SummaryThe mechanisms underlying the silencing of alternative fate potentials in very early B cell precursors remain unclear. Using gain- and loss-of-function approaches together with a synthetic Zinc-finger polypeptide (6ZFP) engineered to prevent transcription factor binding to a defined cis element, we show that the transcription factor EBF1 promotes B cell lineage commitment by directly repressing expression of the T-cell-lineage-requisite Gata3 gene. Ebf1-deficient lymphoid progenitors exhibited increased T cell lineage potential and elevated Gata3 transcript expression, whereas enforced EBF1 expression inhibited T cell differentiation and caused rapid loss of Gata3 mRNA. Notably, 6ZFP-mediated perturbation of EBF1 binding to a Gata3 regulatory region restored Gata3 expression, abrogated EBF1-driven suppression of T cell differentiation, and prevented B cell differentiation via a GATA3-dependent mechanism. Furthermore, EBF1 binding to Gata3 regulatory sites induced repressive histone modifications across this region. These data identify a transcriptional circuit critical for B cell lineage commitment.

Pro-and eukaryotic algal genera, i.e. Lyngbya majuscula, Spirulina subsalsa (Cyanophyceae) and Rhizoclonium hieroglyphicum (Chlorophyceae), were used for bio-recovery of gold (Au) out of aqueous solution. Au (III) spiked with 198 Au was used for the experiment. Batch laboratory experiments indicated quick metabolic independent binding of Au to the algae followed by active accumulation and subsequent reduction. Gold accumulation by different algal genera was found in order of R. hieroglyphicum > L. majuscula > S. subsalsa (3.28, 1.93 and 1.73 mg g -1 , respectively). It was observed that the algal biomass and the media used for the experiment turned purple in colour indicating reduction of Au (III) to Au (0) at intra-and extracellular level. This was confirmed by TEM studies of L. majuscula biomass exposed in HAuCl 4 solution where <20-nm-sized gold particles were found both inside as well as on the surface of the cell. Up to 90-100% of accumulated gold was recovered from the algal biomass by using nitric acid and acidic thiourea solution.

What governs the increased apoptosis sensitivity of HIV-specific CD8 ؉ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8 ؉ T cells from HIV ؉ patients and this could not be attributed to their different differentiation status. MM High phenotype characterized those CD8 ؉ T cells from HIV ؉ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38 ؉ and CD38 ؊ HIVspecific CD8 ؉ T cells. Although CD38 ؉ HIV-specific CD8 ؉ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8 ؉ T cells, as CD38 ؊ HIV-specific CD8 ؉ T cells were more apoptotic than CD38 ؉ CMV-specific ones. Proapoptotic HIVspecific CD8 ؉ T cells were CD38 ؉ Bcl-2 Low MM High . Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8 ؉ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8 ؉ T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8 ؉ T cells. IntroductionCD8 ϩ T-cell response is a critical player for controlling HIV infection and AIDS progression. 1,2 However, HIV-specific CD8 ϩ T cells ultimately fail to control the virus. Various mechanisms related either to HIV-infected cells or to intrinsic defects in CD8 ϩ T cells themselves have been proposed to explain this failure. [3][4][5] Among others, apoptosis of HIV-specific CD8 ϩ T cells has been suggested as a strategy employed by HIV to evade the immune system. 6,7 What governs this apoptosis sensitivity, however, remains to be elucidated.CD8 ϩ T cells from HIV-infected patients are susceptible to spontaneous and CD95/Fas-induced apoptosis. [8][9][10] We recently found HIVspecific CD8 ϩ T cells to be highly sensitive to apoptosis 11 whereas this is not the case for CMV-specific CD8 ϩ T cells from HIV ϩ individuals. 11 This sensitivity is associated with a remarkable down-regulation of Bcl-2 and Bcl-xL antiapoptotic molecules, 12 suggesting a role of mitochondria in this apoptotic process. Several studies have revealed a mitochondrial dysfunction in T cells during HIV infection. 13,14 CD95/ Fas cross-linking initiates a complex signaling process involving CD95/Fas capping and formation of death-inducing signaling complex (DISC), 15,16 ultimately leading to activation of the executor caspase-3 directly by caspase-8 or through mitochondrial-secreted proapoptotic factors. 17 The cross-talk of these 2 pathways in apoptosis of primary T cells, particularly in CD8 ϩ T cells from HIV ϩ patients, is currently unknown. Furthermore, no studies have addressed the role and impact of ...

