Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinetics of Antiviral Activity by Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes (CTL) and Rapid Selection of CTL Escape Virus In Vitro

ABSTRACT The antiviral activity of a CD8+ cytotoxic T-lymphocyte (CTL) clone (TCC108) directed against a newly identified HLA-B14-restricted epitope, human immunodeficiency virus type 1 (HIV-1) Rev(67-75) SAEPVPLQL, was analyzed with respect to its kinetics of target cell lysis and inhibition of HIV-1 production. Addition of TCC108 cells or CD8+ reverse transcriptase-specific CTLs to HLA-matched CD4+ T cells at different times after infection with HIV-1 IIIB showed that infected cells became susceptible to CTL-mediated lysis before peak virus production but after the onset of progeny virus release. When either of these CTLs were added to part of the infected cells immediately after infection, p55 expression and virus production were significantly suppressed. These data support a model in which CTLs, apart from exerting cytolytic activity which may prevent continued virus release, can interfere with viral protein expression during the eclipse phase via noncytolytic mechanisms. TCC108-mediated inhibition of virus replication in peripheral blood mononuclear cells caused rapid selection of a virus with a mutation (69E→K) in the Rev(67-75) CTL epitope which abolished recognition by TCC108 cells. Taken together, these data suggest that both cytolytic and noncytolytic antiviral mechanisms of CTLs can be specifically targeted to HIV-1-infected cells.
Phosphorylation of CREB in Ovine Pars Tuberalis is Regulated both by cyclic AMP‐Dependent and cyclic AMP‐Independent Mechanisms

This study used a combination of Western blotting and immunocytochemistry to test whether signalling pathways independent of cyclic AMP have the potential to induce phospho‐CREB (pCREB)‐like immunoreactivity (‐ir) in the oPT. Western blot analysis of extracts of primary cultures of oPT using an antiserum against CREB, revealed a major band of CREB‐ir at 44 KDa. The intensity of this band did not vary systematically with treatment. In extracts from untreated cells, Western blot analysis revealed a major band of pCREB‐ir at 42 KDa which was not sensitive to agonist treatment. Treatment of cells with forskolin (10−6 M) increased the intensity of a number of other pCREB‐ir bands at between ca. 38 and 44 KDa. The band at 44 KDa probably represented native pCREB whilst the other bands induced by forskolin probably represented pCREB‐like proteins. Melatonin (10−6 M) alone had no effect on pCREB‐ir, but it did inhibit the effect of forskolin on the ca. 38 and 44 KDa pCREB‐ir bands. Treatment with lamb serum (1%) consistently increased the intensity of the ca. 38 and 44 KDa pCREB‐ir bands relative to control cells, as assessed by Western blot. However, Western blot analysis did not reveal a consistent effect of melatonin on the pCREB‐ir response to serum. The effect of serum on pCREB‐ir in oPT cells was characterized further by immunocytochemical analysis. In contrast to experiments utilizing Western blotting, untreated cells did not possess detectable pCREB‐ir. In serum‐starved oPT and oPD cultures, treatment with serum induced exclusively nuclear pCREB‐ir. A large majority of oPT cells (≥90%) were sensitive to serum (1%), and serum caused a time‐ and dose‐dependent increase of nuclear pCREB‐ir. Melatonin attenuated the response to serum in the oPT. This inhibition of the response to serum was not apparent in the oPD, demonstrating that the effect of melatonin was specific for a tissue known to express melatonin receptors. In oPT cultures, physiological concentrations of melatonin (10−9 M) partially reversed (ca. 70%) the inductive effect of 0.1% serum on nuclear pCREB‐ir. However, in contrast to studies applying forskolin, the induction of pCREB‐ir by serum occurred in the absence of measurable changes in the concentration of cyclic AMP, indicating that components of serum are able to stimulate the phosphorylation of CREB in the oPT through mechanisms independent of cyclic AMP. Both adenosine and prostaglandin E2 (PGE2) also induced nuclear pCREB‐ir in the absence of increased levels of cyclic AMP. These results demonstrate that transcriptional activities in the oPT which are under the control of CREB may be modulated by convergent cyclic AMP‐dependent and cyclic AMP‐independent pathways. Regulation of these pathways by melatonin and other factors present in serum may be an important control‐point in the generation of seasonal neuroendocrine cycles.
Cardiovascular outcomes in Fabry disease are linked to severity of chronic kidney disease

