Miracle-dz/UniFAR-FTUs huggingface dataset:
Calcineurin Inhibition Causes α2δ-1–Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2δ-1–GluN1 complexes in the spinal cord and the level of α2δ-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1–NMDAR interaction with α2δ-1Tat peptide completely reversed the effects of FK506. In α2δ-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2δ-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2δ-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2δ-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS. SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2δ-1 and NMDARs and their synaptic trafficking in the spinal cord. α2δ-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2δ-1 or disrupting α2δ-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2δ-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.
Grape-Leaf Extract Attenuates Alcohol-Induced Liver Injury via Interference with NF-κB Signaling Pathway

Grape (Vitis vinifera) leaf extracts (GLEs) are known to be rich in phenolic compounds that exert potent antioxidant effects. Given the vulnerability of the liver to oxidative damage, antioxidants have been proposed as therapeutic agents and coadjuvant drugs to ameliorate liver pathologies. The current study was designed to characterize secondary metabolites and investigate the hepatoprotective effects of GLE and its underlying mechanisms. The secondary metabolites were profiled using HPLC–PDA–ESI-MS, and forty-five compounds were tentatively identified. In experimental in vivo design, liver injury was induced by oral administration of high doses of ethanol (EtOH) for 12 days to male Sprague Dawley rats that were split into five different groups. Blood samples and livers were then collected, and used for various biochemical, immunohistochemical, and histopathological analyses. Results showed that GLE-attenuated liver injury and promoted marked hepatic antioxidant effects, in addition to suppressing the increased heat-shock protein-70 expression. Moreover, GLE suppressed EtOH-induced expression of nuclear factor-κB (NF-κB) p65 subunit and proinflammatory cytokine tumor necrosis factor-α. Caspase-3 and survivin were enhanced by EtOH intake and suppressed by GLE intake. Finally, EtOH-induced histopathological changes in liver sections were markedly normalized by GLE. In conclusion, our results suggested that GLE interferes with NF-κB signaling and induces antioxidant effects, which both play a role in attenuating apoptosis and associated liver injury in a model of EtOH-induced liver damage in rats.
Test-Retest Reliability of the Closed Kinetic Chain Upper Extremity Stability Test (CKCUEST) in a Modified Test Position in Division I Collegiate Basketball Players.

Background The closed kinetic chain upper extremity stability test (CKCUEST) as originally described may not be appropriate for assessing athletes interchangeably considering body size variations. A modified test position may be warranted to normalize the CKCUEST to body size, in order to reflect an accurate representation of upper limb function. Purpose To determine test-retest reliability of the CKCUEST in a modified test position in Division I collegiate basketball players. Study Design Test-retest reliability. Methods 15 subjects (8 male, 7 female) were recruited from Division I basketball teams. Subjects began in a push-up position with their hands located directly under their shoulders. Subjects performed one 15 second trial of the modified CKCUEST initially and a second trial one week later. Hand-written data was transferred to a spreadsheet for analysis using Minitab Statistical Software for comparison. Results Test-retest reliability was 0.88 for men's basketball, 0.79 for women's basketball, and 0.90 when both teams were combined. Test mean for men's basketball were 29.5 ± 4.78, and retest mean were 31.88 ± 4.99. Test mean for women's basketball were 24.86 ± 5.52, and retest mean were 26.71 ± 5.41. Test mean for both teams combined were 27.33 ± 5.5, and retest mean were 29.47 ± 5.67. Conclusions The CKCUEST in a modified test position is a reliable assessment tool. Results support previous findings and may contribute to injury prevention and return to sport decision-making. Level of Evidence 3b.
Financial Industry Views on the Prospective Role of Long-Term Care Insurance and Reverse Mortgages in Financing Long-Term Care in Croatia

ABSTRACT Due to the government’s modest role in taking care of aging adults, as well as a rapidly aging demographic and a high share of home ownership, Croatia is an interesting case for private long-term care (LTC) financing. This study uses a qualitative survey through interviews (N = 21) with specialists from the financial industry to examine the prospects for developing LTC insurance (LTCI) and reverse mortgages. The most important obstacles to developing reverse mortgages and LTCI are an emotional attachment to real estate and strong family ties. However, inadequately regulated and nontransparent housing and LTC markets, the weak rule of law, poor financial literacy, low trust in financial institutions, and the perception of government as the savior of last resort pose additional challenges. Combined insurance products with clearly defined benefits are the products showing the most market potential.
A pilot study of lncRNAs expression profile in serum of progressive multiple sclerosis patients.

