Miracle-dz/UniFAR-FTUs huggingface dataset:
The 3A6‐TCR/superagonist/HLA‐DR2a complex shows similar interface and reduced flexibility compared to the complex with self‐peptide

T‐cell receptor (TCR) recognition of the myelin basic protein (MBP) peptide presented by major histocompatibility complex (MHC) protein HLA‐DR2a, one of the MHC class II alleles associated with multiple sclerosis, is highly variable. Interactions in the trimolecular complex between the TCR of the MBP83‐99‐specific T cell clone 3A6 with the MBP‐peptide/HLA‐DR2a (abbreviated TCR/pMHC) lead to substantially different proliferative responses when comparing the wild‐type decapeptide MBP90‐99 and a superagonist peptide, which differs mainly in the residues that point toward the TCR. Here, we investigate the influence of the peptide sequence on the interface and intrinsic plasticity of the TCR/pMHC trimolecular and pMHC bimolecular complexes by molecular dynamics simulations. The intermolecular contacts at the TCR/pMHC interface are similar for the complexes with the superagonist and the MBP self‐peptide. The orientation angle between TCR and pMHC fluctuates less in the complex with the superagonist peptide. Thus, the higher structural stability of the TCR/pMHC tripartite complex with the superagonist peptide, rather than a major difference in binding mode with respect to the self‐peptide, seems to be responsible for the stronger proliferative response.
Incidence and risk factors for osteoporotic fractures in patients with systemic lupus erythematosus versus matched controls

Background/Aims Despite recent improvements in the quality of life of patients with systemic lupus erythematosus (SLE), osteoporosis, and osteoporotic fractures are one of the major complications of SLE. Furthermore, limited data are available on the incidence and predictor of osteoporotic fractures in Korean patients with SLE. Herein, we aimed to assess the incidence and risk factors for osteoporotic fractures in Korean SLE patients compared to those without SLE. Methods SLE patients aged ≥ 40 years (n = 10,434; mean age, 51.3 ± 9.1 years; women, 89.7%) were selected from the Korean National Health Insurance Service database, spanning a period from 2008 to 2014. Age- and sex-matched controls (n = 52,170) were randomly sampled in a 5:1 ratio from non-SLE individuals. The primary outcome was the first occurrence of osteoporotic fracture. Results The incidence of osteoporotic fractures was significantly higher in the SLE patients (19.085 per 1,000 person-years) than in matched controls (6.530 per 1,000 person-years). According to the multivariable Cox proportional analysis, patients with SLE exhibited a higher osteoporotic fracture rate than the control group (hazards ratio, 2.964; 95% confidence interval, 2.754 to 3.188), even after adjustment for confounding variables. In the subgroup analysis, male SLE patients or SLE patients aged 40 to 65 years were associated with a higher osteoporotic fracture rate than women SLE patients or SLE patients aged ≥ 65 years, respectively. Conclusions We found a 2.964-fold increased risk of osteoporotic fracture in SLE patients compared to age- and sex-matched non-SLE controls. Male or middle-aged SLE patients had a relatively higher fracture risk among patients with SLE.
Effects of Work Practice Environment, Work Engagement, and Work Pressure on Turnover Intention Among Community Health Nurses: Mediated Moderation Model.

AIM To test the relationship between work practice environment and turnover intention, considering the mediation of work engagement and the moderation of work pressure among community health nurses. DESIGN A cross-sectional survey design. METHODS A total of 410 nurses were recruited from thirty-two community health centers between September 2016 - January 2017 with survey on work practice environment, work engagement, work pressure and turnover intention. Structural equation modelling was used to test a mediated moderation model. RESULTS Work practice environment was positively associated with higher work engagement and lower turnover intention and work engagement partially mediated the relationship between work practice environment and turnover intention. In addition, work pressure moderated the relationship between work practice environment and work engagement. CONCLUSION The improvement of work practice environment including the physical and humanitarian environment could enhance nurse engagement and reduce turnover intention in community, which was more pronounced among high-pressure nurses. IMPACT In front of the nursing shortage, especially in communities, the strategies on how to retain and motivate nurses have become the focus of concern. Based on the job demands-resources model and the conservation of resources theory, this study examined the effect of work practice environment on turnover intention with the mediation role of work engagement and the moderation role of work pressure among community health nurses. The nurse managers of communities should pay attention to the role of work practice environment in stimulating nurses' engagement and decreasing turnover intention, especially when nurses are under high work pressure. This article is protected by copyright. All rights reserved.
Resistance Exercise-Induced Hormonal Response Promotes Satellite Cell Proliferation in Untrained Men but not in Women.