Objectives Assess the impact of end-stage renal disease (chronic kidney disease stage 5 (CKD5)) on cardiovascular outcomes in patients with Fabry disease on enzyme replacement therapy. Background Fabry disease, an X-linked lysosomal storage disease, causes hypertrophic cardiomyopathy and cardiovascular dysfunction. Methods Cardiac and renal function of 25 male patients with Fabry disease were analysed at 0, 1, 2, 5, 7 and 10 years after initiation of treatment. Patients were grouped at baseline into those with CKD5 (n=10) and those without (n=15). ECG and echocardiography were performed 6 and 12 monthly, respectively, while renal function was measured yearly. Results After 10 years of treatment, cardiac and renal function in non-CKD5 patients remained unchanged. In contrast, CKD5 was associated with worse baseline cardiac parameters and progressive LV hypertrophy. LV mass index grew by 35.4±31.8 g/m2.7 in CKD5 versus 5.7±7.9 g/m2.7, p=0.044 in non-CKD5, predominantly due to increased interventricular septal wall thickness (7.7±5.5 mm vs 1.3±1.7 mm, p=0.003). Cardiovascular events, including sudden death, arrhythmia and pacing device insertion, occurred in 100% patients with CKD5 (21 events) and 26% non-CKD5 patients (7 events), p<0.0001. Additionally, estimated LV filling pressure (E/Ea) was significantly higher in patients having cardiovascular events (21.1±7.7 vs 12.5±4.5, p=0.008) irrespective of renal function. Conclusions End-stage renal disease was the strongest indicator of cardiovascular disease progression in Fabry disease. Enzyme replacement initiated prior to CKD5 was associated with stability in cardiac and renal disease while patients with CKD5 showed ongoing deterioration. Additionally, E/Ea ≥15 may predict risk of cardiac events.
Spiral precipitation patterns in confined chemical gardens

Significance Chemical gardens are plant-like mineral forms existing in nature at various scales. Even though they have been described for more than three centuries thanks to their beauty and analogies with biological forms, their growth mechanisms remain largely not understood. To gain insight into their formation processes, we develop an innovative strategy to study these systems in which chemical gardens grow in a quasi-2D confined geometry upon injecting one reagent solution into the other. The advantage of this procedure over previous works is to allow studying, in controlled and reproducible conditions, the effects of variable concentrations and injection rates on the selected morphology. Chemical gardens are mineral aggregates that grow in three dimensions with plant-like forms and share properties with self-assembled structures like nanoscale tubes, brinicles, or chimneys at hydrothermal vents. The analysis of their shapes remains a challenge, as their growth is influenced by osmosis, buoyancy, and reaction–diffusion processes. Here we show that chemical gardens grown by injection of one reactant into the other in confined conditions feature a wealth of new patterns including spirals, flowers, and filaments. The confinement decreases the influence of buoyancy, reduces the spatial degrees of freedom, and allows analysis of the patterns by tools classically used to analyze 2D patterns. Injection moreover allows the study in controlled conditions of the effects of variable concentrations on the selected morphology. We illustrate these innovative aspects by characterizing quantitatively, with a simple geometrical model, a new class of self-similar logarithmic spirals observed in a large zone of the parameter space.
Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC). Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate). Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P = 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P = 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P = 0.0089 and P = 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/BRAF-mutant cohort of patients (P = 0.0052) and appeared as a strong independent prognostic factor (P = 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P = 0.67). Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment. Clin Cancer Res; 22(12); 3067–77. ©2016 AACR.
Effect of Impairment‐Testing Disclosures on the Cost of Equity Capital

