The rockefeller university

The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T-B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh-B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.

In psoriasis, an IL-17-mediated inflammatory skin disease, skin lesions resolve with therapy, but often recur in the same locations when therapy is discontinued. We propose that residual T cell populations in resolved psoriatic lesions represent the pathogenic T cells of origin in this disease. Utilizing high-throughput screening (HTS) of the T cell receptor (TCR) and immunostaining, we found that clinically resolved psoriatic lesions contained oligoclonal populations of T cells that produced IL-17A in both resolved and active psoriatic lesions. Putative pathogenic clones preferentially utilized particular V beta and V alpha subfamilies. We identified 15 TCR beta and 4 TCR alpha antigen receptor sequences shared between psoriasis patients and not observed in healthy controls or other inflammatory skin conditions. To address the relative roles of alpha beta versus gamma delta T cells in psoriasis, we carried out TCR/delta HTS. These studies demonstrated that the majority of T cells in psoriasis and healthy skin are alpha beta T cells. gamma delta T cells made up 1% of T cells in active psoriasis, less than 1% in resolved psoriatic lesions, and less than 2% in healthy skin. All of the 70 most frequent putative pathogenic T cell clones were alpha beta T cells. In summary, IL-17-producing alpha beta T cell clones with psoriasis-specific antigen receptors exist in clinically resolved psoriatic skin lesions. These cells likely represent the disease-initiating pathogenic T cells in psoriasis, suggesting that lasting control of this disease will require suppression of these resident T cell populations.

Voltage-gated Na+ channels (Na-v) modulate neuronal excitability, but the roles of the various Na-v subtypes in specific neuronal functions such as synaptic transmission are unclear. We investigated expression of the three major brain Na-v subtypes (Na(v)1.1, Na(v)1.2, Na(v)1.6) in area CA1 and dentate gyrus of rat hippocampus. Using light and electron microscopy, we found labeling for all three Na-v subtypes on dendrites, dendritic spines, and axon terminals, but the proportion of pre- and post-synaptic labeling for each subtype varied within and between subregions of CA1 and dentate gyrus. In the central hilus (CH) of the dentate gyrus, Na(v)1.1 immunoreactivity was selectively expressed in presynaptic profiles, while Na(v)1.2 and Na(v)1.6 were expressed both pre- and post-synaptically. In contrast, in the stratum radiatum (SR) of CA1, Na(v)1.1, Na(v)1.2, and Na(v)1.6 were selectively expressed in postsynaptic profiles. We next compared differences in Na-v subtype expression between CH and SR axon terminals and between CH and SR dendrites and spines. Na(v)1.1 and Na(v)1.2 immunoreactivity was preferentially localized to CH axon terminals compared to SR, and in SR dendrites and spines compared to CH. No differences in Na(v)1.6 immunoreactivity were found between axon terminals of CH and SR or between dendrites and spines of CH and SR. All Na-v subtypes in both CH and SR were preferentially associated with asymmetric synapses rather than symmetric synapses. These findings indicate selective presynaptic and postsynaptic Na-v expression in glutamatergic synapses of CH and SR supporting neurotransmitter release and synaptic plasticity.

Background: Oil palm is the most productive oil crop and the efficiency of pollination has a direct impact on the yield of oil. Pollination by wind can occur but maximal pollination is mediated by the weevil E. kamerunicus. These weevils complete their life cycle by feeding on male flowers. Attraction of weevils to oil palm flowers is due to the emission of methylchavicol by both male and female flowers. In search for male flowers, the weevils visit female flowers by accident due to methylchavicol fragrance and deposit pollen. Given the importance of methylchavicol emission on pollination, we performed comparative transcriptome analysis of oil palm flowers and leaves to identify candidate genes involved in methylchavicol production in flowers. Results: RNA sequencing (RNA-Seq) of male open flowers, female open flowers and leaves was performed using Illumina HiSeq 2000 platform. Analysis of the transcriptome data revealed that the transcripts of methylchavicol biosynthesis genes were strongly up-regulated whereas transcripts encoding genes involved in lignin production such as, caffeic acid O-methyltransferase (COMT) and Ferulate-5-hydroxylase (F5H) were found to be suppressed in oil palm flowers. Among the transcripts encoding transcription factors, an EAR-motif-containing R2R3-MYB transcription factor (EgMYB4) was found to be enriched in oil palm flowers. We determined that EgMYB4 can suppress the expression of a monolignol pathway gene, EgCOMT, in vivo by binding to the AC elements present in the promoter region. EgMYB4 was further functionally characterized in sweet basil which also produces phenylpropenes like oil palm. Transgenic sweet basil plants showed significant reduction in lignin content but produced more phenylpropenes. Conclusions: Our results suggest that EgMYB4 possibly restrains lignin biosynthesis in oil palm flowers thus allowing enhanced carbon flux into the phenylpropene pathway. This study augments our understanding of the diverse roles that EAR-motif-containing MYBs play to fine tune the metabolic flux along the various branches of core phenylpropanoid pathway. This will aid in metabolic engineering of plant aromatic compounds.

The discovery of sodium taurocholate cotransporting polypeptide (NTCP) as the hepatitis B virus (HBV) receptor enabled researchers to create hepatoma cell lines susceptible to HBV infection. Infection in current systems, however, is inefficient and virus fails to spread. Infection efficiency is enhanced by treating cells with polyethylene glycol 8000 (PEG) during infection. However, this alone does not promote virus spread. Here we show that maintaining PEG in culture medium increases the rate of infection by at least one order of magnitude, and, most importantly, promotes virus spread. To demonstrate the utility of this system, we show that two interferon-stimulated genes (ISGs), ISG20 and tetherin, restrict HBV spread in NTCP-expressing hepatoma cells. Thus, this protocol can be easily applied to existing cell culture systems to study the complete HBV life cycle, including virus spread.

