Miracle-dz/UniFAR-FTUs huggingface dataset:
Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo

PI3K-AKT-mTOR signaling is a valuable treatment target for human glioma. LY3023414 is a novel, highly-potent and pan PI3K-AKT-mTOR inhibitor. Here, we show that LY3023414 efficiently inhibited survival and proliferation of primary and established human glioma cells. Meanwhile, apoptosis activation was observed in LY3023414-treated glioma cells. LY3023414 blocked AKT-mTOR activation in human glioma cells. Further studies show that LY3023414 induced feedback activation of autophagy in U251MG cells. On the other hand, autophagy inhibition via adding pharmacological inhibitors or silencing Beclin-1/ATG-5 significantly potentiated LY3023414-induced glioma cell apoptosis. In vivo studies demonstrated that U251MG xenograft tumor growth in mice was suppressed by oral administration of LY3023414. Remarkably, LY3023414's anti-tumor activity was further augmented against the Beclin-1-silenced U251MG tumors. Together, our results suggest that targeting PI3K-AKT-mTOR cascade by LY3023414 inhibits human glioma cell growth in vitro and in vivo. Autophagy inhibition could further sensitize LY3023414 against human glioma cells.
Transcriptome Changes in Culex quinquefasciatus (Diptera: Culicidae) Salivary Glands During West Nile Virus Infection

ABSTRACT Persistent West Nile virus (WNV) infection in the mosquito Culex quinquefasciatus Say (Diptera: Culicidae) is associated with pathological changes in the salivary glands, including apoptotic cell death and a corresponding reduction in virus transmission over time. The vector host response to WNV infection and the molecular basis of WNV pathogenesis in Cx. quinquefasciatus was investigated using oligonucleotide microarrays designed to detect differences in the salivary gland transcriptome between WNV-infected mosquitoes and uninfected controls. Transcripts with increased abundance in infected salivary glands included those related to immunity, transcription, protein transport and degradation, amino acid and nucleotide metabolism, signal transduction, and cellular detoxification. Microarray-based analysis detected a decrease in transcript levels of a Culex inhibitor of apoptosis gene (IAP-1) and a decrease in abundance of 11 transcripts encoding salivary gland proteins, Transcript levels for an endonuclease, a proline-rich mucin, and several D7 protein family members also decreased. Transcripts with the greatest change in abundance during infection had either no similarity to sequences found in GenBank, VectorBase, and FlyBase, or were similar to sequences with uncharacterized protein products. These transcripts represent exciting targets for future analysis. Results from this study suggest that WNV infection influences transcriptional changes in an invertebrate host target tissue that may confer an advantage to the replicating virus, induce a host defense response, and alter the composition of vector saliva. The ramifications of these changes are discussed in terms of mosquito vector competence and WNV pathogenesis.
Poorly Neutralizing Cross-Reactive Antibodies against the Fusion Loop of West Nile Virus Envelope Protein Protect In Vivo via Fcγ Receptor and Complement-Dependent Effector Mechanisms

ABSTRACT The human antibody response to flavivirus infection is dominantly directed against a cross-reactive epitope on the fusion loop of domain II (DII-FL) of the envelope (E) protein. Although antibodies against this epitope fail to recognize fully mature West Nile virus (WNV) virions and accordingly neutralize infection poorly in vitro, their functional properties in vivo remain less well understood. Here, we show that while passive transfer of poorly neutralizing monoclonal antibodies (MAb) and polyclonal antibodies against the DII-FL epitope protect against lethal WNV infection in wild-type mice, they fail to protect mice lacking activating Fcγ receptors (FcγR) and the complement opsonin C1q. Consistent with this, an aglycosyl chimeric mouse-human DII-FL MAb (E28) variant that lacks the ability to engage FcγR and C1q also did not protect against WNV infection in wild-type mice. Using a series of immunodeficient mice and antibody depletions of individual immune cell populations, we demonstrate that the nonneutralizing DII-FL MAb E28 does not require T, B, or NK cells, inflammatory monocytes, or neutrophils for protection. Rather, E28 treatment decreased viral load in the serum early in the course of infection, which resulted in blunted dissemination to the brain, an effect that required phagocytic cells, C1q, and FcγRIII (CD16). Overall, these studies enhance our understanding of the functional significance of immunodominant, poorly neutralizing antibodies in the polyclonal human anti-flavivirus response and highlight the limitations of current in vitro surrogate markers of protection, such as cell-based neutralization assays, which cannot account for the beneficial effects conferred by these antibodies.
Sitting time and all-cause mortality risk in 222 497 Australian adults.