Information risk – the uncertainty regarding the parameters of the distribution of firms’ future cash flows – generates valuation errors and is costly to investors who require a higher return to compensate for greater information risk. We argue that, on average, through their impairment‐testing disclosures, managers convey information that reduces information risk. Using disclosures from firms included in the SBF 250 index of Euronext Paris over the period 2006–2009, we document a negative association between impairment‐testing disclosures and implied cost of equity capital. We find that prospective entity‐specific impairment‐testing disclosures are negatively associated with cost of capital whereas descriptive disclosures exhibit no association with cost of capital. Additionally, we document that firms which avoid booking impairments when low performance indicators suggest a greater likelihood of impairments exhibit no association between impairment‐testing disclosures and cost of capital. This suggests that those firms’ disclosures are perceived as less accurate by investors. We also find that prospective impairment‐testing disclosures are negatively related to analysts’ forecast errors. Our study adds to the literature on the economic consequences of financial reporting and sheds light on the consequences of one accounting mechanism, namely impairment‐testing disclosures, ensuring conservatism of financial reporting.
Differences in the response heterogeneity of educational attainment and achievement to the same instrumental variable

ABSTRACT The typical econometric application of instrumental variable (IV) estimates imposes a constant-treatment-effect model for all individuals. Using regression discontinuity design, we find while older school starters tend to have lower educational attainment, they are more likely to achieve qualifications at different educational levels for the UK. This finding joins the discussion on instruments for educational outcomes by offering some evidence that school starting age can affect treated individuals diversely. We highlight that identifying the treatment effect with methods similar to IV estimates should be concerned in the context of heterogeneous treatments; that is, the instrument in question has an effect on treatment for particular subpopulations only, and those subpopulations may not be the same for different treatments.
The choice of role models by students at a culturally diverse South African medical school

Role models have long been considered important in training medical students in the professional and ethical values of medicine. This report discusses role models identified by South African medical students in Years 1–5 of their study in a traditional programme. Most students considering having a role model important. As students progressed, faculty role models were more likely to be selected. A parent (the mother, in particular) or parents were, however, most frequently identified as role models by all students. Attributes ascribed to parents as role models (caring, sympathetic, self-sacrificing) are similar to those considered desirable for professional role models in medicine. These findings are considered in the light of global medical training and the need for faculties to provide appropriate role models for students.
Differential wiring of local excitatory and inhibitory synaptic inputs to islet cells in rat spinal lamina II demonstrated by laser scanning photostimulation

The substantia gelatinosa (lamina II) of the spinal dorsal horn contains inhibitory and excitatory interneurons that are thought to play a critical role in the modulation of nociception. However, the organization of the intrinsic circuitry within lamina II remains poorly understood. We used glutamate uncaging by laser scanning photostimulation to map the location of neurons that give rise to local synaptic inputs to islet cells, a major class of inhibitory interneuron in lamina II. We also mapped the distribution of sites on the islet cells that exhibited direct (non‐synaptic) responses to uncaging of excitatory and inhibitory transmitters. Local synaptic inputs to islet cells arose almost entirely from within lamina II, and these local inputs included both excitatory and inhibitory components. Furthermore, there was a striking segregation in the location of sites that evoked excitatory versus inhibitory synaptic inputs, such that inhibitory presynaptic neurons were distributed more proximal to the islet cell soma. This was paralleled in part by a differential distribution of transmitter receptor sites on the islet cell, in that inhibitory sites were confined to the peri‐somatic region while excitatory sites were more widespread. This differential organization of excitatory and inhibitory inputs suggests a principle for the wiring of local circuitry within the substantia gelatinosa.
Internalized Timing of Isochronous Sounds Is Represented in Neuromagnetic Beta Oscillations

