Miracle-dz/UniFAR-FTUs huggingface dataset:
GCN2 Protein Kinase Is Required to Activate Amino Acid Deprivation Responses in Mice Treated with the Anti-cancer Agent l-Asparaginase*

Asparaginase depletes circulating asparagine and glutamine, activating amino acid deprivation responses (AADR) such as phosphorylation of eukaryotic initiation factor 2 (p-eIF2) leading to increased mRNA levels of asparagine synthetase and CCAAT/enhancer-binding protein β homologous protein (CHOP) and decreased mammalian target of rapamycin complex 1 (mTORC1) signaling. The objectives of this study were to assess the role of the eIF2 kinases and protein kinase R-like endoplasmic reticulum resident kinase (PERK) in controlling AADR to asparaginase and to compare the effects of asparaginase on mTORC1 to that of rapamycin. In experiment 1, asparaginase increased hepatic p-eIF2 in wild-type mice and mice with a liver-specific PERK deletion but not in GCN2 null mice nor in GCN2-PERK double null livers. In experiment 2, wild-type and GCN2 null mice were treated with asparaginase (3 IU per g of body weight), rapamycin (2 mg per kg of body weight), or both. In wild-type mice, asparaginase but not rapamycin increased p-eIF2, p-ERK1/2, p-Akt, and mRNA levels of asparagine synthetase and CHOP in liver. Asparaginase and rapamycin each inhibited mTORC1 signaling in liver and pancreas but maximally together. In GCN2 null livers, all responses to asparaginase were precluded except CHOP mRNA expression, which remained partially elevated. Interestingly, rapamycin blocked CHOP induction by asparaginase in both wild-type and GCN2 null livers. These results indicate that GCN2 is required for activation of AADR to asparaginase in liver. Rapamycin modifies the hepatic AADR to asparaginase by preventing CHOP induction while maximizing inhibition of mTORC1.
Heterogeneity in cytokine profiles of Babesia bovis-specific bovine CD4+ T cells clones activated in vitro

The central role of T cells in the immune response against hemoprotozoan parasites, both as helper cells for T cell-dependent antibody production and as effector cells acting on intracellular parasites through the elaboration of cytokines, has prompted an investigation of the bovine cellular immune response against Babesia bovis antigens. CD4+ T helper (Th) cell clones generated from four B. bovis-immune cattle by in vitro stimulation with a soluble or membrane-associated merozoite antigen were characterized for reactivity against various forms of antigen and against different geographical isolates of B. bovis and B. bigemina and analyzed for cytokine production following mitogenic stimulation with concanavalin A. Biological assays to measure interleukin-2 (IL-2), IL-4, gamma interferon (IFN-gamma), and tumor necrosis factor alpha or tumor necrosis factor beta and Northern (RNA) blot analysis to verify the expression of IL-2, IL-4, IFN-gamma, and tumor necrosis factor alpha revealed differential production of cytokines by the Th cell clones. The majority of clones expressed the Th0 pattern of cytokines: IFN-gamma, IL-4, and IL-2. One clone expressed the Th1 profile (IFN-gamma and IL-2 but not IL-4), whereas none of the clones expressed the Th2 profile. All of the Th cell clones examined expressed the low-molecular-weight isoform of the leukocyte common antigen associated with a memory cell phenotype (CD45RO), and all expressed the lymph node homing receptor (L-selectin). These results extend our previous finding of differential cytokine expression by B. bovis-specific Th cell clones and confirm the identity of the specific cytokines produced, showing that a Th0 response is preferentially induced in a panel of 20 CD4+ T cell clones obtained from immune cattle.
Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression.

OBJECTIVE To evaluate the prognostic value of bronchoalveolar lavage (BAL) cellular profiles in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS BAL cellularity was examined in relation to mortality (n = 141), serial pulmonary function findings (n = 134), and "progression-free survival" (n = 134), by proportional hazards analysis. Baseline severity was quantified according to the extent of disease on high-resolution computed tomography, the diffusing capacity for carbon monoxide, and the presence or absence of pulmonary hypertension. Mortality was subclassified into overall mortality (during 10 years of followup), early mortality (occurring within 2 years of presentation), and late mortality (occurring 2-10 years after presentation). RESULTS Overall mortality was associated with neutrophilia on BAL (hazard ratio 2.23 [95% confidence interval 1.20-4.14], P = 0.01), but this effect was lost when disease severity was taken into account. Early mortality was associated with neutrophilia on BAL (hazard ratio 8.40 [95% confidence interval 1.91-36.95], P = 0.005), independent of disease severity. Late mortality was not associated with neutrophilia on BAL. The presence of neutrophilia on BAL was not associated with time to decline in pulmonary function or progression-free survival. Neither eosinophilia nor lymphocytosis on BAL was associated with mortality, rapidity of functional deterioration, or progression-free survival. These findings were unaltered when treatment status was taken into account. CONCLUSION BAL findings provide only limited prognostic information in SSc-ILD. Neutrophilia on BAL is linked to early mortality, but BAL findings are not linked to long-term survival or the rapidity of progression of lung disease. The usefulness of BAL to define alveolitis in SSc is questionable.
Exome-Wide Meta-Analysis Identifies Rare 3′-UTR Variant in ERCC1/CD3EAP Associated with Symptoms of Sleep Apnea

Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10−9, βmeta = 0.99). Rs2229918 overlaps with the 3′ untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research.
Gender and Age Differences in Food Cognition

Results from three studies relevant to a model of food cognition based on the evaluative dimensions pleasure, health, and convenience are reported. In the first study, discriminant analyses of the evaluative ratings (n = 248) of 35 meals and snacks yielded significant gender and age differences on the pleasure and health dimensions. Separate factor analyses of the pleasure and health ratings revealed that males and females grouped foods differently on these criteria. The factor analysis of convenience ratings suggested that males and females perceive the meaning of convenience differently. In the second study, 336 college students rated 27 meals on the three evaluative dimensions and also indicated their preferences for each meal. Multiple regression analyses showed that preferences could be significantly predicted, and other results showed that as compared to males, females give higher health, pleasure and convenience ratings to healthy meals. The third study employed a modified free association technique to investigate gender and age differences in the meanings of nine familiar foods. Data from 96 males and females aged 18 to 86 revealed a substantial variety of significant age and gender differences for specific foods. It is suggested that taken together, these results indicate important cognitive and affective sources for gender and age-related food attitudes.
Factors Associated with Non-Adherence to HBV Antiviral Therapy

Background HBV antiviral therapy has the potential to reduce the burden of HBV-related liver disease by suppressing HBV DNA replication to undetectable levels, reducing the progression of liver fibrosis and reducing the risk of hepatocellular carcinoma (HCC) development. Treatment outcomes and long-term benefits require adherence to medication regimens. This study aimed to identify the prevalence and factors associated with non-adherence to antiviral therapy. Methods A cross-sectional survey of patients receiving HBV antiviral therapies was conducted in three Sydney hospitals. Participants were asked to complete an online questionnaire. Logistic regression was used to assess the associations between non-adherence (defined as missing more than 1 day of medication in the last 30 days) and demographic, socio-economic, disease, treatment, healthcare system and individual-related factors. Results Of the 277 participants, 66 (23.8%) were non-adherent, missing a mean 1.7 days of medication (sd 4.8) in the last 30 days. In multivariate analysis, non-adherent behaviour declined with age (odds ratio [OR] 0.9, 95% CI 0.97, 0.99; P<0.013). Participants who reported having no established routine to take their medication (OR 5.0, 95% CI 1.4, 17.4; P<0.012) and having inadequate health literacy (OR 2.7, 95% CI 1.3, 5.5; P<0.007) were more likely to be non-adherent. Conclusions Almost a quarter of participants in the current study were non-adherent. Adherence is potentially modifiable through person-centred education, collaborative models of patient care and interventions designed to improve health literacy and establish medication routines. Findings have the potential to improve health service delivery to patients at risk of non-adherence to HBV antiviral therapy.
Internal antenna for UHF-band mobile RFID system

UHF-band radio frequency identification (RFID) antenna for mobile handset applications is presented. The proposed antenna consists of a radiating element and a parasitic element connected to the ground plane. The radiation pattern of proposed antenna is orthogonal to that of a monopole antenna. The impedance bandwidth (902 MHz ~ 923 MHz) covers a Korea mobile RFID service (908.55 MHz ~ 913.95 MHz). The measured antenna peak gain is -0.37 dBi at 911 MHz.
Transforming growth factor-beta 2 levels in aqueous humor of glaucomatous eyes.

PURPOSE To determine whether clinical characteristics are correlated with increased levels of transforming growth factor-beta 2 (TGF-beta 2) in aqueous humor in glaucomatous eyes. METHODS Aqueous humor samples were collected from 91 glaucomatous eyes. Included were samples from primary open-angle glaucoma (POAG) in 40 eyes, (pseudo)exfoliation syndrome (EXS) in 18 eyes, primary angle-closure glaucoma (PACG) in 26 eyes and uveitis-related secondary glaucoma (SG) in 7 eyes. TGF-beta 2 in aqueous humor was assessed with a specific-capture ELISA. RESULTS The mean concentration (+/- standard error) of mature (biologically active) TGF-beta 2 in the aqueous humor of eyes with POAG was 293.6 +/- 33.6 pg/ml, significantly higher than that in eyes with PACG, EXS and SG: 147.5 +/- 28.1, 135.8 +/- 30.2 and 41.0 +/- 10.7 pg/ml, respectively (P = 0.0006, P = 0.0010 and P = 0.0003; analysis of variance). The mean concentration (+/- standard error) of total TGF-beta 2 in the aqueous humor of eyes with POAG was 1647.6 +/- 124.5 pg/ml, not significantly different from that in eyes with PACG, EXS and SG: 1482.9 +/- 148.2, 1442.7 +/- 187.8 and 1929.0 +/- 367.6 pg/ml, respectively. A multivariate analysis using logistic regression showed significant correlations between mature TGF-beta 2 concentration and history of cataract surgery (P = 0.0225) and the use of carbonic anhydrase inhibitors (P = 0.0143). CONCLUSIONS Our results indicate that increased levels of TGF-beta 2 may play an important role in the pathogenesis of POAG.
Patient Adherence and Medical Treatment Outcomes: A Meta-Analysis