BACKGROUND Prolonged sitting is considered detrimental to health, but evidence regarding the independent relationship of total sitting time with all-cause mortality is limited. This study aimed to determine the independent relationship of sitting time with all-cause mortality. METHODS We linked prospective questionnaire data from 222 497 individuals 45 years or older from the 45 and Up Study to mortality data from the New South Wales Registry of Births, Deaths, and Marriages (Australia) from February 1, 2006, through December 31, 2010. Cox proportional hazards models examined all-cause mortality in relation to sitting time, adjusting for potential confounders that included sex, age, education, urban/rural residence, physical activity, body mass index, smoking status, self-rated health, and disability. RESULTS During 621 695 person-years of follow-up (mean follow-up, 2.8 years), 5405 deaths were registered. All-cause mortality hazard ratios were 1.02 (95% CI, 0.95-1.09), 1.15 (1.06-1.25), and 1.40 (1.27-1.55) for 4 to less than 8, 8 to less than 11, and 11 or more h/d of sitting, respectively, compared with less than 4 h/d, adjusting for physical activity and other confounders. The population-attributable fraction for sitting was 6.9%. The association between sitting and all-cause mortality appeared consistent across the sexes, age groups, body mass index categories, and physical activity levels and across healthy participants compared with participants with preexisting cardiovascular disease or diabetes mellitus. CONCLUSIONS Prolonged sitting is a risk factor for all-cause mortality, independent of physical activity. Public health programs should focus on reducing sitting time in addition to increasing physical activity levels.
Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study.

OBJECTIVE Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures. METHOD A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals. RESULTS Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms. CONCLUSIONS The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.
Genetic polymorphisms of the human cytomegalovirus UL144 gene in colorectal cancer and its association with clinical outcome.

Human cytomegalovirus (HCMV) has been increasingly detected in colorectal cancer (CRC), and genetic polymorphisms in HCMV affect its pathogenesis. This study aimed to investigate HCMV genetic polymorphisms in CRC and its correlation with the clinical outcomes. We performed PCR and sequencing of a viral immunomodulatory gene, UL144, in clinical isolates and CRC specimens. The nucleotide and amino acid sequences were aligned, and a phylogenetic tree was constructed. The clinical, pathological and survival data were compared among tumours with different UL144 genotypes. HCMV was detected in 49 (47.8 %) of the tumour specimens. Genotype A predominated in 43 samples (22/43; 51.2 %) with successful sequencing, followed by genotype B (13/43; 30.2 %) and genotype C (8/43; 18.6 %). The genotypic distribution was similar to that of the clinical isolates and those reported in other Asian populations. The amino acid sequence of genotype B was the most conserved. For stage II and III CRC patients with HCMV-positive tumours, disease-free survival (DFS) varied among the three major genotypes (P50.0046). The presence of genotype B virus in the tumours was associated with a shorter DFS and independently predicted tumour recurrence in a multivariate Cox proportional hazards model (hazard ratio, 5.79; 95 % confidence interval, 1.30–25.81; P50.021). By reverse transcription PCR, tumour samples with genotype B viruses had the highest rate of UL144 expression. Our results suggest that genetic polymorphisms of HCMV UL144 are associated with clinical outcome in CRC and that HCMV may play an immunomodulatory role in the tumour microenvironment of CRC.
Urothelial neoplasms in patients 20 years or younger: a clinicopathological analysis using the world health organization 2004 bladder consensus classification.

PURPOSE Urothelial neoplasms in patients younger than 20 years are rare, with conflicting data regarding clinical outcomes. MATERIALS AND METHODS We identified 23 patients 4 to 20 years old with urothelial neoplasms, reclassified the microscopic diagnoses using the 2004 WHO/International Society of Urologic Pathology grading classification and collected data on presentation, risk factors and outcomes. RESULTS Pathological grading revealed 2 urothelial papillomas, 10 papillary urothelial neoplasms of low malignant potential (PUNLMPs), and 8 low grade and 3 high grade papillary urothelial cancers, all without invasion. Mean patient age was 13.2 years (range 4 to 20), 19 patients were male and 19 presented with gross hematuria. All lesions were solitary and measured 0.1 to 6 cm. One patient had a history of smoking and 1 had parents who smoked. Three patients (13%) had recurrences classified as either urothelial papilloma (1) or PUNLMP (2). All patients were alive with no evidence of disease after a mean followup of 4.5 years (range 6 months to 13 years). CONCLUSIONS Urothelial neoplasms in individuals younger than 20 years more commonly occur in males and are predominantly low grade with a favorable clinical outcome. Before the current classification system the 10 patients with a diagnosis of PUNLMP would have been classified as having papillary carcinoma. Thus, the diagnostic category of PUNLMP allowed 43.5% of patients in this series to avoid being labeled with "cancer" at a young age.
Pharmacodynamics and pharmacokinetics of sodium zirconium cyclosilicate [ZS-9] in the treatment of hyperkalemia