Moving in synchrony with an auditory rhythm requires predictive action based on neurodynamic representation of temporal information. Although it is known that a regular auditory rhythm can facilitate rhythmic movement, the neural mechanisms underlying this phenomenon remain poorly understood. In this experiment using human magnetoencephalography, 12 young healthy adults listened passively to an isochronous auditory rhythm without producing rhythmic movement. We hypothesized that the dynamics of neuromagnetic beta-band oscillations (∼20 Hz)—which are known to reflect changes in an active status of sensorimotor functions—would show modulations in both power and phase-coherence related to the rate of the auditory rhythm across both auditory and motor systems. Despite the absence of an intention to move, modulation of beta amplitude as well as changes in cortico-cortical coherence followed the tempo of sound stimulation in auditory cortices and motor-related areas including the sensorimotor cortex, inferior-frontal gyrus, supplementary motor area, and the cerebellum. The time course of beta decrease after stimulus onset was consistent regardless of the rate or regularity of the stimulus, but the time course of the following beta rebound depended on the stimulus rate only in the regular stimulus conditions such that the beta amplitude reached its maximum just before the occurrence of the next sound. Our results suggest that the time course of beta modulation provides a mechanism for maintaining predictive timing, that beta oscillations reflect functional coordination between auditory and motor systems, and that coherence in beta oscillations dynamically configure the sensorimotor networks for auditory-motor coupling.
A Systematic Approach to Analysing Gene-Gene Interactions: Polymorphisms at the Microsomal Epoxide Hydrolase EPHX and Glutathione S-transferase GSTM1, GSTT1, and GSTP1 Loci and Breast Cancer Risk

Objective: We undertook a case-control study in an Australian Caucasian population-based sample of 1,246 cases and 664 controls to assess the roles of detoxification gene polymorphisms EPHX T>C Tyr113His, GSTT1 deletion, GSTM1 deletion, and GSTP1 A>G Ile105Val on risk of breast cancer. Methods: We systematically addressed the main effects and possible gene-gene interactions using unconditional logistic regression to estimate odds ratios (OR) adjusted for potential confounders and using standard model building approaches based on likelihood theory. Results: There was a decreased risk associated with the EPHX CC genotype [OR, 0.60; 95% confidence interval (95% CI), 0.43-0.84; P = 0.003], marginally significant evidence of increased risk with GSTM1 null genotype (OR, 1.21; 95% CI, 1.00-1.47; P = 0.05), but no association with GSTT1 null genotype (OR, 1.12; 95% CI, 0.86-1.45; P = 0.4) or GSTP1 (OR, 0.95; 95% CI, 0.82-1.10; P = 0.5) genotype. The full model with all interactions gave a significantly better fit than a main-effects-only model (P < 0.001), providing evidence for gene-gene interactions. The most parsimonious model included main effects for EPHX, GSTT1, and GSTM1; a two-way interaction between EPHX and GSTM1; and a three-way interaction between EPHX, GSTM1, and GSTT1. Predicted risks were greatest for women carrying deletions of both GSTT1 and GSTM1, with either the EPHX TC genotype (OR, 2.02; 95% CI, 1.19-3.45; P = 0.009) or EPHX CC genotype (OR, 3.54; 95% CI, 1.29-9.72; P = 0.14). Conclusion: Detoxification gene polymorphisms may interact with each other to result in small groups of individuals at modestly increased risk. We caution against overinterpretation and suggest that pooling of similarly large studies is needed to clarify the possible role of such complex gene-gene interactions on breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):769–74)
Hip protectors for preventing hip fractures in older people.

