The rockefeller university

The cloning of the ob gene and its gene product, leptin, has led to the elucidation of a robust physiologic system that maintains fat stores at a relatively constant level. Leptin is a peptide hormone secreted by adipose tissue in proportion to its mass. Recessive mutations in the leptin gene are associated with massive obesity in mice and humans, establishing a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall, stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. The discovery of leptin has advanced our understanding of metabolic disease in a number of respects. Its identification has revealed a new endocrine system regulating body weight. This system provides a means by which changes in nutritional state regulate other physiologic systems. A number of leptin deficiency syndromes that are treatable with leptin replacement have been identified. The majority of obese subjects are leptin resistant, which establishes that obesity is the result of hormone resistance. Leptin treatment results in weight loss in a subset of obese patients and can also synergize with other anti-obesity agents to reduce weight in the general population. Leptin provides an entry point for studying a complex human behavior. Finally, this research has established that there is a powerful biological basis for obesity, a fact that is (correctly) changing public perception about the pathogenesis of this medical condition. (Keio J Med 60 (1) : 1-9, March 2011)

Current rodent models of menopause fail to adequately recapitulate the menopause transition. The intact aging model fails to achieve very low estrogen levels, and the ovariectomy model lacks a perimenopause phase. A new rodent model of accelerated ovarian failure (AOF) successfully replicates human perimenopause and postrnenopause, including estrous acyclicity and fluctuating, followed by undetectable, estrogen levels, and allows for the dissociation of the effects of hormone levels from the effects of aging. In this model, an ovotoxic chemical, 4-vinylcyclohexene diepoxide (VCD), selective for primary and primordial follicles, is injected intraperitonelly in animals for 15 days. As the mature follicle population is depleted through natural cycling, ovarian failure follows increasing periods of acyclity. Administered at low doses, VCD specifically causes apoptotic cell death of primordial follicles but does not affect other peripheral tissues, including the liver and spleen, nor does it affect brain inflammation markers. In addition to reducing confounds associated with genetic and surgical manipulations, the AOF model maintains the presence of ovarian tissue which importantly parallels to the menopause transition in humans. The VCD injection procedure can be applied to studies using transgenic or knockout mice strains, or in other disease-state models (e.g., ischemia, atherosclerosis, or diabetes). This AOF model of menopause will generate new insights into women's health particularly in determining the critical periods (i.e., a window of opportunity) during perimenopause for restoring ovarian hormones for the most efficacious effect on memory and mood disorders as well as other menopausal symptoms. (C) 2011 Elsevier B.V. All rights reserved.

Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects. (C) 2010 Elsevier Ltd. All rights reserved.

Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA(-/-) mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABA(A) receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.

Psoriasis is a complex inflammatory disease mediated by tumor necrosis factor (TNF)-alpha and cytokines secreted by specialized T-cell populations, e. g., IL-17, IL-22, and IFN-gamma. The mechanisms by which innate and adaptive immune cytokines regulate inflammation in psoriasis are not completely understood. We sought to investigate the effects of TNF-alpha and IL-17 on keratinocyte (KC) gene profile, to identify genes that might be coregulated by these cytokines and determine how synergistically activated genes relate to the psoriasis transcriptome. Primary KCs were stimulated with IL-17 or TNF-alpha alone, or in combination. KC responses were assessed by gene array analysis, followed by reverse transcriptase-PCR confirmation for significant genes. We identified 160 genes that were synergistically upregulated by IL-17 and TNF-alpha, and 196 genes in which the two cytokines had at least an additive effect. Synergistically upregulated genes included some of the highest expressed genes in psoriatic skin with an impressive correlation between IL-17/TNF-alpha-induced genes and the psoriasis gene signature. KCs may be key drivers of pathogenic inflammation in psoriasis through integrating responses to TNF-alpha and IL-17. Our data predict that psoriasis therapy with either TNF or IL-17 antagonists will produce greater modulation of the synergistic/additive gene set, which consists of the most highly expressed genes in psoriasis skin lesions.

We present a search for a new narrow, spin-1, high mass resonance decaying to mu(+)mu(-) + X, using a matrix-element-based likelihood and a simultaneous measurement of the resonance mass and production rate. In data with 4.6 fb(-1) of integrated luminosity collected by the CDF detector in p (p) over bar collisions at root s = 1960 GeV, the most likely signal cross section is consistent with zero at 16% confidence level. We therefore do not observe evidence for a high mass resonance and place limits on models predicting spin-1 resonances, including M > 1071 GeV/c(2) at 95% confidence level for a Z' boson with the same couplings to fermions as the Z boson.

A measurement of the b-hadron production cross section in proton-proton collisions at root s = 7 TeV is presented. The dataset, corresponding to 85 nb(-1), was recorded with the CMS experiment at the LHC using a low-threshold single-muon trigger. Events are selected by the presence of a muon with transverse momentum p(T)(mu) > 6 GeV with respect to the beam direction and pseudorapidity vertical bar eta(mu)vertical bar < 2.1. The transverse momentum of the muon with respect to the closest jet discriminates events containing b hadrons from background. The inclusive b-hadron production cross section is presented as a function of muon transverse momentum and pseudorapidity. The measured total cross section in the kinematic acceptance is sigma(pp -> b + X -> mu + X') = 1.32 +/- 0.01(stat) +/- 0: 30(syst) +/- 0.15(lumi)mu b.

Natural product gene clusters are often tightly regulated, resulting in gene cluster silencing in laboratory fermentation studies. The systematic overexpression of transcription factors (TFs) associated with biosynthetic gene clusters found in the genome of Burkholderia thailandensis E264 identified a set of TFs that, when overexpressed, alter the secondary metabolome of this bacterium. The isolation and characterization of burkholdacs A and B, two new acyldepsitripeptide histone deacetylase inhibitors produced by B. thailandensis overexpressing the TF bhcM, is reported.

Human hematolymphoid mice have become valuable tools for the study of human hematopoiesis and uniquely human pathogens in vivo. Recent improvements in xenorecipient strains allow for long-term reconstitution with a human immune system. However, certain hematopoietic lineages, for example, the myeloid lineage, are underrepresented, possibly because of the limited cross-reactivity of murine and human cytokines. Therefore, we created a nonobese diabetic/severe combined immunodeficiency/interleukin2 receptor-gamma-null (NOD-SCID IL2R gamma(null)) mouse strain that expressed human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3, termed NSG-SGM3. Transplantation of CD34(+) human hematopoietic stem cells into NSG-SGM3 mice led to robust human hematopoietic reconstitution in blood, spleen, bone marrow, and liver. Human myeloid cell frequencies, specifically, myeloid dendritic cells, were elevated in the bone marrow of humanized NSG-SGM3 mice compared with nontransgenic NSG recipients. Most significant, however, was the increase in the CD4(+)FoxP3(+) regulatory T-cell population in all compartments analyzed. These CD4(+)FoxP3(+) regulatory T cells were functional, as evidenced by their ability to suppress T-cell proliferation. In conclusion, humanized NSGSGM3 mice might serve as a useful model to study human regulatory T-cell development in vivo, but this unexpected lineage skewing also highlights the importance of adequate spatiotemporal expression of human cytokines for future xenorecipient strain development. (Blood. 2011; 117(11): 3076-3086)