The purpose was to determine the effect of resistance exercise (RE)-induced hormonal changes on satellite cell (SC) myogenic state in response to muscle damage. Untrained men (n=10, 22±3y) and women (n=9, 21±4y) completed 2 sessions of 80 unilateral maximal eccentric knee extensions followed by either an upper body RE protocol (EX) or a 20-min rest (CON). Muscle samples were collected and analyzed for protein content of Pax7, MyoD, myogenin, cyclin D1, p21 before (PRE), 12h, and 24h after the session was completed. Serum testosterone, growth hormone, cortisol, and myoglobin concentrations were analyzed at PRE, post damage, immediately after (IP), 15, 30, and 60 min after the session was completed. Testosterone was significantly (p<0.05) higher immediately after the session in EX versus CON for men. A significant time × gender x condition interaction was found for MyoD with an increase in EX (men) and CON (women) at 12h. A significant time x condition interaction was found for Pax7 with a decrease in EX and increase in CON at 24h. A significant time effect was found for myogenin, p21, and cyclin D1. Myogenin and p21 were increased at 12h and 24h and Cyclin D1 was increased at 12h. These results suggest that the acute RE-induced hormonal response can be important for men to promote SC proliferation after muscle damage but had no effect in women. Markers of SC differentiation appeared unaffected by the hormonal response but increased in response to muscle damage.
Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention

The search for effective methods of cancer treatment and prevention has been a continuous effort since the disease was discovered. Recently, there has been increasing interest in exploring plants and fruits for molecules that may have potential as either adjuvants or as chemopreventive agents against cancer. One of the promising compounds under extensive research is nobiletin (NOB), a polymethoxyflavone (PMF) extracted exclusively from citrus peel. Not only does nobiletin itself exhibit anti-cancer properties, but its derivatives are also promising chemopreventive agents; examples of derivatives with anti-cancer activity include 3′-demethylnobiletin (3′-DMN), 4′-demethylnobiletin (4′-DMN), 3′,4′-didemethylnobiletin (3′,4′-DMN) and 5-demethylnobiletin (5-DMN). In vitro studies have demonstrated differential efficacies and mechanisms of NOB and its derivatives in inhibiting and killing of colon cancer cells. The chemopreventive potential of NOB has also been well demonstrated in several in vivo colon carcinogenesis animal models. NOB and its derivatives target multiple pathways in cancer progression and inhibit several of the hallmark features of colorectal cancer (CRC) pathophysiology, including arresting the cell cycle, inhibiting cell proliferation, inducing apoptosis, preventing tumour formation, reducing inflammatory effects and limiting angiogenesis. However, these substances have low oral bioavailability that limits their clinical utility, hence there have been numerous efforts exploring better drug delivery strategies for NOB and these are part of this review. We also reviewed data related to patents involving NOB to illustrate the extensiveness of each research area and its direction of commercialisation. Furthermore, this review also provides suggested directions for future research to advance NOB as the next promising candidate in CRC chemoprevention.
NKG2D–DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity

ABSTRACT Natural killer (NK) cells eliminate abnormal cells through the release of cytolytic granule contents. In this process, NK cells must adhere to target cells through integrin-mediated adhesion, which is highly dependent on the generation of F-actin. Ena/VASP-like (EVL) is an actin regulatory protein previously shown to regulate integrin-mediated adhesion in other cell types, but its role in NK cell biology is not known. Herein, we show that EVL is recruited to the NK cell cytotoxic synapse and is required for NK cell cytotoxicity. Significantly, EVL is involved in the generation of F-actin at the cytotoxic synapse, antibody-stimulated spreading, and NK cell-target cell adhesion. EVL interacts with WASP (also known as WAS) and VASP and is required for localization of both proteins to the synapse. Recruitment of EVL to points of cellular activation occurs through the receptor NKG2D–DAP10 (also known as KLRK1 and HCST, respectively) via a binding site previously implicated in VAV1 and Grb2 recruitment. Taken together, this study implicates DAP10-mediated Grb2 and VAV1 signaling in the recruitment of an EVL-containing actin regulatory complex to the cytotoxic synapse where it can promote F-actin nucleation leading to NK cell-mediated killing. Summary: The NK activating receptor NKG2D–DAP10 recruits EVL to the cytotoxic synapse via a Grb2–VAV1 signaling node to promote F-actin generation, target cell adhesion and the development of cell-mediated cytotoxicity.
Evaluation of a Companion Robot for Individuals With Dementia: Quantitative Findings of the MARIO Project in an Irish Residential Care Setting.

The current study focuses on the short-term effect of MARIO, a social robot, on quality of life, depression, and perceived social support in persons with dementia (PWD) and evaluates their acceptability of MARIO. Ten PWD in one nursing home took part in a 4-week pilot study, where each participant had up to 12 sessions with MARIO. Sessions comprised engagement in music, news, reminiscence, games, and calendar applications. Standardized questionnaires were administered before and after the 4-week period. Participants had a sustained interest in MARIO during their interactions and an acceptance of MARIO's appearance, sound, and applications. Consequently, participants spent more time socially engaged. No statistically significant differences were found in quality of life, depression, and perceived social support. PWD can engage with a social robot in a real-world nursing home. Future research should incorporate a larger sample and longer intervention period. [Journal of Gerontological Nursing, 45(7), 36-45. ].
TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3–Related Skeletal Dysplasias

TransCon CNP is a C-type natriuretic peptide (CNP-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule, designed to provide sustained systemic CNP levels upon weekly subcutaneous administration. TransCon CNP is in clinical development for the treatment of comorbidities associated with achondroplasia. In both mice and cynomolgus monkeys, sustained exposure to CNP via TransCon CNP was more efficacious in stimulating bone growth than intermittent CNP exposure. TransCon CNP was well tolerated with no adverse cardiovascular effects observed at exposure levels exceeding the expected clinical therapeutic exposure. At equivalent dose levels, reductions in blood pressure and/or an increase in heart rate were seen following single subcutaneous injections of the unconjugated CNP-38 molecule or a daily CNP-39 molecule (same amino acid sequence as Vosoritide, USAN:INN). The half-life of the daily CNP-39 molecule in cynomolgus monkey was estimated to be 20 minutes, compared with 90 hours for CNP-38, released from TransCon CNP. Cmax for the CNP-39 molecule (20 µg/kg) was approximately 100-fold higher, compared with the peak CNP level associated with administration of 100 µg/kg CNP as TransCon CNP. Furthermore, CNP exposure for the daily CNP-39 molecule was only evident for up to 2 hours postdose (lower limit of quantification 37 pmol/l), whereas TransCon CNP gave rise to systemic exposure to CNP-38 for at least 7 days postdose. The prolonged CNP exposure and associated hemodynamically safe peak serum concentrations associated with TransCon CNP administration are suggested to improve efficacy, compared with short-lived CNP molecules, due to better therapeutic drug coverage and decreased risk of hypotension. SIGNIFICANCE STATEMENT The hormone C-type natriuretic peptide (CNP) is in clinical development for the treatment of comorbidities associated with achondroplasia, the most common form of human dwarfism. The TransCon Technology was used to design TransCon CNP, a prodrug that slowly releases active CNP in the body over several days. Preclinical data show great promise for TransCon CNP to be an effective and well-tolerated drug that provides sustained levels of CNP in a convenient once-weekly dose, while avoiding high systemic CNP bolus concentrations that can induce cardiovascular side effects.
Contribution of the Lung to the Genesis of Cheyne‐Stokes Respiration in Heart Failure: Plant Gain Beyond Chemoreflex Gain and Circulation Time

