Miracle-dz/UniFAR-FTUs huggingface dataset:
Bovine and Human Insulin Activate CD8+-Autoreactive CTL Expressing Both Type 1 and Type 2 Cytokines in C57BL/6 Mice1

CD8+ T cells down-regulate a variety of immune responses. For example, porcine and human insulin do not stimulate Abs in C57BL/6 mice because CD8+ T cells inhibit CD4+ helper T cells. By contrast, bovine insulin induces Ab in C57BL/6 mice, and removal of CD8+ T cells does not alter this response. This raises the question of whether porcine, but not bovine, insulin activates CD8+ T cells or whether both insulins activate CD8+ T cells but CD4+ helper T cells are differentially inhibited by them. In this study, we show that insulin-specific CD8+ CTL can be cultured from C57BL/6 mice primed with either bovine or human insulin in CFA. Thus, exogenous Ags, besides OVA, induce CD8+ CTL when administered in an adjuvant, suggesting this is a typical response. These CTL are H-2Kb restricted and produce IL-5, IL-10, IFN-γ, and small amounts of IL-4, which is distinct from IFN-γ and TNF-α that are typically secreted by virus-specific CTL. Moreover, the CTL primed with either bovine or human insulin recognize an A-chain peptide that is identical to the mouse insulin sequence. That foreign proteins, which are closely related to self-proteins, activated autoreactive, CD8+ T cells in vivo is a novel finding. It raises the possibility that self-reactive CTL may be activated by cross-reacting Ags and once activated they might participate in autoimmunity. These results also suggest that down-regulation of insulin-specific responses by autoreactive CD8+ T cells is most likely due to the differential sensitivity of bovine and human insulin-specific CD4+ T cells.
Retinoic acid suppresses interleukin 6 production in normal human osteoblasts.

Systemic long-term retinoid therapy for chronic skin diseases significantly reduced bone turnover markers within days and led to bone abnormalities. Retinoic acid (RA) plays a key role in the regulation of mouse bone cell proliferation, differentiation and functions. Meanwhile, there is little information of RA effect on human osteoblast and osteoclast cell development and function. Interleukin 6 (IL-6) is a pleiotropic cytokine with profound effects on bone metabolism. Thus, the present study examined the RA effect on cell differentiation, alkaline phosphatase and osteocalcin production as well as IL-6 production in normal human osteoblasts. The number of large differentiated osteoblast cells decreased in RA-treated cultures P<0.05. The production of bone specific markers, alkaline phosphatase and osteocalcin, was also reduced in RA-treated cultures. Normal human osteoblasts produced 31.0+/-4.8 pg IL-6 per ml in control cultures. Within 24 h, RA at all four concentrations reduced Il-6 production from normal human osteoblasts. The pharmacological concentration of 10(-5) M RA suppressed 90% of IL-6 production. The present study shows for the first time that RA profoundly inhibits IL-6 production in normal human osteoblasts within 24 h and in a dose-dependent manner. RA was shown previously to inhibit IL-6 production in several other normal and malignant human cell types. The associated decrease in osteoblast cell differentiation, alkaline phosphatase and osteocalcin production could result from the rapid RA-inhibition of IL-6 production. Thus, RA inhibition of IL-6 production in normal human osteoblasts may contribute to the bone abnormalities seen after systemic long-term retinoid therapy in some patients.
Global Analysis Reveals the Crucial Roles of DNA Methylation during Rice Seed Development1[OPEN]

