopathology in children in a Kenyan socio-cultural context: a cross-sectional study.

BACKGROUND: Our objective was to determine levels of agreement between parents, teachers and children on mental symptoms in the children. Teachers, children and parents constitute the TRIAD in the perception of psychopathology in children. Analyzing the perceptions of psychopathology from the perspectives of parents, teachers, and children is essential for a comprehensive understanding of a child's mental health. METHODS: We identified 195 participants across ten randomly sampled primary schools in South East Kenya. Potential participants were randomly selected and a sampling interval calculated to determine the study participants. The children (Class 5-8; aged 11-14) completed the Youth Self-Report (YSR) scale, the parents the Child Behavior Check List (CBCL) on their children and the teachers completed the Teachers Rating Form (TRF) on the children. Only parents and teachers who gave consent as well as children who gave assent were included in the study. Analysis was conducted using Stata 14.1 and Pearson correlation coefficients used to calculate the correlations between CBCL, YSR and TRF. RESULTS: The children agreed least with the parents and more with the teachers. There was a greater agreement between the children and their teachers in 5 (2 internalizing disorders and 3 externalizing disorders) out of the 8 conditions. Children and parents agreed only on somatic disorders and conduct disorders. YSR mean scores were significantly lower than those for CBCL for all problem scales. Mean scores of TRF and YSR were comparable in the majority of the problems measured. CONCLUSION: We suggest broad-based psychoeducation to include children, parents/guardians and teachers to enhance shared awareness of psychopathology and uptake of treatment and for the consideration of an integrated mental health system.

Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway.

Chronic stress significantly elevates the expression levels of various neurotransmitters in the tumour microenvironment, thereby promoting the cell growth and metastasis of lung adenocarcinoma (LUAD). However, the role of chronic stress in the progression of LUAD remains unclear. In this study, we found that chronic restraint stress increases the levels of the neurotransmitter acetylcholine (ACh), and the α5-nicotinic acetylcholine receptor (α5-nAChR) and decreased fragile histidine triad (FHIT) expression in vivo. Crucially, the increased ACh levels promoted LUAD cell migration and invasion via modulation of the α5-nAChR/DNA methyltransferase 1 (DNMT1)/FHIT axis. In a chronic unpredictable stress (CUMS) mouse model, chronic stress promotes tumour development, accompanied by changes in α5-nAChR, DNMT1, FHIT, and vimentin. Together, these findings reveal a novel chronic stress-mediated LUAD signalling pathway: chronic stress enforces lung adenocarcinoma cell invasion and migration via the ACh/α5-nAChR/FHIT axis, which could be a potential therapeutic target for chronic stress-related LUAD.

Different views on collaboration between older persons, informal caregivers and care professionals.

BACKGROUND: Informal care features high on the policy agenda of many countries to deal with workforce shortages. As a consequence, care provision increasingly takes place in the care triad of care recipients, informal caregivers and care professionals. How collaboration between care partners takes shape depends on how the different partners perceive this collaboration. This paper aims to investigate the relative importance of the different aspects of collaboration from the perspectives of care recipients, informal caregivers and care professionals in the context of the care for older persons in The Netherlands. METHODS: Using Q-methodology, 32 participants ranked 28 statements that reflect different aspects of collaboration in the care triad and explained their ranking during a follow-up interview. Participants comprised 9 older persons, 10 informal caregivers and 13 care professionals. Data were analysed using by-person factor analysis to identify common patterns in the rankings of the statements. Emerging patterns were interpreted and described as views on collaboration using aggregated rankings and qualitative data from the interviews. RESULTS: Five distinct views on collaboration were found: (1) Emphasizing warm collaboration, (2) trusting care professional's expertise, (3) open and compassionate care professionals, (4) responsive decision-making by autonomous care professionals and (5) prioritizing care recipient's and informal caregiver's interests. Care recipients and/or informal caregivers were associated with views 1, 3 and, 5, whereas care professionals were associated with all five views. CONCLUSIONS: Our study highlights the importance of recognizing the potential diversity of views between and within different partner groups in care triads. Governmental and organizational policy makers, as well as healthcare professionals who aim to increase or support the involvement of informal caregivers, should take this heterogeneity into consideration. PATIENT OR PUBLIC CONTRIBUTION: An advisory board of older persons (care recipients and informal caregivers) was involved in the recruitment of the participants, the formulation of the statements and the reflection on the findings of the study and potential implications.