OBJECTIVE Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease that affect both white and gray matter. The relapsing and the eventually progressive course of MS is heterogeneous; thus, a confident long-term prediction of individual prognosis is not possible yet. Recent studies have demonstrated the role of long non-coding RNA (lncRNAs) as potential biomarkers that could provide information to predict disease activity and progression. PATIENTS AND METHODS By qRT-PCR, we analysed the lncRNAs expression in the serum of 16 secondary progressive MS (SP-MS), 12 primary progressive (PP-MS) patients and 8 healthy controls. RESULTS We found that TUG1 was upregulated in SP-MS, while the comparison of PP-MS vs. controls showed a downregulation of non-protein coding RNA 188 (LRRC75A-AS1) and a significant upregulation of two lncRNAs: long intergenic non-protein coding RNA 293 (LINC00293) and RP11-29G8.3. Moreover, we performed an in-silico analysis using DIANA-LncBase v2 and HMDD v3.0 software, in order to predict the possible interaction of these four lncRNAs with miRNAs. We identified 21 miRNAs prediction targets possibly involved in MS. CONCLUSIONS Our data indicate a regulatory function of these lncRNAs in autoimmune and inflammatory processes related to MS suggesting their potential role in progressive MS pathogenesis.
Microbiome Study of Initial Gut Microbiota from Newborn Infants to Children Reveals that Diet Determines Its Compositional Development

To understand the formation of initial gut microbiota, three initial fecal samples were collected from two groups of two breast milk-fed (BM1) and seven formula milk–fed (FM1) infants, and the compositional changes in gut microbiota were determined using metagenomics. Compositional change analysis during week one showed that Bifidobacterium increased from the first to the third fecal samples in the BM1 group (1.3% to 35.1%), while Klebsiella and Serratia were detected in the third fecal sample of the FM1 group (4.4% and 34.2%, respectively), suggesting the beneficial effect of breast milk intake. To further understand the compositional changes during progression from infancy to childhood (i.e., from three weeks to five years of age), additional fecal samples were collected from four groups of two breast milk–fed infants (BM2), one formula milk–fed toddler (FM2), three weaning food–fed toddlers (WF), and three solid food–fed children (SF). Subsequent compositional change analysis and principal coordinates analysis (PCoA) revealed that the composition of the gut microbiota changed from an infant-like composition to an adult-like one in conjunction with dietary changes. Interestingly, overall gut microbiota composition analyses during the period of progression from infancy to childhood suggested increasing complexity of gut microbiota as well as emergence of a new species of bacteria capable of digesting complex carbohydrates in WF and SF groups, substantiating that diet type is a key factor in determining the composition of gut microbiota. Consequently, this study may be useful as a guide to understanding the development of initial gut microbiota based on diet.
Efecto del seguimiento telefónico en la adherencia al tratamiento en los pacientes con falla cardiaca

Objetivo: Determinar el efecto del seguimiento telefónico en los niveles de adherencia al tratamiento farmacológico y no farmacológico en los pacientes que asisten a un programa de falla cardiaca de una institución de cuarto nivel de atención. Método: Ensayo clínico controlado (n = 61) en el que los pacientes se aleatorizaron a seguimiento telefónico o a seguimiento usual. Para determinar el efecto de la intervención se realizaron tres mediciones de los niveles de adherencia: antes del seguimiento, a los 12 meses y 6 meses después de finalizar el seguimiento. Se utilizaron la prueba de tendencia de Cochrane-Armitage y un análisis multivariado con un modelo logístico mixto de cuantiles. Resultados: Los pacientes con seguimiento telefónico tuvieron tendencia a clasificarse en niveles de mayor adherencia que los del grupo control (p < 0.0001). En el modelo multivariado se encuentra una asociación entre los puntajes de adherencia y el seguimiento telefónico, que dependen del tiempo, en los percentiles estudiados en la distribución. Hubo mayor adherencia con la intervención de la segunda visita en los cuantiles bajos de la distribución (P10 y P25) y, en la tercera, en los cuantiles más altos (P50, P75 y P90). Variables como sexo masculino (P10 y P25), universitarios (P10 y P90) y presencia de cuidador (P90) estuvieron asociadas con mayores niveles de adherencia. Conclusiones: El seguimiento telefónico se convierte en una intervención efectiva que promueve la motivación, la autogestión y la comunicación asertiva con el paciente, siempre y cuando se realice de manera estandarizada y a lo largo del tiempo.
Identification of Some cry1 Genes and Toxicity Determination in Bacillus thuringiensis Isolates Obtained from Mills and Warehouses in Turkey

