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Coalicion de Salud Comunitaria (COSACO): using a Healthy Community Partnership framework to integrate short-term global health experiences into broader community development

Wed, 09/28/2016 - 11:27am

BACKGROUND: There is growing concern that short-term experiences in global health experiences (STEGH), undertaken by healthcare providers, trainees, and volunteers from high income countries in lower and middle income countries, risk harming the community by creating a parallel system of care separate from established community development efforts. At the same time, the inclusion of non-traditional actors in health planning has been the basis of the development of many Healthy Community Partnerships (HCP) being rolled out in Canada and the United States. These partnerships aim to bring all stakeholders with a role to play in health to the table to align efforts, goals and programs towards broad community health goals.

RESULTS: This methodology paper reports on the process used in La Romana, Dominican Republic, in applying a modified HCP framework. This project succeeded at bringing visiting STEGH organizations into a coalition with key community partners and supported attempts to embed the work of STEGH within longer-term, established development plans.

CONCLUSIONS: In presenting the work and process and lessons learned, the hope is that other communities that encounter significant investment from STEGH groups, and will gain the same benefits that were seen in La Romana with regards to improved information exchange, increased cross-communication between silos, and the integration of STEGH into the work of community partners.

Adipose Tissue Depots and Their Cross-Sectional Associations With Circulating Biomarkers of Metabolic Regulation

Wed, 09/28/2016 - 11:27am

BACKGROUND: Visceral adipose tissue (VAT) and fatty liver differ in their associations with cardiovascular risk compared with subcutaneous adipose tissue (SAT). Several biomarkers have been linked to metabolic derangements and may contribute to the pathogenicity of fat depots. We examined the association between fat depots on multidetector computed tomography and metabolic regulatory biomarkers.

METHODS AND RESULTS: Participants from the Framingham Heart Study (n=1583, 47% women) underwent assessment of SAT, VAT, and liver attenuation. We measured circulating biomarkers secreted by adipose tissue or liver (adiponectin, leptin, leptin receptor, fatty acid binding protein 4, fetuin-A, and retinol binding protein 4). Using multivariable linear regression models, we examined relations of fat depots with biomarkers. Higher levels of fat depots were positively associated with leptin and fatty acid binding protein 4 but negatively associated with adiponectin (all P < 0.001). Associations with leptin receptor, fetuin-A, and retinol binding protein 4 varied according to fat depot type or sex. When comparing the associations of SAT and VAT with biomarkers, VAT was the stronger correlate of adiponectin (beta=-0.28 [women]; beta=-0.30 [men]; both P < 0.001), whereas SAT was the stronger correlate of leptin (beta=0.62 [women]; beta=0.49 [men]; both P < 0.001; P < 0.001 for comparing VAT versus SAT). Although fetuin-A and retinol binding protein 4 are secreted by the liver in addition to adipose tissue, associations of liver attenuation with these biomarkers was not stronger than that of SAT or VAT.

CONCLUSIONS: SAT, VAT, and liver attenuation are associated with metabolic regulatory biomarkers with differences in the associations by fat depot type and sex. These findings support the possibility of biological differences between fat depots.

Ensemble cryo-EM uncovers inchworm-like translocation of a viral IRES through the ribosome

Wed, 09/28/2016 - 11:27am

Internal ribosome entry sites (IRESs) mediate cap-independent translation of viral mRNAs. Using electron cryo-microscopy of a single specimen, we present five ribosome structures formed with the Taura syndrome virus IRES and translocase eEF2*GTP bound with sordarin. The structures suggest a trajectory of IRES translocation, required for translation initiation, and provide an unprecedented view of eEF2 dynamics. The IRES rearranges from extended to bent to extended conformations. This inchworm-like movement is coupled with ribosomal inter-subunit rotation and 40S head swivel. eEF2, attached to the 60S subunit, slides along the rotating 40S subunit to enter the A site. Its diphthamide-bearing tip at domain IV separates the tRNA-mRNA-like pseudoknot I (PKI) of the IRES from the decoding center. This unlocks 40S domains, facilitating head swivel and biasing IRES translocation via hitherto-elusive intermediates with PKI captured between the A and P sites. The structures suggest missing links in our understanding of tRNA translocation.