ABSTRACT Introduction: Hyperkalemia is a common electrolyte disorder that arises from dysfunctional homeostatic mechanisms or as a consequence of decreased renal function. Sodium zirconium cyclosilicate (ZS-9) is a potential new therapy for hyperkalemia in both acute and chronic settings. Areas Covered: Here we discuss mechanisms of potassium homeostasis and preclinical and clinical studies that present pharmacokinetics/pharmacodynamics, efficacy and safety profiles of ZS-9. Expert Opinion: ZS-9 has a unique mechanism of action consisting of thermodynamically favorable sequestration of potassium ions, enabling rapid trapping and removal of excess potassium. The potassium lowering action of ZS-9 is predictable and rapid, leading to significant reduction of serum potassium within 1 hour of administration by irreversibly eliminating excess potassium rather than acting via intracellular translocation. Its safety profile, including gastrointestinal events, has been generally similar to that of placebo, with the exception of infrequent but manageable events of peripheral edema and transient hypokalemia. ZS-9 has demonstrated potential for enabling renin-angiotensin-aldosterone system inhibitors in mid-term studies, with long-term studies ongoing.
Effect of surface treatments on the adhesion of self-adhesive resin cements to titanium.

PURPOSE To evaluate the effect of different chemical surface treatments on the adhesion of self-adhesive resin cements to commercially pure titanium (cp Ti) by means of strain energy release rate (G-value, J/m²). MATERIALS AND METHODS Machined cp Ti plates grade II were prepared and divided into ten groups in each test according to the surface treatment used; Gr 1: control, machined; Gr 2: sandblasted; Gr 3: methylene chloride (CH2Cl2) for 5 min; Gr 4: CH2Cl2 for 10 min; Gr 5: 10% hydrogen peroxide (H₂O₂) for 5 min; Gr 6: 10% H₂O₂ for 10 min; Gr 7: 30% H₂O₂ for 5 min; Gr 8: 30% H₂O₂ for 10 min; Gr 9: 9% hydrofluoric acid (HF) for 5 min; Gr 10: 9% HF for 10 min. For bond strength testing, each group was further divided into two subgroups according to the type of resin cement used (G-CEM and Rely × Unicem). Surface roughness examination and SEM analysis of treated cp Ti surfaces were carried out. Data were analyzed using ANOVA and Tukey's test. Statistical significance was set at the 0.05 probability level. RESULTS The cp Ti/G-CEM and cp Ti/Rely × Unicem (9% HF for 5 or 10 min) groups showed the highest G-values (13.7 ± 2.2, 13.8 ± 2.1, 11.6 ± 1.6 and 11.8 ± 1.2, respectively) among their groups. The sandblasted group showed the highest surface roughness value (3.4 ± 0.2 µm) when compared with other treated groups. CONCLUSION Adhesion between resin cements and cp Ti can be improved by the use of certain chemical baths as surface treatments of titanium prior to cementation as alternative techniques to sandblasting treatment.
Adaptive molecular evolution of MC1R gene reveals the evidence for positive diversifying selection in indigenous goat populations

Abstract Detecting signatures of selection can provide a new insight into the mechanism of contemporary breeding and artificial selection and further reveal the causal genes associated to the phenotypic variation. However, the signatures of selection on genes entailing for profitable traits between Chinese commercial and indigenous goats have been poorly interpreted. We noticed footprints of positive selection at MC1R gene containing SNPs genotyped in five Chinese native goat breeds. An experimental distribution of F ST was built based on approximations of F ST for each SNP across five breeds. We identified selection using the high F ST outlier method and found that MC1R candidate gene show evidence of positive selection. Furthermore, adaptive selection pressure on specific codons was determined using different codon based on maximum‐likelihood methods; signature of positive selection in mammalian MC1R was explored in individual codons. Evolutionary analyses were inferred under maximum likelihood models, the HyPhy package implemented in the DATAMONKEY Web Server. The results of codon selection displayed positive diversifying selection at the sites were mainly involved in development of genetic variations in coat color in various mammalian species. Positive diversifying selection inferred with recent evolutionary changes in domesticated goat MC1R provides new insights that the gene evolution may have been modulated by domestication events in goats.
How older people in the United States and Germany fared in the growth years of the 1980s: a cross-sectional versus a longitudinal view.