The links of subjective and psychological well-being with the Dark Triad traits: A meta-analysis.

OBJECTIVE: The aim of this study is to investigate the specific links that the Dark Triad traits have with subjective and psychological well-being through a meta-analysis of the existing literature. BACKGROUND: Over the past few years, associations between the Dark Triad traits and well-being have been a stimulating but understudied topic in personality research. METHOD: Cross-sectional, correlational studies examining these relationships were searched in the PsycINFO, PubMed, and Web of Science databases. Meta-analyses were performed at the dimension- and facet-level to account for the multidimensional structure of the Dark Triad traits. RESULTS: A total of 55 studies were included (n = 26,252). In general, grandiose narcissism and boldness/dominance related to higher well-being, while vulnerable narcissism, antagonism, disinhibition, and Machiavellianism related to lower levels of well-being. Age and gender moderated few of these associations. CONCLUSIONS: We recommend including multidimensional measures of the Dark Triad traits as an essential step to move the field forward.

Clinical Presentation of Atopic Dermatitis.

Atopic dermatitis, commonly known as eczema, is a chronic inflammatory dermatosis that can affect individuals from infancy to adulthood. Also referred to as "the itch that rashes," atopic dermatitis is classically associated with significant pruritus that is accompanied by characteristic cutaneous and other clinical findings. The diagnosis of atopic dermatitis can be challenging due to the wide range of clinical presentations based on patient factors such as age, skin type, ethnicity, and other comorbid conditions. This chapter reviews the classical findings as well as the less common manifestations of atopic dermatitis.

Attachment anxiety and the dark triad increase stalking after breakups of romantic relationships through psychological maltreatment of romantic partners and reactions to breakups.

This study examined whether two personality traits, attachment anxiety, and the Dark Triad, longitudinally promote stalking behaviors after romantic breakups through psychological maltreatment of partners during relationships and maladjusted reactions to breakups. We conducted a prospective longitudinal study across four waves of assessment for 1 year of individuals in romantic relationships in Japan. They completed measures of attachment anxiety, the Dark Triad, need for control, and psychological intimate partner violence (IPV) perpetration at Wave 1, and measures of maladjusted reactions to breakups (i.e., anger and rumination) and stalking behaviors at a wave after breakups. The final sample consisted of 356 participants who were involved in romantic relationships at Wave 1 and left by their partners during the survey period. Correlational analysis showed that the Dark Triad at Wave 1 was significantly positively associated with future stalking behaviors, but attachment anxiety was not. Structural equation modeling showed that attachment anxiety and the Dark Triad increased future stalking behaviors after breakups through psychological IPV perpetration during relationships. Additionally, attachment anxiety increased future stalking behaviors through higher levels of postbreakup anger and rumination. Conversely, we did not find any indirect effects of the Dark Triad on stalking behaviors through these reactions toward breakups. Overall, these results suggest that it is necessary to consider personality traits that could damage intimate relationships and to focus on the quality of romantic relationships to prevent stalking after romantic breakups. These results also indicate that emotion regulation may be useful in preventing stalking caused by attachment anxiety.

Postoperative mobilization after terrible triad injury: systematic review and single-arm meta-analysis.

