Ghrelin causes hyperphagia and obesity in rats.

Ghrelin, a circulating growth hormone–releasing pep-tide derived from the stomach, stimulates food intake. The lowest systemically effective orexigenic dose of ghrelin was investigated and the resulting plasma ghre-lin concentration was compared with that during fast-ing. The lowest dose of ghrelin that produced a significant stimulation of feeding after intraperitoneal injection was 1 nmol. The plasma ghrelin concentration after intraperitoneal injection of 1 nmol of ghrelin (2.83 0.13 pmol/ml at 60 min postinjection) was not significantly different from that occurring after a 24-h fast (2.79 0.32 pmol/ml). After microinjection into defined hypothalamic sites, ghrelin (30 pmol) stimu-lated food intake most markedly in the arcuate nucleus (Arc) (0–1 h food intake, 427 43 % of control; P &lt

LR characterization of chirotopes of finite planar families of pairwise disjoint convex bodies

We extend the classical LR characterization of chirotopes of finite planar families of points to chirotopes of finite planar families of pairwise disjoint convex bodies: a map \c{hi} on the set of 3-subsets of a finite set I is a chirotope of finite planar families of pairwise disjoint convex bodies if and only if for every 3-, 4-, and 5-subset J of I the restriction of \c{hi} to the set of 3-subsets of J is a chirotope of finite planar families of pairwise disjoint convex bodies. Our main tool is the polarity map, i.e., the map that assigns to a convex body the set of lines missing its interior, from which we derive the key notion of arrangements of double pseudolines, introduced for the first time in this paper.Comment: 100 pages, 73 figures; accepted manuscript versio

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

Cycles of Police Reform in Latin America.

yesOver the last quarter century post-conflict and post-authoritarian transitions in Latin America have been accompanied by a surge in social violence, acquisitive crime, and insecurity. These phenomena have been driven by an expanding international narcotics trade, by the long-term effects of civil war and counter-insurgency (resulting in, inter alia, an increased availability of small arms and a pervasive grammar of violence), and by structural stresses on society (unemployment, hyper-inflation, widening income inequality). Local police forces proved to be generally ineffective in preventing, resolving, or detecting such crime and forms of “new violence”3 due to corruption, frequent complicity in criminal networks, poor training and low pay, and the routine use of excessive force without due sanction. Why, then, have governments been slow to prioritize police reform and why have reform efforts borne largely “limited or nonexistent” long-term results? This chapter highlights a number of lessons suggested by various efforts to reform the police in Latin America over the period 1995-2010 . It focuses on two clusters of countries in Latin America. One is Brazil and the Southern Cone countries (Chile, Argentina, and Uruguay), which made the transition to democracy from prolonged military authoritarian rule in the mid- to late 1980s. The other is Central America and the Andean region (principally El Salvador, Guatemala, Honduras, Peru, and Colombia), which emerged/have been emerging from armed conflict since the mid- 1990s. The chapter examines first the long history of international involvement in police and security sector reform in order to identify long-run tropes and path dependencies. It then focuses on a number of recurring themes: cycles of de- and re-militarization of the policing function; the “security gap” and “democratization dilemmas” involved in structural reforms; the opportunities offered by decentralization for more community-oriented police; and police capacity to resist reform and undermine accountability mechanisms

IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses.

Mouse and human dendritic cells (DCs) are composed of functionally specialized subsets, but precise interspecies correlation is currently incomplete. Here, we showed that murine lung and gut lamina propria CD11b+ DC populations were comprised of two subsets: FLT3- and IRF4-dependent CD24(+)CD64(-) DCs and contaminating CSF-1R-dependent CD24(-)CD64(+) macrophages. Functionally, loss of CD24(+)CD11b(+) DCs abrogated CD4+ T cell-mediated interleukin-17 (IL-17) production in steady state and after Aspergillus fumigatus challenge. Human CD1c+ DCs, the equivalent of murine CD24(+)CD11b(+) DCs, also expressed IRF4, secreted IL-23, and promoted T helper 17 cell responses. Our data revealed heterogeneity in the mouse CD11b+ DC compartment and identifed mucosal tissues IRF4-expressing DCs specialized in instructing IL-17 responses in both mouse and human. The demonstration of mouse and human DC subsets specialized in driving IL-17 responses highlights the conservation of key immune functions across species and will facilitate the translation of mouse in vivo findings to advance DC-based clinical therapies

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Developmental Regulation of Hepatitis B Virus Biosynthesis by Hepatocyte Nuclear Factor 4α

The host cellular factors that promote persistent viral infections in vivo are, in general, poorly understood. Utilizing the hepatitis B virus (HBV) transgenic mouse model of chronic infection, we demonstrate that the nuclear receptor, hepatocyte nuclear factor 4α (HNF4α, NR2A1), is essential for viral biosynthesis in the liver. The dependency of HBV transcription on HNF4α links viral biosynthesis and persistence to a developmentally regulated transcription factor essential for host viability

Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics

BACKGROUND: Recently, it has been shown that increasing body mass index (BMI) in asthma is associated with reduced exhaled NO. Our objective in this study was to determine if the BMI-related changes in exhaled NO differ across asthmatics and controls, and to determine if these changes are related to increased airway oxidative stress and systemic levels of leptin and adiponectin. METHODS: Observational study of the association of BMI, leptin, and adiponectin with exhaled nitric oxide (NO) and exhaled 8-isoprostanes in 67 non-smoking patients with moderate to severe persistent asthma during baseline conditions and 47 controls. Measurements included plasma levels of leptin, adiponectin, exhaled breath condensates for 8-isoprostanes, exhaled NO, pulmonary function tests, and questionnaires regarding asthma severity and control. RESULTS: In asthmatics, BMI and the ratio of leptin to adiponectin were respectively associated with reduced levels of exhaled NO (β = -0.04 [95% C.I. -0.07, -0.1], p < 0.003) and (β = -0.0018 [95% C.I. -0.003, -0.00034], p = 0.01) after adjusting for confounders. Also, BMI was associated with increased levels of exhaled 8-isoprostanes (β = 0.30 [95% C.I. 0.003, 0.6], p = 0.03) after adjusting for confounders. In contrast, we did not observe these associations in the control group of healthy non-asthmatics with a similar weight distribution. CONCLUSION: In adults with stable moderate to severe persistent asthma, but not in controls, BMI and the plasma ratio of leptin/adiponectin is associated with reduced exhaled NO. Also, BMI is associated with increased exhaled 8-isoprostanes. These results suggest that BMI in asthmatics may increase airway oxidative stress and could explain the BMI-related reductions in exhaled NO

Exon expression in lymphoblastoid cell lines from subjects with schizophrenia before and after glucose deprivation

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to examine the effects of glucose reduction stress on lymphoblastic cell line (LCL) gene expression in subjects with schizophrenia compared to non-psychotic relatives.</p> <p>Methods</p> <p>LCLs were grown under two glucose conditions to measure the effects of glucose reduction stress on exon expression in subjects with schizophrenia compared to unaffected family member controls. A second aim of this project was to identify cis-regulated transcripts associated with diagnosis.</p> <p>Results</p> <p>There were a total of 122 transcripts with significant diagnosis by probeset interaction effects and 328 transcripts with glucose deprivation by probeset interaction probeset effects after corrections for multiple comparisons. There were 8 transcripts with expression significantly affected by the interaction between diagnosis and glucose deprivation and probeset after correction for multiple comparisons. The overall validation rate by qPCR of 13 diagnosis effect genes identified through microarray was 62%, and all genes tested by qPCR showed concordant up- or down-regulation by qPCR and microarray. We assessed brain gene expression of five genes found to be altered by diagnosis and glucose deprivation in LCLs and found a significant decrease in expression of one gene, glutaminase, in the dorsolateral prefrontal cortex (DLPFC). One SNP with previously identified regulation by a 3' UTR SNP was found to influence IRF5 expression in both brain and lymphocytes. The relationship between the 3' UTR rs10954213 genotype and IRF5 expression was significant in LCLs (p = 0.0001), DLPFC (p = 0.007), and anterior cingulate cortex (p = 0.002).</p> <p>Conclusion</p> <p>Experimental manipulation of cells lines from subjects with schizophrenia may be a useful approach to explore stress related gene expression alterations in schizophrenia and to identify SNP variants associated with gene expression.</p

Applying unmixing to gene expression data for tumor phylogeny inference

<p>Abstract</p> <p>Background</p> <p>While in principle a seemingly infinite variety of combinations of mutations could result in tumor development, in practice it appears that most human cancers fall into a relatively small number of "sub-types," each characterized a roughly equivalent sequence of mutations by which it progresses in different patients. There is currently great interest in identifying the common sub-types and applying them to the development of diagnostics or therapeutics. Phylogenetic methods have shown great promise for inferring common patterns of tumor progression, but suffer from limits of the technologies available for assaying differences between and within tumors. One approach to tumor phylogenetics uses differences between single cells within tumors, gaining valuable information about intra-tumor heterogeneity but allowing only a few markers per cell. An alternative approach uses tissue-wide measures of whole tumors to provide a detailed picture of averaged tumor state but at the cost of losing information about intra-tumor heterogeneity.</p> <p>Results</p> <p>The present work applies "unmixing" methods, which separate complex data sets into combinations of simpler components, to attempt to gain advantages of both tissue-wide and single-cell approaches to cancer phylogenetics. We develop an unmixing method to infer recurring cell states from microarray measurements of tumor populations and use the inferred mixtures of states in individual tumors to identify possible evolutionary relationships among tumor cells. Validation on simulated data shows the method can accurately separate small numbers of cell states and infer phylogenetic relationships among them. Application to a lung cancer dataset shows that the method can identify cell states corresponding to common lung tumor types and suggest possible evolutionary relationships among them that show good correspondence with our current understanding of lung tumor development.</p> <p>Conclusions</p> <p>Unmixing methods provide a way to make use of both intra-tumor heterogeneity and large probe sets for tumor phylogeny inference, establishing a new avenue towards the construction of detailed, accurate portraits of common tumor sub-types and the mechanisms by which they develop. These reconstructions are likely to have future value in discovering and diagnosing novel cancer sub-types and in identifying targets for therapeutic development.</p