Fifty four isolates of Bacillus thuringiensis (Bt) were isolated from grain products and dust in flour mills and warehouses in Turkey. These isolates were analyzed to determine the presence of cryl type genes using specific primers for crylAb/Ac, crylAc, crylAd, cry1B, and crylD genes. PCR results showed that ND7.2 and ND11.3 isolates harbored crylAb/Ac, crylAc, crylAd, cry1B, and crylD genes. SDS-PAGE profile showed that local isolates produced several protein bands, with molecular masses ranging from 28 to 130 kDa. The insecticidal activity of these isolates against Ephestia kuehniella and Plodia interpunctella larvae was tested. Percentage mortalities against E. kuehniella and P. interpunctella at the lowest concentration (lmg/ml) ranged between 24 to 56%, and 27 to 73%, respectively. Respective mortalities at the highest used concentration (4mg /ml), ranged from 58 to 73%, and 53 to 97%. LC50 for the tested isolates were ranged from 1.631 to 2.649 and 1.675 to 2.665 mg/ml for E. kuehniella and P. interpunctella, respectively, while the corresponding LC50 for Btk were 1.111 and 1.157 mg/ml for both insects. Variations in efficacy of isolates suggest that insecticidal potency of the isolates is not directly related to their cry gene content. However, the presence of three of the investigated cryl genes (crylAd171, cry lAc180 and cry1A216) in all Bt isolates under investigation indicated that these isolates can be used to produce spore-crystal mixture for controlling lepidopteran pests.
Peptide Hormone Regulation of DNA Damage Responses.

DNA damage response (DDR) and repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR functioning results in accumulation of unrepaired DNA damage, increased frequency of tumorigenic mutations, and premature aging. Recent evidence suggests that polypeptide hormones play a role in modulating DDR and DNA damage repair, while DNA damage accumulation may also affect hormonal status. We review the available reports elucidating involvement of IGF1, GH, αMSH, and GnRH/gonadotrophins in DDR and DNA repair as well as the current understanding of pathways enabling these actions. We discuss effects of DNA damage pathway mutations, including Fanconi anemia, on endocrine function and consider mechanisms underlying these phenotypes.
Loneliness and Self-Rated Physical Health Among Gay, Bisexual and other Men who have Sex with Men in Vancouver, Canada