BACKGROUND: Terrible triad injury is a complex injury of the elbow, involving elbow dislocation with associated fracture of the radial head, avulsion or tear of the lateral ulnar collateral ligament, and fracture of the coronoid. These injuries are commonly managed surgically with fixation or replacement of the radial head and repair of the collateral ligaments with or without fixation of the coronoid. Postoperative mobilization is a significant factor that may affect patient outcomes; however, the optimal postoperative mobilization protocol is unclear. This study aimed to systematically review the available literature regarding postoperative rehabilitation of terrible triad injuries to aid clinical decision making. METHODS: We systematically reviewed the PubMed, Embase, Cochrane, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The inclusion criteria were studies with populations aged ≥16 years with terrible triad injury in which operative treatment was performed, a clear postoperative mobilization protocol was defined, and the Mayo Elbow Performance Score (MEPS) was reported. Secondary outcomes were pain, instability, and range of motion (ROM). Postoperative mobilization was classified as either "early," defined as active ROM commencement before or up to 14 days, or "late," defined as active ROM commencement after 14 days. RESULTS: A total of 119 articles were identified from the initial search, of which 11 (301 patients) were included in the final review. The most common protocols (6 studies) favored early mobilization, whereas 5 studies undertook late mobilization. Meta-regression analysis including mobilization as a covariate showed an estimated mean difference in the pooled mean MEPS between early and late mobilization of 6.1 (95% confidence interval, 0.2-12) with a higher pooled mean MEPS for early mobilization (MEPS, 91.2) than for late mobilization (MEPS, 85; P = .041). Rates of instability reported ranged from 4.5% to 19% (8%-11.5% for early mobilization and 4.5%-19% for late mobilization). CONCLUSION: Our findings suggest that early postoperative mobilization may confer a benefit in terms of functional outcomes following surgical management of terrible triad injuries without appearing to confer an increased instability risk. Further research in the form of randomized controlled trials between early and late mobilization is advised to provide a higher level of evidence.

Total Knee Arthroplasty Periprosthetic Joint Infection With Concomitant Extensor Mechanism Disruption and Soft-Tissue Defect: The Knee Arthroplasty Terrible Triad.

BACKGROUND: Periprosthetic infection (PJI) with concomitant extensor mechanism disruption (EMD) and soft-tissue defect-hereinafter termed the "Terrible Triad"-is a devastating complication following total knee arthroplasty. The purpose of this study was to define the surgical and clinical outcomes following management of a cohort of patients who have the Terrible Triad. METHODS: From 2000 to 2022, 127 patients underwent operative management for PJI alone, 25 for PJI with soft-tissue defects (defined as defects requiring flap reconstruction or being a factor contributing to the decision of performing above-knee amputation or arthrodesis), 14 for PJI with EMD, and 22 for the Terrible Triad. A composite outcome of infection status, range of motion, extensor lag, and ambulatory status at final follow-up was used to compare the proportion of patients in each group with a favorable overall knee outcome. Differences between groups were determined using one-way analyses of variance with post hoc Tukey's tests and Pearson's Chi-square tests or Fisher's exact tests with post hoc Bonferroni adjustments, where applicable. Odds ratios (OR) were calculated for comparison of the overall knee outcome between groups. A Kaplan-Meier survival analysis for patient mortality was performed. RESULTS: The mean follow-up was 8.4 years and similar between groups (P = .064). Patients who had the Terrible Triad had a 45.5% incidence of above-knee amputation, or arthrodesis, and an 86.4% incidence of an unfavorable outcome. Compared to patients in the PJI group, patients in the PJI who had a soft-tissue defect (OR = 5.8, 95% CI [confidence interval] 2.2 to 15.7), PJI with EMD (OR = 3.7, 95%CI 1.0 to 12.9), and Terrible Triad groups (OR = 11.6, 95% CI 3.3 to 41.5) showed higher odds of an unfavorable knee outcome. CONCLUSIONS: This study demonstrates that the total knee arthroplasty Terrible Triad is a dreaded diagnosis with poor outcomes. Clinicians and patients might consider early treatment with amputation or arthrodesis. LEVEL OF EVIDENCE: III.

Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD. OBJECTIVE: Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. METHODS: A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production. RESULTS: Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis. CONCLUSION: Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.

Emergence of Catalytic Triad by Short Peptide Based Nanofibrillar Assemblies.