BACKGROUND Hip fracture in older people usually results from a fall on the hip. Hip protectors have been advocated as a means to reduce the risk of hip fracture. OBJECTIVES To determine if external hip protectors reduce the incidence of hip fractures in older people following a fall. SEARCH STRATEGY We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (January 2010), The Cochrane Library 2010, Issue 2, MEDLINE (1950 to November 2009), MEDLINE in-process (30 December 2009), EMBASE (1988 to 2009 week 52), CINAHL (1982 to February 2009), BioMed Central (January 2010) and reference lists of relevant articles. SELECTION CRITERIA All randomised or quasi-randomised controlled trials comparing the use of hip protectors with an unprotected control group. DATA COLLECTION AND ANALYSIS Two authors independently assessed risk of bias and extracted data. We sought additional information from trialists. Data were pooled using fixed-effect or random-effects models as appropriate. MAIN RESULTS Pooling of data from 13 studies (11,573 participants) conducted in nursing or residential care settings found a marginally significant reduction in hip fracture risk (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.66 to 0.99); statistical significance was lost following exclusion of five studies (3757 participants) assessed at high risk of bias (RR 0.93, 95% CI 0.74 to 1.18). Pooling of data from three trials (5135 community-dwelling participants) showed no evidence of reduction in hip fracture risk (RR 1.14, 95% CI 0.83 to 1.57). There was no evidence of a statistically significant effect on incidence of pelvic or other fractures, or on rate of falls. No important adverse effects of the hip protectors were reported but adherence, particularly in the long term, was poor. AUTHORS' CONCLUSIONS The effectiveness of the provision of hip protectors in reducing the incidence of hip fracture in older people is still not clearly established, although they may reduce the rate of hip fractures if made available to frail older people in nursing care. It remains unknown from studies identified to date if these findings apply to all types of hip protectors. Some cluster-randomised trials have been associated with high risk of bias. Poor acceptance and adherence by older people offered hip protectors have been key factors contributing to the continuing uncertainty.
Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation

Human-induced pluripotent stem cells (hiPSCs) are generated from somatic cells by ectopic expression of the 4 reprogramming factors (RFs) Oct-4, Sox2, Klf4, and c-Myc. To better define the stoichiometric requirements and dynamic expression patterns required for successful hiPSC induction, we generated 4 bicistronic lentiviral vectors encoding the 4 RFs co-expressed with discernable fluorescent proteins. Using this system, we define the optimal stoichiometry of RF expression to be highly sensitive to Oct4 dosage, and we demonstrate the impact that variations in the relative ratios of RF expression exert on the efficiency of hiPSC induction. Monitoring of expression of each individual RF in single cells during the course of reprogramming revealed that vector silencing follows acquisition of pluripotent cell markers. Pronounced lentiviral vector silencing was a characteristic of successfully reprogrammed hiPSC clones, but lack of complete silencing did not hinder hiPSC induction, maintenance, or directed differentiation. The vector system described here presents a powerful tool for mechanistic studies of reprogramming and the optimization of hiPSC generation.
PERBANDINGAN EFEKTIVITAS HEDGING KONTRAK FUTURES KOMODITI EMAS DENGAN OLEIN

Penelitian ini bertujuan untuk melakukan perbandingkan efektivitas hedging pada komoditi emas dan olein. Dengan menggunakan model Ordinary Least Square (OLS) untuk menentukan nilai rasio hedge, ditemukan bahwa nilai rasio hedge olein lebih besar dibandingkan dengan nilai rasio hedge emas. Nilai rasio hedge olein yang lebih besar daripada rasio hedge emas menunjukkan bahwa untuk mengeleminasi kerugian komoditi olein di pasar fisik diperlukan sejumlah kontrak yang lebih besar dibandingkan jika mengeleminasi kerugian komoditi emas di pasar fisik. Namun, hasil uji-t independent terhadap varians return hedged kedua komoditi menunjukkan tidak adanya perbedaan varians. Hal ini mengindikasikan bahwa varians return dari hedged komoditi emas sama dengan varians return hedged komoditi olein. Sehingga penanganan risiko sistimatis yang dihadapi oleh hedger olein sama efektivnya dengan hedger emas. Apabila dalam melakukan strategi hedging tidak tersedia instrumen yang sama dengan aset yang di hedge, maka hedger dapat mempertimbangkan untuk melakukan strategi cross hedging dengan terlebih dahulu menentukan rasio hedge yang optimal antara aset yang akan di hedge dengan instrumen hedgenya, karena dengan rasio hedge yang optimal akan dapat menurunkan tingkat varians return yang diakibatkan dari risiko pasar (systematic risk).