Background. Adherence is a factor in the outcome of medical treatment, but the strength and moderators of the adherence-outcome association have not been systematically assessed. Objectives. A quantitative review using meta-analysis of three decades of empirical research correlating adherence with objective measures of treatment outcomes. Method. Sixty-three studies assessing patient adherence and outcomes of medical treatment were found involving medical regimens recommended by a nonpsychiatrist physician, and measuring patient adherence and health outcomes. Studies were analyzed according to disease (acute/chronic, severity), population (adult/child), type of regimen (preventive/treatment, use of medication), and type and sensitivity of adherence and outcomes measurements. Results. Overall, the outcome difference between high and low adherence is 26%. According to a stringent random effects model, adherence is most strongly related to outcomes in studies of nonmedication regimens, where measures of adherence are continuous, and where the disease is chronic (particularly hypertension, hypercholesterolemia, intestinal disease, and sleep apnea). A less stringent fixed effects model shows a trend for higher adherence-outcome correlations in studies of less serious conditions, of pediatric patients, and in those studies using self-reports of adherence, multiple measures of adherence, and less specific measures of outcomes. Intercorrelations among moderator variables in multiple regression show that the best predictor of the adherence-outcome relationship is methodological—the sensitivity/quality of the adherence assessment.
Interrelationship among vitamin D metabolism, true calcium absorption, parathyroid function, and age in women: Evidence of an age‐related intestinal resistance to 1,25‐dihydroxyvitamin D action

We studied the mechanism of impaired calcium absorption with aging in 51 healthy women whose ages ranged from 26 to 88 years. Serum concentrations of 1,25‐dihydroxyvitamin D [1,25‐(OH)2D, mean of four measurements per subject] increased with age by 22% (P < 0.05) but, by split‐point analysis, plateaued or decreased slightly after age 65. In a subset of 20 subjects, [3H]1,25‐(OH)2D3 kinetic analysis showed that this increase with age resulted from both increased production and decreased metabolic clearance of 1,25‐(OH)2D. Despite the increase in serum 1,25‐(OH)2D concentration, true calcium absorption did not change with age. The expected inverse correlation between true fractional calcium absorption and dietary calcium intake, however, was easily demonstrated (r = 0.66, P < 0.001). Serum intact parathyroid hormone (PTH) increased with age by 35% (P < 0.02) and serum bone gla protein (BGP, osteocalcin) increased by 47% (P < 0.001); the increases in serum PTH and serum BGP were directly correlated (r = 0.32, P < 0.05). The data are consistent with the following hypothetical model: (1) intestinal resistance to 1,25‐(OH)2D action accounts for the increase in serum 1,25‐(OH)2D concentrations with aging with no change in true calcium absorption; (2) this results in a compensatory increase in PTH secretion and in 1,25‐(OH)2D production that prevents true calcium absorption from decreasing; (3) the previously described defect in 25‐hydroxyvitamin D (25‐OHD) 1α‐hydroxylase activity in aging animals and humans acccounts for the leveling off in serum 1,25‐(OH)2D concentration after age 65 years; and (4) the secondary hyperparathyroidism leads to increased bone turnover and thus contributes to age‐related bone loss.
IL‐23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

IL‐23, a proximal regulator of IL‐17, may be a major driving force in the induction of autoimmune inflammation. We have used a model of subdiabetogenic treatment with multiple low doses of streptozotocin (MLD‐STZ; 4 × 40 mg/kg body weight) in male C57BL/6 mice to study the effect of IL‐23 on immune‐mediated β cell damage and the development of diabetes, as evaluated by blood glucose, quantitative histology, immunohistochemistry and expression of relevant cytokines in the islets. Ten daily injections of 400 ng IL‐23, starting on the first day of MLD‐STZ administration led to significant and sustained hyperglycemia along with weight loss compared with controls (no IL‐23), and a significant increase in the number of infiltrating cells, a lower insulin content, enhanced apoptosis, expression of IFN‐γ and IL‐17 (not seen in the controls) and a significant increase in the expression of TNF‐α and IL‐18 in the pancreatic islets. IL‐23 treatment started 5 days prior to MLD‐STZ administration had no effect on diabetogenesis or cytokines expression in the pancreatic islets. We provide the first evidence in an animal model that IL‐23 is involved in the development of type‐1 diabetes, by inducing IL‐17 and possibly IFN‐γ production in the target tissue.
A new approach to prevent HIV transmission: Project Protect intervention for recently infected individuals