Background The contribution of the lung or the plant gain (PG; ie, change in blood gases per unit change in ventilation) to Cheyne‐Stokes respiration (CSR) in heart failure has only been hypothesized by mathematical models, but never been directly evaluated. Methods and Results Twenty patients with systolic heart failure (age, 72.4±6.4 years; left ventricular ejection fraction, 31.5±5.8%), 10 with relevant CSR (24‐hour apnea‐hypopnea index [AHI] ≥10 events/h) and 10 without (AHI <10 events/h) at 24‐hour cardiorespiratory monitoring underwent evaluation of chemoreflex gain (CG) to hypoxia (CGO2) and hypercapnia (CGCO2) by rebreathing technique, lung‐to‐finger circulation time, and PG assessment through a visual system. PG test was feasible and reproducible (intraclass correlation coefficient, 0.98; 95% CI, 0.91–0.99); the best‐fitting curve to express the PG was a hyperbola (R 2≥0.98). Patients with CSR showed increased PG, CGCO2 (but not CGO2), and lung‐to‐finger circulation time, compared with patients without CSR (all P<0.05). PG was the only predictor of the daytime AHI (R=0.56, P=0.01) and together with the CGCO2 also predicted the nighttime AHI (R=0.81, P=0.0003) and the 24‐hour AHI (R=0.71, P=0.001). Lung‐to‐finger circulation time was the only predictor of CSR cycle length (R=0.82, P=0.00006). Conclusions PG is a powerful contributor of CSR and should be evaluated together with the CG and circulation time to individualize treatments aimed at stabilizing breathing in heart failure.
Edaravone inhibits the conformational transition of amyloid-β42: insights from molecular dynamics simulations

Abstract Previous work has shown that edaravone inhibits fibrillogenesis of amyloid-β protein (Aβ). However, the detailed mechanism by which edaravone inhibits the conformational transition of the Aβ42 monomer is not known at the molecular level. Here, explicit-solvent molecular dynamics (MD) simulations were coupled with molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) method to address the issue. MD simulations confirmed that edaravone inhibits the conformational transition of the Aβ42 monomer in a dose-dependent manner. It was found that the direct interactions between edaravone and Aβ42 are responsible for its inhibiting effects. The analysis of binding free energy using the MM–PBSA method demonstrated that the nonpolar interactions provide favourable contributions (about −71.7 kcal/mol). Conversely, the polar interactions are unfavourable for the binding process. A total of 14 residues were identified as greatly contributing to the binding free energy between edaravone and the Aβ42 monomer. In addition, the intra-peptide hydrophobic interactions were weakened and the salt bridge D23–K28 was interrupted by edaravone. Therefore, the conformational transition was inhibited. Our studies provide molecular-level insights into how edaravone molecules inhibit the conformational transition of the Aβ42 monomer, which may be useful for designing amyloid inhibitors. Communicated by Ramaswamy H. Sarma
Prediction of Titanium Implant Success by Analysis of microRNA Expression in Peri-Implant Tissue. A 5-Year Follow-Up Study

The aim of the present study is to evaluate the expression of microRNA (miRNA) in peri-implant soft tissue and to correlate epigenetic information with the clinical outcomes of the implants up to the five-year follow-up. Seven patients have been rehabilitated with fixed screw-retained bridges each supported by implants. Peri-implant bone resorption and soft tissue health parameters have been recorded over time with a five-year follow-up. Mini-invasive samples of soft peri-implant tissue have been taken three months after implant insertion. miRNA have been extracted from cells of the soft tissue samples to evaluate gene-expression at the implant sites by microarray analysis. The epigenomic data obtained by microarray technology has been statistically analyzed by dedicated software and compared with measured clinical parameters. Specific miRNA expression profiles predictive of specific clinical outcomes were found. In particular, some specific miRNA signatures appeared to be “protective” from bone resorption despite the presence of plaque accumulation. miRNA may be predictors of dental implant clinical outcomes and may be used as biomarkers for diagnostic and prognostic purposes in the field of implant dentistry.
Effectivenesss of ivacaftor in severe cystic fibrosis patients and non‐G551D gating mutations

Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined.
Neural modeling of the DCN: cross-correlation analysis using short-duration tone-burst stimuli

A computer model of an isofrequency patch of the dorsal cochlear nucleus (DCN) was created to explore possible mechanisms for various stimulus-dependent features observed in the cross-correlations of spike trains from type-II-type-IV unit pairs. Consistent with the functional inhibitory type-II-type-IV interaction, model I-cells provide inhibitory input to model P-cells. Simulated short-duration BF tone-bursts of either 50- or 200-ms duration in 200 trials of 250- or 1000-ms duration, respectively, were presented to the model at several sound pressure levels and difference cross-correlograms of I-cell-P-cell activity were computed. Inhibitory troughs were present in the I-cell-P-cell difference histograms derived from the 200-ms paradigm, but not present when derived from the 50-ms paradigm. <<ETX>>
Inappropriate drug use in the elderly outpatient population in a West-African metropolitan community .

OBJECTIVE Most studies investigating drug use patterns in the elderly have evaluated the prescribers' behavior with little focus on the target population who consume the drugs. This is a community-based study to evaluate drug use patterns in the elderly, a special population because of the high risk of adverse drug reactions including drug hypersensitivity syndrome, which is associated with a higher mortality in this population. MATERIALS AND METHODS A house-to-house survey was carried out, and drug use was determined by interviewing respondents using a questionnaire. The study population included adults aged 60 years and above. RESULTS A total of 270 respondents were interviewed. The majority (88.1%) had at least one chronic medical disorder. Hypertension was the most common disease. Multimorbidity and polypharmacy were uncommon in this population. Approximately half (46.4%) of the respondents with chronic diseases were either not on treatment (14.5%) or were on inappropriate drugs and/or drug combinations (31.9%). Of these, 5.1% were on potentially inappropriate medications judging from the Beers Criteria. Inappropriate drug combinations observed in this study included an inappropriate drug for the disease diagnosed, inadvertent use of two different brands of the same drug as two drugs, combining two drugs from the same class, or inappropriate drug class combination among hypertensive patients. Aspirin was the most commonly used drug, some hypertensive patients were taking aspirin without being on concomitant antihypertensive drugs. CONCLUSION Contrary to reports of polypharmacy, inappropriate drug combinations and a high rate of aspirin use were prominent in the population studied.
Genetic manipulation allows in vivo tracking of the life cycle of the son‐killer symbiont, Arsenophonus nasoniae, and reveals patterns of host invasion, tropism and pathology

Summary Maternally heritable symbionts are common in arthropods and represent important partners and antagonists. A major impediment to understanding the mechanistic basis of these symbioses has been lack of genetic manipulation tools, for instance, those enabling transgenic GFP expression systems for in vivo visualization. Here, we transform the ‘son‐killer’ reproductive parasite Arsenophonus nasoniae that infects the parasitic wasp Nasonia vitripennis with the plasmid pOM1‐gfp, re‐introduce this strain to N. vitripennis and then used this system to track symbiont life history in vivo. These data revealed transfer of the symbiont into the fly pupa by N. vitripennis during oviposition and N. vitripennis larvae developing infection over time through feeding. A strong tropism of A. nasoniae to the N. vitripennis ovipositor developed during wasp pupation, which aids onward transmission. The symbiont was also visualized in diapause larvae. Occasional necrotic diapause larvae were observed which displayed intense systemic infection alongside widespread melanotic nodules indicative of an active but failed immune response. Our results provide the foundation for the study of this symbiosis through in vivo tracking of the fate of symbionts through host development, which is rarely achieved in heritable microbe/insect interactions.