The rockefeller university

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day > 20 vs. a parts per thousand currency sign10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95 % C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Background: A 2-day consensus working meeting, hosted by the United States National Institutes of Health and the Veterans Administration, focused on issues related to dissemination and implementation (D&I) research in measurement and reporting. Meeting participants included 23 researchers, practitioners, and decision makers from the USA and Canada who concluded that the field would greatly benefit from measurement resources to enhance the ease, harmonization, and rigor of D&I evaluation efforts. This paper describes the findings from an environmental scan and literature review of resources for D&I measures. Findings: We identified a total of 17 resources, including four web-based repositories and 12 static reviews or tools that attempted to synthesize and evaluate existing measures for D&I research. Thirteen resources came from the health discipline, and 11 were populated from database reviews. Ten focused on quantitative measures, and all were generated as a resource for researchers. Fourteen were organized according to an established D&I theory or framework, with the number of constructs and measures ranging from 1 to more than 450. Measure metadata was quite variable with only six providing information on the psychometric properties of measures. Conclusions: Additional guidance on the development and use of measures are needed. A number of approaches, resources, and critical areas for future work are discussed. Researchers and stakeholders are encouraged to take advantage of a number of funding mechanisms supporting this type of work.

Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days) after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor a (ER alpha) and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR) and vasopressin receptor in the medial amygdala (MeA) and medial preoptic area (MPOA). Estrogen treatment led to decreased ER alpha mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ER alpha mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional activation due to exogenous estrogen treatment, and thereby results in different effects on maternal behavior.

The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

The intake of a high fat diet (HFD), in addition to stimulating orexigenic neuropeptides in the hypothalamus while promoting overeating and reducing locomotor behavior, is known to increase inflammatory mediators that modulate neuronal systems in the brain. To understand the involvement of chemokines in the effects of a HFD, we examined in rats whether HFD intake affects a specific chemokine. CXCL12, and its receptors. CXCR4 and CXCR7, in the hypothalamus together with the neuropeptides and whether CXCL12 itself acts similarly to a HFD in stimulating the neuropeptides and altering ingestion and locomotor behavior. Compared to low-fat chow, a HFD for 5 days significantly increased the expression of CXCL1 2 and its receptors, in both the paraventricular nucleus (PVN) where the neuropeptides enkephalin (ENK) and galanin were also stimulated and the perifornical lateral hypothalamus (PFLH) where orexin (OX) and melanin-concentrating hormone (MCH) were increased. In contrast, the HFD had no impact on expression of CXCL12 or its receptors in the arcuate nucleus (ARC) where the carbohydrate-related peptide, neuropeptide Y (NPY), was suppressed. Analysis of protein levels revealed a similar stimulatory effect of a HFD on CXCL12 levels in the PVN and PFLH, as well as in blood, and an increase in the number of CXGR4-positive cells in the PVN. In the ARC, in contrast, levels of CXCL12 and number of CXCR4-positive cells were too low to measure. When centrally administered, CXCL12 was found to have similar effects to a HFD. Injection of CXCL12 into the third cerebral ventricle immediately anterior to the hypothalamus significantly stimulated the ingestion of a HFD, reduced novelty-induced locomotor activity, and increased expression of ENK in the PVN where the CXCR4 receptors were dense. It had no impact, however, on NPY in the ARC or on OX and MCH in the PFLH where the CXCR4 receptors were not detected. These results, showing CXCL1 2 in the hypothalamus to be stimulated by a HFD and to mimic the effects of the HFD where its receptors are located, suggest that this chemokine system may have a role in mediating both the neuronal and behavioral effects induced by a fat-rich diet.

Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and overexpressed in metastatic breast, melanoma, and colon cancers. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy.

Kaposi sarcoma (KS) is an endothelial malignancy caused by human herpes virus-8 (HHV-8) infection. The epidemic and iatrogenic forms of childhood KS result from a profound and acquired T cell deficiency. Recent studies have shown that classic KS of childhood can result from rare single-gene inborn errors of immunity, with mutations in WAS, IFNGR1, STIM1, and TNFRSF4. The pathogenesis of the endemic form of childhood KS has remained elusive. We review childhood KS pathogenesis and its relationship to inherited and acquired immunodeficiency to oncogenic HHV-8.

Natural auditory scenes possess highly structured statistical regularities, which are dictated by the physics of sound production in nature, such as scale-invariance. We recently identified that natural water sounds exhibit a particular type of scale invariance, in which the temporal modulation within spectral bands scales with the centre frequency of the band. Here, we tested how neurons in the mammalian primary auditory cortex encode sounds that exhibit this property, but differ in their statistical parameters. The stimuli varied in spectro-temporal density and cyclo-temporal statistics over several orders of magnitude, corresponding to a range of water-like percepts, from pattering of rain to a slow stream. We recorded neuronal activity in the primary auditory cortex of awake rats presented with these stimuli. The responses of the majority of individual neurons were selective for a subset of stimuli with specific statistics. However, as a neuronal population, the responses were remarkably stable over large changes in stimulus statistics, exhibiting a similar range in firing rate, response strength, variability and information rate, and only minor variation in receptive field parameters. This pattern of neuronal responses suggests a potentially general principle for cortical encoding of complex acoustic scenes: while individual cortical neurons exhibit selectivity for specific statistical features, a neuronal population preserves a constant response structure across a broad range of statistical parameters.

Low-fidelity RNA-dependent RNA polymerases for many RNA virus mutators have been shown to confer attenuated phenotypes, presumably due to increased mutation rates. Additionally, for many RNA viruses, replication to high titers results in the production of defective interfering particles (DIs) that also attenuate infection. We hypothesized that fidelity, recombination, and DI production are tightly linked. We show that a Sindbis virus mutator replicating at a high multiplicity of infection manifests an earlier and greater accumulation of DIs than its wild-type counterpart. The isolated DIs interfere with the replication of full-length virus in a dose-dependent manner. Importantly, the ability of the mutator virus to overproduce DIs could be linked to an increased recombination frequency. These data confirm that RNA-dependent RNA polymerase fidelity and recombination are inversely correlated for this mutator. Our findings suggest that defective interference resulting from higher recombination rates may be more detrimental to RNA virus mutators than the increase in mutational burden. IMPORTANCE Replication, adaptation, and evolution of RNA viruses rely in large part on their low-fidelity RNA-dependent RNA polymerase. Viruses artificially modified in their polymerases to decrease fidelity (mutator viruses) are attenuated in vivo, demonstrating the important role of fidelity in viral fitness. However, attenuation was attributed solely to the modification of the viral mutation rate and the accumulation of detrimental point mutations. In this work, we described an additional phenotype of mutator viruses: an increased recombination rate leading to defective interfering particle (DI) overproduction. Because DIs are known for their inhibitory effect on viral replication, our work suggests that fidelity variants may be attenuated in vivo via several mechanisms. This has important implications in the development of fidelity variants as live attenuated vaccine strains.