DNA methylome dynamics show crucial roles for DNA methylation in seed development. Seed development is an important process of reproductive development and consists of embryo and endosperm development; both comprise several key processes. To determine and investigate the functions of the dynamic DNA methylome during seed development, we profiled the DNA methylation genome wide in a series of developmental stages of rice (Oryza sativa) embryo and endosperm by methylcytosine immunoprecipitation followed by Illumina sequencing. The results showed that embryo is hypermethylated predominantly around non-transposable element (TE) genes, short DNA-TEs, and short interspersed TEs compared with endosperm, and non-TE genes have the most diverse methylation status across seed development. In addition, lowly expressed genes are significantly enriched in hypermethylated genes, but not vice versa, confirming the crucial role of DNA methylation in suppressing gene transcription. Further analysis revealed the significantly decreased methylation at early developing stages (from 2 to 3 d after pollination), indicating a predominant role of demethylation during early endosperm development and that genes with a consistent negative correlation between DNA methylation change and expression change may be potentially directly regulated by DNA methylation. Interestingly, comparative analysis of the DNA methylation profiles revealed that both rice indica and japonica subspecies showed robust fluctuant profiles of DNA methylation levels in embryo and endosperm across seed development, with the highest methylation level at 6 d after pollination (2 d after pollination of endosperm in japonica as well), indicating that a complex and finely controlled methylation pattern is closely associated with seed development regulation. The systemic characterization of the dynamic DNA methylome in developing rice seeds will help us understand the effects and mechanism of epigenetic regulation in seed development.
Theobald Palm and His Remarkable Observation: How the Sunshine Vitamin Came to Be Recognized

The seminal discovery that sunlight was important in the prevention of nutritional rickets was made in 1890 by Theobald A. Palm, a medical missionary who contrasted the prevalence of rickets in northern European urban areas with similar areas in Japan and other tropical countries. He surmised that exposure to sunlight prevented rickets. Over the next 40 years his observation led to an understanding of ultraviolet irradiation and its role in vitamin D synthesis. This opened a new era of appreciation for the curative powers of the sun and “the sunshine vitamin”. While Palm’s observations were in some ways obscure, they had a potent effect on the development of photobiology.
Biomarker-related risk for myocardial infarction and serious infections in patients with rheumatoid arthritis: a population-based study

Background Rheumatoid arthritis (RA) disease activity and associated systemic inflammation has been associated with serious infection (SIEs), myocardial infarction (MI) and coronary heart disease (CHD) events based on a few registry studies or clinical trials. There are few data from large-scale population-based studies given feasibility challenges in conducting such investigations. Methods Multibiomarker disease activity (MBDA) test scores (n=77 641) were linked to Medicare for US patients with RA. Outcomes of interest were hospitalised pneumonia/sepsis (SIE), MI and a composite CHD outcome. The MBDA score ranges from 1 to 100 and was analysed as time-varying. Cox proportional hazards models evaluated the association between MBDA score and SIEs, MI and CHD events, controlling for potential confounders. A sensitivity analysis excluded C reactive protein (CRP) from the MBDA score. Results There were 17 433 and 16 796 patients eligible for the SIE and MI/CHD analyses, respectively. Mean (SD) age was 69 (11) years, 79% were women, 81% were white and 38% were disabled. Over 16 424 person-years of follow-up, there were 452 SIE events, 132 MIs and 181 CHD events. Higher MBDA scores were associated with SIEs (HR=1.32, 95% CI 1.23 to 1.41 per 10 unit MBDA score change). For MI/CHD events, a threshold effect was present; higher disease activity by MBDA score was associated with increased MI (HR=1.52, 95% CI 0.92 to 2.49) and CHD rates (HR=1.54, 95% CI 1.01 to 2.34, comparing scores ≥30 vs <30). Analyses of the MBDA score without CRP yielded similar results. Conclusion Higher MBDA scores were associated with hospitalised infection, MI and CHD events in a large, predominantly older, US RA population.
Early Induction of Humoral and Cellular Immune Responses during Experimental Mycobacterium avium subsp. paratuberculosis Infection of Calves