The magnetic and phonon properties of polycrystalline magnetoelectric/multiferroic GaFeO(3) are studied. Using high field (57)Fe Mossbauer spectroscopy, occupation of Fe is observed at four cation sites. A Fe population of about 6% is observed at the tetrahedral Ga1 site, which explains the observed pinched-like M-H curve and initial sharp increase of the magnetization. The calculated net magnetization value from Mossbauer data suggests that the Fe moment at the Ga1 site is parallel to Fe1 and opposite to that of Fe2 and Ga2 sites, resulting in ferrimagnetism. From low temperature Raman data, anomalous temperature variation in frequency at T(C) is observed for the mode at ∼700 cm(-1).

About one third of acquired immunodeficiency syndrome cases in the USA have been attributed to the use of injected addictive drugs, frequently involving opioids like heroin and morphine, establishing them as significant predisposing risk factors for contracting human immuno-deficiency virus type 1 (HIV-1). Accumulating evidence from in vitro and in vivo experimental systems indicates that opioids act in concert with HIV-1 proteins to exacerbate dysregulation of neural and immune cell function and survival through diverse molecular mechanisms. In contrast, the impact of opioid exposure and withdrawal on the viral life cycle and HIV-1 disease progression itself is unclear, with conflicting reports emerging from the simian immunodeficiency virus and simian–human immunodeficiency virus infection models. However, these studies suggest a potential role of opioids in elevated viral production. Because human microglia, astrocytes, CD4+ T lymphocytes, and monocyte-derived macrophages express opioid receptors, it is likely that intracellular signaling events triggered by morphine facilitate enhancement of HIV-1 infection in these target cell populations. This review highlights the biochemical changes that accompany prolonged exposure to and withdrawal from morphine that synergize with HIV-1 proteins to disrupt normal cellular physiological functions especially within the central nervous system. More importantly, it collates evidence from epidemiological studies, animal models, and heterologous cell systems to propose a mechanistic link between such physiological adaptations and direct modulation of HIV-1 production. Understanding the opioid–HIV-1 interface at the molecular level is vitally important in designing better treatment strategies for HIV-1-infected patients who abuse opioids.

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Background:Musculoskeletal disorders (MSD) are the major cause of morbidity throughout the world, having a substantial influence on quality of life (QOL). We studied QOL ascertained by limitations of activities of daily living, impact on family and social relationships, and sleep disturbances among patients with MSD.Aim:Ascertain QOL in MSD.Materials and Methods:A cross-sectional study among 2633 randomly selected subjects. The study was carried out in the field practice area of D Y Patil Medical College, Pune, India. In the first phase of the study, patients of MSD were identified by house-to-house surveys, by face-to-face interviews, and clinical examination carried out by trained interns in random samples of selected households. Subsequently, QOL in patients with MSD was elicited by measuring limitations of activities of daily living, impact on family and social relationships and sleep disturbances by structured instrument, using Likert/Dichotomous Scale. Statistical software EPI Info 2002 was used for estimation of sample size, data entry, and analysis. Data were summarized using proportions and percentages. Association of gender and rural–urban background with prevalence of musculoskeletal disorders was explored with odds ratio (OR) with 95% confidence intervals.Results:A total of 2633 subjects were examined. Out of these, 190 (7.2%) suffered from various types of MSD, with higher prevalence in females than males (OR=1.43, 95% CI=1.05 to 1.95). Prevalence was also higher in the rural population compared with urban (OR=2.02, 95% CI=1.45 to 2.83). However, the rural–urban difference may be due to the confounding effect of age, as prevalence was higher in the elderly (48.78%) and the mean age of the rural population was significantly higher than the urban population. Different degrees of limitations among patients of MSD in carrying out specific activities were: Dressing 9.5%, washing hair 11.6%, rising from bed 50%, feeding themselves 6%, walking 39%, taking bath 10%, toilet 37%, rising from chair 47%, rising from floor 55%, boarding bus 30%, and sleep disturbances 47%. These limitations also had impact on their family and social relationships.Conclusions:Patients of musculoskeletal disorders face appreciable limitations in their activities of daily living, which adversely impact their QOL.

YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.