Background-Low-density lipoprotein cholesterol (LDL-C) control is higher among insured than uninsured adults, but data on time trends and contributing factors are incomplete and important for improving health equity. Methods and Results-Awareness, treatment, and control of elevated LDL-C were compared among insured versus uninsured and publicly versus privately insured adults, aged 21 to 64 years, in National Health and Nutrition Examination Surveys from 2001 to 2004, 2005 to 2008, and 2009 to 2012 using Adult Treatment Panel-3 criteria. Compared with insured adults, uninsured adults were younger; were more often minority; reported lower incomes, less education, and fewer healthcare encounters; and had lower awareness and treatment of elevated LDL-C (P<0.0001). LDL-C control was higher among insured than uninsured adults in 2001 to 2004 (mean +/- SEM, 21.4 +/- 1.6% versus 10.5 +/- 2.6%; P<0.01), and the gap widened by 2009 to 2012 (35.1 +/- 1.9% versus 11.3 +/- 2.2%; P<0.0001). Despite more minorities (P<0.01), greater poverty, and less education (P<0.001), publicly insured adults had more healthcare visits/year than privately insured adults (P<0.001) and similar awareness, treatment, and control of LDL-C from 2001 to 2012. In multivariable logistic regression, significant positive predictors of cholesterol awareness, treatment, and control included more frequent health care (strongest), increasing age, private healthcare insurance versus uninsured, and hypertension. Public insurance (versus uninsured) was a significant positive predictor of LDL-C control, whereas income <200% versus >= 200% of federal poverty was a significant negative predictor. Conclusions-LDL-C control improved similarly over time in publicly and privately insured adults but was stagnant among the uninsured. Healthcare insurance largely addresses socioeconomic barriers to effective LDL-C management, yet poverty retains an independent adverse effect.

OBJECTIVE: Our objective was to estimate the contribution of preimplantation genetic screening to in vitro fertilization pregnancy outcomes in donor oocyte-recipient cycles. STUDY DESIGN: This was a retrospective cross-sectional study of US national data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2005 and 2013. Society for Assisted Reproductive Technology Clinic Outcome Reporting relies on voluntarily annual reports by more than 90% of US in vitro fertilization centers. We evaluated pregnancy and live birth rates in donor oocyte-recipient cycles after the first embryo transfer with day 5/6 embryos. Statistical models, adjusted for patient and donor ages, number of embryos transferred, race, infertility diagnosis, and cycle year were created to compare live birth rates in 392 preimplantation genetic screening and 20,616 control cycles. RESULTS: Overall, pregnancy and live birth rates were significantly lower in preimplantation genetic screening cycles than in control cycles. Adjusted odds of live birth for preimplantation genetic screening cycles were reduced by 35% (odds ratio, 0.65, 95% confidence interval, 0.53-0.80; P < .001). CONCLUSION: Preimplantation genetic screening, as practiced in donor oocyte-recipient cycles over the past 9 years, has not been associated with improved odds of live birth or reduction in miscarriage rates.

In addition to storing and mobilizing energy, adipocytes secrete circulating factors to signal to other tissues and coordinate energy metabolism. These functions can become disrupted in the setting of obesity, contributing to the development of diabetes, cardiovascular disease, and cancer. Since the discovery of leptin and adiponectin, an increasing number of adipokines have been identified and their functions elucidated. More recent studies have highlighted other modes by which adipose tissue can participate in crosstalk with other cell types and tissues. These modes of communication, which are reviewed here, include the secretion of enzymes, lipid species, and exosomes. Advances in profiling technology suggest that a substantial number of adipose-derived factors remain to be characterized. Further advances in this growing field are likely to provide important basic insights into the molecular control of metabolism.

We assess the applicability of the Wigner function formulation in its present form to the chiral magnetic effect and note some issues regarding the conservation and the consistency of the electric current in the presence of an inhomogeneous and time-dependent axial chemical potential. The problems are rooted in the ultraviolet divergence of the underlying field theory associated with the axial anomaly and can be fixed with the Pauli-Villars regularization of the Wigner function. The chiral magnetic current with a nonconstant axial chemical potential is calculated with the regularized Wigner function and the phenomenological implications are discussed.

Psoriasis is a common immune-mediated disease that affects 2%-4% of individuals in North America and Europe. In the past decade, advances in research have led to an improved understanding of immune pathways involved in the pathogenesis of psoriasis and has spurred the development of targeted therapeutics. Recently, three psoriasis autoantigens have been described: cathelicidin (LL37), a disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5), and lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D). It is important to establish the expression, regulation and therapeutic modulation of these psoriasis autoantigens. In this study, we performed immunohistochemistry and two-colour immunofluorescence on non-lesional and lesional psoriasis skin to characterize ADAMTSL5 and LL37, and their co-expression with T cells, dendritic cells, neutrophils and macrophages, which are the main immune cells that drive this disease. Our results showed that ADAMTSL5 and LL37 are significantly (P<.05) increased in lesional skin and are co-expressed by many dendritic cells, macrophages and some T cells in the dermis. Gene expression analysis showed significant (P<.05) upregulation of LL37 in lesional skin and significant downregulation following treatment with etanercept. ADAMTSL5 and LL37 are also significantly decreased by IL-17 or TNF- blockade, suggesting feed-forward induction of psoriasis autoantigens by disease-related cytokines.