OBJECTIVES The goal of the study was to show that cross-sectional and longitudinal data yield dramatically different answers to a basic question: "How did older persons fare in the recovery years of the 1980s? " METHODS The United States Panel Study of Income Dynamics and the German Socio-Economic Panel are used cross-sectionally to capture changes in the economic well-being of older persons in the trough and peak years of the 1980s business cycle, and longitudinally to trace how the economic well-being of a given cohort of older persons changed over those years. Kernel density estimation is then used to show how the distribution of economic well-being of these populations changed over these years. RESULTS Cross-sectional comparisons confirm that persons aged 65 and over in the peak year were better off than persons aged 65 and over in the trough year in both countries. Longitudinal comparisons, however, show that persons aged 65 and over in the trough year who survived to the peak year received a substantially smaller share of the rewards of economic recovery than cross-sectional comparisons imply. Moreover, the entire income distribution of older persons in the United States shifted downwards. DISCUSSION Compositional changes in the cross-sectional data, caused by the entry of high-income persons who are young in the peak year but old in the trough year, obscure the decline in the economic well-being of the cohort of older persons who survived the trough year, in cross-sectional comparisons of older populations in the United States in the 1980s.
Fabricating PLGA microparticles with high loads of the small molecule antioxidant N‐acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress

Reactive oxygen species (ROS), encompassing all oxygen radical or non‐radical oxidizing agents, play key roles in disease progression. Controlled delivery of antioxidants is therapeutically relevant in such oxidant‐stressed environments. Encapsulating small hydrophilic molecules into hydrophobic polymer microparticles via traditional emulsion methods has long been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed a simple alteration to the existing water‐in‐oil‐in‐water (W/O/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. PLGA microparticles with diameters ranging from 0.6 to 0.9 micrometers were fabricated, encapsulating high loads of 0.6–0.9 µm diameter PLGA microparticles were fabricated, encapsulating high loads of the antioxidant N‐acetylcysteine (NAC), and released active, ROS‐scavenging NAC for up to 5 weeks. Encapsulation efficiencies, normalized to the theoretical load of traditional encapsulation without doping, ranged from 96% to 400%, indicating that NAC‐loaded external water phases not only prevented drug loss due to diffusion, but also doped the particles with additional drug. Antioxidant‐doped particles positively affected the metabolism of oligodendrocyte progenitor cells (OPCs) under H2O2‐mediated oxidative stress when administered both before (protection) or after (rescue) injury. Antioxidant doped particles improved outcomes of OPCs experiencing multiple doses of H2O2 by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. Furthermore, antioxidant‐doped particles preserve cell number, number of process extensions, cytoskeletal morphology, and nuclear size of H2O2‐stressed OPCs relative to the injury control. These NAC‐doped particles have the potential to provide temporally‐controlled antioxidant therapy in neurodegenerative disorders such as multiple sclerosis (MS) that are characterized by continuous oxidative stress.
Pharmacokinetics, pharmacodynamics, and hepatitis C viral kinetics during antiviral therapy: The null responder

Our aim was to study the effect of ribavirin on viral kinetics and to study the early patterns of response to antiviral therapy of hepatitis C and their correlation with interferon pharmacokinetics and pharmacodynamics. We conducted a randomized, controlled trial of peginterferon alfa‐2a with or without ribavirin in interferon naïve patients with HCV genotype 1. HCV RNA levels were measured at frequent intervals during treatment together with serum levels of peginterferon alfa‐2a and 2′5′oligoadenylate synthetase (OAS). Of 29 patients treated, 14 had a complete response at day 29 while 15 had a null response (less than 1 log decline in HCV RNA). There were no significant differences between complete and null responders with regard to gender, age, race, body mass index, HCV subtype, baseline HCV RNA levels, serum aminotransferase activities, stage of fibrosis, peak OAS, or interferon levels. Mean serum IFN levels at day 29 and OAS levels at day 3 were no different between complete and null responders (15,525 vs. 30,768 pg/ml and 2,044 vs. 2,323 pM/hr, respectively, P = n.s.). Addition of ribavirin to pegylated IFN did not significantly affect day 29 IFN levels or Day 3 OAS levels. In conclusion, null responders to either peginterferon alone or in combination with ribavirin have little or no decrease in serum HCV RNA early in therapy and rarely go on to achieve sustained virologic response and have no apparent host differences than complete responders, suggesting that interferon resistance in these patients may be virally rather than host‐determined. J. Med. Virol. 78:446–451, 2006. © 2006 Wiley‐Liss, Inc.
Comparison of incremental with multipoint MUNE methods in transgenic ALS mice

Several methods of motor unit number estimation (MUNE) are in current use. Uncertainty still exists about which is preferable and how results obtained from one method compare to another. We studied changes with MUNE over time in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS), using both incremental and multipoint methods. This mouse model of motor neuron degeneration is highly consistent, with a monotonic decline in motor neuron number starting at approximately 60 days of life. Five mice were studied four times each, starting at day 60 of life and approximately every 20 days thereafter, using both methods. Results were quite comparable for both methods, with the incremental method yielding slightly higher estimates of motor unit size, and hence smaller MUNEs. Correlations between the two methods were 0.71 for single motor unit action potential (SMUAP) amplitude and 0.95 for MUNE. In this model, therefore, both MUNE methods yield similar estimates and are equally effective at documenting progression of a lower motor neuron disorder. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 39–42, 2002