Through millions of years of the evolutionary journey, contemporary enzymes observed in extant metabolic pathways have evolved to become specialized, in contrast to their ancestors, which displayed promiscuous activities with wider substrate specificities. However, there remain critical gaps in our understanding of how these early enzymes could show such catalytic versatility despite lacking the complex three-dimensional folds of the existing modern-day enzymes. Herein, we report the emergence of a promiscuous catalytic triad by short amyloid peptide based nanofibers that access paracrystalline folds of ß-sheets to expose three residues (lysine, imidazole, and tyrosine) toward solvent. The ordered folded nanostructures could simultaneously catalyze two metabolically relevant chemical transformations via C-O and C-C bond manipulations, displaying both hydrolase and retro-aldolase-like activities. Further, the latent catalytic capabilities of the short peptide based promiscuous folds also helped in processing a cascade transformation, suggesting the important role they might have played in protometabolism and early evolutionary processes.

Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease.

The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying new subtypes of necrotic neuronal cell death. The present review provides an updated summary of necrosis subtypes and discusses their potential roles in neurodegenerative cell death. Among numerous necrosis subtypes, including necroptosis, paraptosis, ferroptosis, and pyroptosis, transcriptional repression-induced atypical cell death (TRIAD) has been identified as a potential mechanism of neuronal cell death. TRIAD is induced by functional deficiency of TEAD-YAP and self-amplifies via the release of HMGB1. TRIAD is a feasible potential mechanism of neuronal cell death in Alzheimer's disease and other neurodegenerative diseases. In addition to induction of cell death, HMGB1 released during TRIAD activates brain inflammatory responses, which is a potential link between neurodegeneration and neuroinflammation.

Hormonal contraception for female athletes presents special needs and concerns.

PURPOSE: Oral contraceptives (OCs) are commonly used by female athletes raising concerns regarding the possible adverse effects of OCs on physical performance, musculoskeletal injuries, and bone density. We aimed to review all current studies on the physiological effects of OCs in physically active women. MATERIALS AND METHODS: A review of literature in electronic search in PubMed and Google Scholar databases from December 2002 to December 2022 using relevant keywords. The reference lists of the articles found eligible were also reviewed. RESULTS: Out of 344 articles in the initial database, 54 clinical studies were eligible for inclusion in our literature review. OCs are used by about two-thirds of female athletes. Current research suggests that OCs' effects on endurance performance and muscle strength are mostly reassuring. OCs do not seem to have a major negative impact on bone health or sports injuries. In fact, new data suggests that they may even significantly reduce the risk of anterior cruciate ligament (ACL) injury. CONCLUSIONS: OCs can be safely used by young female athletes, who may also benefit from better menstrual cycle control. OCs offer newly realised protection from ACL injuries. The use of OCs must be carefully individualised according to their preferences, expectations, and experience.

Hormonal contraception can be safely prescribed to active women. The International Olympic Committee advocates a new and wider definition for the 'athlete triad', where low energy availability presents a special challenge for these athletes. New data suggests that the use of oral contraceptives may protect against ACL injury.

Dark Triad personality traits and realistic and symbolic COVID-19 threat: The role of conspiracy mentality.

The COVID-19 pandemic has profoundly altered global social dynamics through extensive containment measures. Understanding how individuals perceive the virus, distinguishing between realistic and symbolic threats, and considering the influence of personality traits is essential for effective public health messaging and interventions. This study explores the linkage between personality traits and perceived COVID-19 threats, mediated by conspiracy mentality, across diverse international contexts. Online survey data were collected in June 2021 from 13,645 participants across seven European countries, the US, and Colombia. The study explores how individuals with different Dark Triad traits perceive the threat of COVID-19, and whether conspiracy mentality mediates these perceptions. The findings reveal distinct associations. Machiavellianism and narcissism were linked to lower perceived COVID-19 threat, while psychopathy was associated with greater perceived threat. Additionally, individuals with higher conspiracy mentality endorsed greater perceived threat related to COVID-19. This study highlights the influence of Dark Triad personality traits on how individuals perceive the threats posed by COVID-19, with conspiracy mentality mediating this relationship. Understanding these associations provides valuable insights into psychological factors affecting COVID-19 perception, informing future research and public health strategies.