ABSTRACT Johne's disease (paratuberculosis) of cattle is widespread and causes significant economic losses for producers due to decreased production and poor health of affected animals. The chronic nature of the disease and the lack of a reproducible model of infection hinder research efforts. In the present study, instillation of Mycobacterium avium subsp. paratuberculosis into the tonsillar crypts of neonatal calves resulted in peripheral colonization as detected by antemortem culture of feces and postmortem (320 days postchallenge) culture of intestinal tissues. Antigen-specific blastogenic, gamma interferon (IFN-γ), and nitric oxide responses by blood mononuclear cells from infected calves exceeded prechallenge responses beginning 194 days postchallenge. Upon in vitro stimulation with paratuberculosis antigens, CD4+ cells from infected calves proliferated, produced IFN-γ, and increased expression of CD26 and CD45RO (indicative of an activated memory phenotype). Utilizing a lipoarabinomannan-based enzyme-linked immunosorbent assay, specific serum immunoglobulin was detected as early as 134 days postchallenge and generally increased after this time point. Two antigens of ∼50 and ∼60 kDa were particularly immunodominant early in infection, as shown by immunoblot with serum collected within 2 weeks postchallenge. Findings indicate that the intratonsillar inoculation route will prove useful as an experimental model for paratuberculosis infection. Additionally, this study confirms that mycobacteria-specific antibody is detectable early in the course of experimental Johne's disease, even preceding the development of specific cell-mediated responses.
Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity—results from the ENCOURAGE study, a prospective, international, multicenter randomized study

Abstract Objectives: To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission. Methods: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2). Results: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation. Conclusions: ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.
Isolation and cloning of Omp alpha, a coiled‐coil protein spanning the periplasmic space of the ancestral eubacterium Thermotoga maritima.

We have discovered a new oligomeric protein component associated with the outer membrane of the ancestral eubacterium Thermotoga maritima. In electron micrographs, the protein, Omp alpha, appears as a rod‐shaped spacer that spans the periplasm, connecting the outer membrane to the inner cell body. Purification, biochemical characterization and sequencing of Omp alpha suggest that it is a homodimer composed of two subunits of 380 amino acids with a calculated M(r) of 43,000 and a pI of 4.54. The sequence of the omp alpha gene indicates a tripartite organization of the protein with a globular NH2‐terminal domain of 64 residues followed by a putative coiled‐coil segment of 300 residues and a COOH‐terminal, membrane‐spanning segment. The predicted length of the coiled‐coil segment (45 nm) correlates closely with the spacing between the inner and outer membranes. Despite sequence similarity to a large number of coiled‐coil proteins and high scores in a coiled‐coil prediction algorithm, the sequence of the central rod‐shaped domain of Omp alpha does not have the typical 3.5 periodicity of coiled‐coil proteins but rather has a periodicity of 3.58 residues. Such a periodicity was also found in the central domain of staphylococcal M protein and beta‐giardin and might be indicative of a subclass of fibrous proteins with packing interactions that are distinct from the ones seen in other two‐stranded coiled‐coils.
Cpx‐dependent expression of YqjA requires cations at elevated pH

Abstract Under alkaline pH conditions, Escherichia coli must maintain a stable cytoplasmic pH of about 7.6 that is acidic relative to the environment. Bacteria employ various mechanisms to survive alkaline pH; however, membrane cation/H+ antiporters play a primary role by facilitating inward transport of protons. Escherichia coli YqjA belongs to the DedA/Tvp38 membrane protein family and, along with its paralog YghB, is required for growth at 42°C, proper cell division and antibiotic resistance. YqjA is required for viability at alkaline pH, requiring cations sodium or potassium to support growth under these conditions, suggesting it may be a transporter. We measured yqjA expression at different pHs and cation concentrations using a yqjA promoter‐lacZ fusion. We found that yqjA promoter activity was highest at alkaline pH. Increased activity of the yqjA promoter required both the transcriptional regulator CpxR, in agreement with previous results, and sodium or potassium salts at alkaline pH. Extracellular cations are also required for activity of cpxP and degP promoters at alkaline pH, suggesting this is a general property of the Cpx regulon. To our knowledge, this is the first demonstration of cation‐dependent expression of Cpx‐regulated genes at alkaline pH.
The WHO-DAS II: Measuring Outcomes of Hearing Aid Intervention for Adults