Background Due to stigma and discrimination, gay, bisexual and other men who have sex with men (gbMSM) potentially carry a heightened burden of loneliness. This analysis investigates loneliness among gbMSM and its relationship with self-rated physical health, along with the mediating effect of depression. Methods Participants were recruited using respondent-driven sampling into the Momentum Health Study (February 2012–February 2015) with follow-up visits occurring every 6 months till February 2018. Using computer-assisted self-interviews, measures of loneliness were assessed using a 6-item Loneliness Scale for Emotional and Social Loneliness (lonely vs not lonely). Current physical health was self-assessed (poor, fair, good, very good or excellent). A multivariable generalised linear-mixed model with a logit link function was used to examine the relationship between loneliness and self-rated physical health. We further investigated the mediating effect of depressive symptomatology on this relationship via the Hospital Anxiety and Depression Scale. Results Of the 770 participants included, we found that 61% (n=471) experienced loneliness at baseline. Of the 674 (88%) who reported good/very good/excellent physical health, 59% (n=391) reported loneliness, compared with 87% (n=80) of those in poor/fair self-rated physical health who reported feeling lonely. After adjustment for confounding, loneliness was associated with poor self-rated physical health (adjusted OR 1.71; 95% CI 1.13 to 2.60). Depressive symptomatology was found to partially mediate this relationship. CONCLUSION There may be a need for the integration of social, mental and physical health programming, targeted towards gbMSM, to alleviate the degree of loneliness experienced and its co-occurrence with poor self-rated physical health.
Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population. METHODS We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro-B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A1c [Hb A1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016-2017; age 71-94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors. RESULTS In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44-3.22]; no diabetes: OR, 2.31 [95%CI, 1.76-3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08-1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22-1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A1c (OR, 1.76 [95% CI, 1.22-2.54]), fructosamine (OR, 1.71 [95% CI, 1.19-2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03-2.03]) with PN were significant only among participants with diabetes. CONCLUSIONS Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.
Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Methicillin-resistant Staphylococcus aureus (MRSA) are one of the main pathogens associated with purulent infections. MRSA clonal complex 97 (CC97) has been identified in a wide diversity of livestock animals. Therefore, we aimed to investigate the antibiotic resistance profiles of MRSA strains isolated from purulent lesions of food-producing rabbits. Samples from purulent lesions of 66 rabbits were collected in a slaughterhouse in Portugal. Samples were seeded onto ORSAB plates with 2 mg/L of oxacillin for MRSA isolation. Susceptibility to antibiotics was tested by the disk diffusion method against 14 antimicrobial agents. The presence of resistance genes, virulence factors and the immune evasion cluster (IEC) system was studied by polymerase chain reaction. All isolates were characterized by multilocus sequence typing (MLST), agr and spa typing. From the 66 samples analyzed, 16 (24.2%) MRSA were detected. All strains were classified as multidrug-resistant as they were resistant to at least three classes of antibiotics. All isolates showed resistance to penicillin, erythromycin and clindamycin. Seven isolates were resistant to gentamicin and harbored the aac(6′)-Ie-aph (2″)-Ia gene. Resistance to tetracycline was detected in 10 isolates harboring the tet(K) gene. The IEC genes were detected in three isolates. MRSA strains belonged to CC97, CC1, CC5, CC15 or CC22. The isolates were assigned to six different spa types. In this study we found a moderate prevalence of multidrug-resistant MRSA strains in food-producing rabbits. This may represent concern for food safety and public health, since cross-contamination may occur, leading to the spread of MRSA and, eventually, the possibility of ingestion of contaminated meat.
Residual Inflammation Indicated by High-Sensitivity C-Reactive Protein Predicts Worse Long-Term Clinical Outcomes in Japanese Patients after Percutaneous Coronary Intervention

The aim of this study was to investigate the long-term clinical impact of residual inflammatory risk (RIR) by evaluating serial high-sensitivity C-reactive protein (hs-CRP) in Asian patients with coronary artery disease (CAD). We evaluated 2032 patients with stable CAD undergoing percutaneous coronary intervention (PCI) with serial hs-CRP measurements (2 measurements, 6–9 months apart) from the period 2000 to 2016. A high-RIR was defined as hs-CRP > 0.9 mg/L according to the median value. Patients were assigned to four groups: persistent-high-RIR, increased-RIR, attenuated-RIR, or persistent-low-RIR. Major adverse cardiac events (MACE) and all-cause death were evaluated. MACE rates in patients with persistent high, increased and attenuated RIR were significantly higher than in patients with persistent low RIR (p < 0.001). Moreover, the rate of all-cause death was significantly higher among patients with persistent high and increased RIR than among patients with attenuated and persistent low RIR (p < 0.001). After adjustment, the presence of persistent high RIR (hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.37–3.67, p = 0.001), increased RIR (HR 2.25, 95%CI 1.09–4.37, p = 0.029), and attenuated RIR (HR 1.94, 95%CI 1.14–3.32, p = 0.015) were predictive for MACE. In addition, presence of persistent high RIR (HR 2.07, 95%CI 1.41–3.08, p < 0.001) and increased RIR (HR 1.94, 95%CI 1.07–3.36, p = 0.029) were predictive for all-cause death. A high RIR was significantly associated with MACE and all-cause death among Japanese CAD patients. An evaluation of changes in inflammation may carry important prognostic information and may guide the therapeutic approach.
Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection

KEY POINTS Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly around the globe in recent months. With deaths from its associated disease, coronavirus disease 2019 (COVID-19), projected to reach into the millions and a vaccine unlikely in the near term, the search is on