Past research suggests that as many as 50% of onward human immunodeficiency virus (HIV) transmissions occur during acute and recent HIV infection. It is clearly important to develop interventions which focus on this highly infectious stage of HIV infection to prevent further transmission in the risk networks of acutely and recently infected individuals. Project Protect tries to find recently and acutely infected individuals and prevents HIV transmission in their risk networks. Participants are recruited by community health outreach workers at community-based HIV testing sites and drug users' community venues, by coupon referrals and through referrals from AIDS clinics. When a network with acute/recent infection is identified, network members are interviewed about their risky behaviors, network information is collected, and blood is drawn for HIV testing. Participants are also educated and given prevention materials (condoms, syringes, educational materials); HIV-infected participants are referred to AIDS clinics and are assisted with access to care. Community alerts about elevated risk of HIV transmission are distributed within the risk networks of recently infected. Overall, 342 people were recruited to the project and screened for acute/recent HIV infection. Only six index cases of recent infection (2.3% of all people screened) were found through primary screening at voluntary counseling and testing (VCT) sites, but six cases of recent infection were found through contact tracing of these recently infected participants (7% of network members who came to the interview). Combining screening at VCT sites and contact tracing the number of recently infected people we located as compared to VCT screening alone. No adverse events were encountered. These first results provide evidence for the theory behind the intervention, i.e., in the risk networks of recently infected people there are other people with recent HIV infection and they can be successfully located without increasing stigma for project participants.
Effect of Contact Lens Wear on the Release of Tear Mediators in Keratoconus

Objectives: The release of different cytokines and mediators in tears of patients with keratoconus (KC) wearing contact lenses (CLs) may contribute to the pathology of KC. Methods: Cohort study was established in patients with KC wearing rigid gas permeable (RGP) CL (group I), patients with ametropia wearing silicone hydrogel (Si-Hi) CL (group II) and ametropic patients wearing RGP CL (group III). Results: Our findings indicate that before CL wear, the release of epidermal growth factor (EGF) and tissue-type plasminogen activator (t-PA) was attenuated, whereas matrix metalloproteinase (MMP)-9, interleukin (IL)-6, chemokine (C-C motif) ligand 5 (CCL5), IL-13, and plasminogen activator inhibitor (PAI)-1 were enhanced in KC compared with ametropes. An increasing linear trend over time was found for MMP-9, EGF, and CXCL8 in KC and MMP-9, MMP-13, IL-6, and CXCL8 in group III. Significant differences were observed in the linear trend over time between groups I and III for MMP-13 and tissue inhibitor of metalloproteinases (TIMP)-1; between groups I and II for MMP-9 and CXCL8; and between groups III and II for MMP-9, CXCL8, and MMP-13. In KC, the release of MMP-9 at week 6 and nerve growth factor (NGF) at 10 min was higher, but NGF at week 2 was lower than that in group II. The release of MMP-13 and NGF at week 2 and 6 were lower in the KC group as compared with group III, and similarly, with IL-6 and CXCL8 at week 2 and PAI at all time points. Conclusions: Contact lens wear can influence the levels and dynamics of various mediators in the tears of patients with KC that might have an impact on the progression of the disease.
Conformational selection or induced fit: A flux description of reaction mechanism

The mechanism of ligand binding coupled to conformational changes in macromolecules has recently attracted considerable interest. The 2 limiting cases are the “induced fit” mechanism (binding first) or “conformational selection” (conformational change first). Described here are the criteria by which the sequence of events can be determined quantitatively. The relative importance of the 2 pathways is determined not by comparing rate constants (a common misconception) but instead by comparing the flux through each pathway. The simple rules for calculating flux in multistep mechanisms are described and then applied to 2 examples from the literature, neither of which has previously been analyzed using the concept of flux. The first example is the mechanism of conformational change in the binding of NADPH to dihydrofolate reductase. The second example is the mechanism of flavodoxin folding coupled to binding of its cofactor, flavin mononucleotide. In both cases, the mechanism switches from being dominated by the conformational selection pathway at low ligand concentration to induced fit at high ligand concentration. Over a wide range of conditions, a significant fraction of the flux occurs through both pathways. Such a mixed mechanism likely will be discovered for many cases of coupled conformational change and ligand binding when kinetic data are analyzed by using a flux-based approach.