The World Health Organization's Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument that provides six domain scores and a total, aggregate score. Two of the domain scores, communication and participation, and the total score, have good validity, internal-consistency reliability, and test-retest stability in individuals with adult-onset hearing loss. As such, these two domain scores and the total WHO-DAS II score may be useful as generic outcome measures to assess the effectiveness of hearing aid intervention for this population. Before the use of the WHO-DAS II in hearing aid clinical trials, however, the responsiveness of the instrument and the short- and long-term outcomes to hearing aid intervention had to be determined. Responsiveness and outcomes were assessed in 380 veterans (approximately half received hearing aids and half served as controls) by examining group differences, effect-size estimates, and individual differences as a function of hearing aid intervention. For comparison, data also were obtained on two disease-specific measures, the APHAB and the HHIE. The WHO-DAS II communication domain and total scores were sufficiently responsive to hearing aid intervention for use in future studies in which group differences are to be detected. The WHO-DAS II participation domain was not sufficiently responsive to hearing aid intervention. The APHAB and HHIE, both disease-specific measures, were more sensitive to hearing aid intervention than the generic measure. The short- and long-term outcomes of hearing aid intervention were also examined in the present study. Group outcomes for hearing aid intervention can be expected to be stable for at least 6 months when measured by WHO-DAS II total score and for at least 12 months when measured by the WHO-DAS II communication domain scores. Effect-size estimates and examination of the number of individuals exhibiting change scores exceeding 90% critical differences for true changes in scores indicate that for clinical applications, disease-specific instruments are more useful than the WHO-DAS II. The findings of this study support the use of the WHO-DAS II as a generic measure in hearing aid trials research so as to allow for comparisons of health-status outcomes across different diseases or disorders.
An essential role of the neuronal cell adhesion molecule contactin in development of the Xenopus primary sensory system.

Contactin is a glycosylphosphatidylinositol-anchored immunoglobulin-like neuronal cell adhesion molecule that has been implicated in cellular interaction during development of the vertebrate central nervous system. Here we report evidence for an essential role of contactin in development of the Xenopus nervous system. Contactin mRNA is detectable by in situ hybridization in subsets of neurons in the brain, primary sensory neurons in the spinal cord, and cells along the trigeminal nerves of tailbud embryos. Contactin immunoreactivities preferentially distribute on axon tracts of the brain, the spinal cord, and the trigeminal sensory nerves. Most prominently, cell bodies and peripheral and spinal axons of primary sensory neurons, Rohon-Beard (RB) cells, are strongly contactin positive. Injection of the contactin overexpression vector into one blastomere of two-cell stage embryos leads to misdirected elongation of the peripheral axons of RB neurons in the injected half. Overexpression of antisense transcript causes depletion of contactin mRNA accumulation and abnormal development of RB neurons. In 52.3% of the injected embryos, RB neurons decrease in number and their peripheral axons in dorsal lateral tracts are defasciculated. These results demonstrate that contactin plays an essential role in development of the Xenopus primary sensory system.
Temporal mapping of CEBPA and CEBPB binding during liver regeneration reveals dynamic occupancy and specific regulatory codes for homeostatic and cell cycle gene batteries

Dynamic shifts in transcription factor binding are central to the regulation of biological processes by allowing rapid changes in gene transcription. However, very few genome-wide studies have examined how transcription factor occupancy is coordinated temporally in vivo in higher animals. Here, we quantified the genome-wide binding patterns of two key hepatocyte transcription factors, CEBPA and CEBPB (also known as C/EBPalpha and C/EBPbeta), at multiple time points during the highly dynamic process of liver regeneration elicited by partial hepatectomy in mouse. Combining these profiles with RNA polymerase II binding data, we find three temporal classes of transcription factor binding to be associated with distinct sets of regulated genes involved in the acute phase response, metabolic/homeostatic functions, or cell cycle progression. Moreover, we demonstrate a previously unrecognized early phase of homeostatic gene expression prior to S-phase entry. By analyzing the three classes of CEBP bound regions, we uncovered mutually exclusive sets of sequence motifs, suggesting temporal codes of CEBP recruitment by differential cobinding with other factors. These findings were validated by sequential ChIP experiments involving a panel of central transcription factors and/or by comparison to external ChIP-seq data. Our quantitative investigation not only provides in vivo evidence for the involvement of many new factors in liver regeneration but also points to similarities in the circuitries regulating self-renewal of differentiated cells. Taken together, our work emphasizes the power of global temporal analyses of transcription factor occupancy to elucidate mechanisms regulating dynamic biological processes in complex higher organisms.
Pengetahuan berhubung hak-hak pengguna semasa berurusan dengan bengkel kenderaan

Perlindungan pengguna lahir daripada penindasan dan penyelewengan peniaga terhadap pengguna. Menurut Mohd Hamdan (2005), perlindungan pengguna yang berkesan perlu berasaskan undang-undang negara dan satu dasar pengguna yang menyeluruh dan terkini. Tahap pendidikan pengguna yang tinggi dan perlindungan undang-undang yang mencukupi merupakan gabungan yang ideal bagi menjamin satu perlindungan pengguna yang berkesan. Pengguna diharap untuk lebih bertanggungjawab dan sedia untuk tampil ke hadapan bagi membuat aduan terhadap sesuatu penyelewengan yang berlaku semasa berurusan dengan peniaga dan pembekal. Pengguna bijak, berani dan proaktif mestilah mengetahui hak-hak mereka dan sedia untuk mempertahankan hak-hak tersebut.
On the mechanism of 4‐aminopyridine action on the cloned mouse brain potassium channel mKv1.1.

1. This study used the whole‐cell patch clamp technique to investigate the mechanism of action of the K+ channel blocker 4‐aminopyridine (4‐AP) on the cloned K+ channel mouse Kv1.1 (mKv1.1) expressed in Chinese hamster ovary cells. 2. Cells transfected with mKv1.1 expressed a non‐inactivating, delayed rectifier‐type K+ current. 4‐AP induced a dose‐, voltage‐ and use‐dependent block of mKv1.1. 3. 4‐AP blockade of mKv1.1 was similar whether 4‐AP was administered extracellularly (IC50 = 147 microM) or intracellularly (IC50 = 117 microM). 4. Inclusion of the first twenty amino acids of the N‐terminus sequence of the Shaker B K+ channel (‘inactivation peptide’) in the patch electrode transformed mKv1.1 into a rapidly inactivating current. The time constant of decay for the modified current was dependent on the concentration of inactivation peptide, and under these conditions extracellular 4‐AP had a reduced potency (IC50 values of 471 and 537 microM for 0.5 and 2 mg ml‐1 inactivation peptide, respectively). 5. A permanently charged analogue of 4‐AP, 4‐aminopyridine methiodide (4‐APMI), was found to block mKv1.1 when applied inside the cell, but was without effect when administered externally. 6. Decreasing the intracellular pH (pHi) to 6.4 caused an increase in 4‐AP potency (IC50 = 76 microM), whereas at pHi 9.0, the 4‐AP potency fell (IC50 = 295 microM). Conversely, increasing extracellular pH (pHo) to 9.0 caused an increase in 4‐AP potency (IC50 = 93 microM), whereas at pHo 6.4, 4‐AP potency decreased (IC50 = 398 microM). 7. Taken together, these findings support the hypotheses that the uncharged form of 4‐AP crosses the membrane, and that it is predominantly the cationic form which acts on mKv1.1 channels intracellularly, possibly at or near to the binding site for the inactivation peptide.