Induction of Protective Immunity to Cryptococcal Infection in Mice by a Heat-Killed, Chitosan-Deficient Strain of Cryptococcus neoformans

Wed, 09/28/2016 - 11:27am

Cryptococcus neoformans is a major opportunistic fungal pathogen that causes fatal meningoencephalitis in immunocompromised individuals and is responsible for a large proportion of AIDS-related deaths. The fungal cell wall is an essential organelle which undergoes constant modification during various stages of growth and is critical for fungal pathogenesis. One critical component of the fungal cell wall is chitin, which in C. neoformans is predominantly deacetylated to chitosan. We previously reported that three chitin deacetylase (CDA) genes have to be deleted to generate a chitosan-deficient C. neoformans strain. This cda1Delta2Delta3Delta strain was avirulent in mice, as it was rapidly cleared from the lungs of infected mice. Here, we report that clearance of the cda1Delta2Delta3Delta strain was associated with sharply spiked concentrations of proinflammatory molecules that are known to be critical mediators of the orchestration of a protective Th1-type adaptive immune response. This was followed by the selective enrichment of the Th1-type T cell population in the cda1Delta2Delta3Delta strain-infected mouse lung. Importantly, this response resulted in the development of robust protective immunity to a subsequent lethal challenge with a virulent wild-type C. neoformans strain. Moreover, protective immunity was also induced in mice vaccinated with heat-killed cda1Delta2Delta3Delta cells and was effective in multiple mouse strains. The results presented here provide a strong framework to develop the cda1Delta2Delta3Delta strain as a potential vaccine candidate for C. neoformans infection.

IMPORTANCE: The most commonly used anticryptococcal therapies include amphotericin B, 5-fluorocytosine, and fluconazole alone or in combination. Major drawbacks of these treatment options are their limited efficacy, poor availability in limited resource areas, and potential toxicity. The development of antifungal vaccines and immune-based therapeutic interventions is promising and an attractive alternative to chemotherapeutics. Currently, there are no fungal vaccines in clinical use. This is the first report of a C. neoformans deletion strain with an avirulent phenotype in mice exhibiting protective immunity when used as a vaccine after heat inactivation, although other strains that overexpress fungal or murine proteins have recently been shown to induce a protective response. The data presented here demonstrate the potential for developing the avirulent cda1Delta2Delta3Delta strain into a vaccine-based therapy to treat C. neoformans infection.

IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis

Wed, 09/28/2016 - 11:27am

BACKGROUND: Interleukin-17A (IL-17A) plays a pathogenic role in several rheumatic diseases including spondyloarthritis and, paradoxically, has been described to both promote and protect from bone formation. We therefore examined the effects of IL-17A on osteoblast differentiation in vitro and on periosteal bone formation in an in vivo model of inflammatory arthritis.

METHODS: K/BxN serum transfer arthritis was induced in IL-17A-deficient and wild-type mice. Clinical and histologic inflammation was assessed and periosteal bone formation was quantitated. Murine calvarial osteoblasts were differentiated in the continuous presence of IL-17A with or without blockade of secreted frizzled related protein (sFRP)1 and effects on differentiation were determined by qRT-PCR and mineralization assays. The impact of IL-17A on expression of Wnt signaling pathway antagonists was also assessed by qRT-PCR. Finally, regulation of Dickkopf (DKK)1 expression in murine synovial fibroblasts was evaluated after treatment with IL-17A, TNF, or IL-17A plus TNF.

RESULTS: IL-17A-deficient mice develop significantly more periosteal bone than wild-type mice at peak inflammation, despite comparable severity of inflammation and bone erosion. IL-17A inhibits calvarial osteoblast differentiation in vitro, inducing mRNA expression of the Wnt antagonist sFRP1 in osteoblasts, and suppressing sFRP3 expression, both potentially contributing to inhibition of osteoblast differentiation. Furthermore, a blocking antibody to sFRP1 reduced the inhibitory effect of IL-17A on differentiation. Although treatment with IL-17A suppresses DKK1 mRNA expression in osteoblasts, IL-17A plus TNF synergistically upregulate DKK1 mRNA expression in synovial fibroblasts.

CONCLUSIONS: IL-17A may limit the extent of bone formation at inflamed periosteal sites in spondyloarthritis. IL-17A inhibits calvarial osteoblast differentiation, in part by regulating expression of Wnt signaling pathway components. These results demonstrate that additional studies focusing on the role of IL-17A in bone formation in spondyloarthritis are indicated.

Complete Genome Sequences of Zika Virus Strains Isolated from the Blood of Patients in Thailand in 2014 and the Philippines in 2012

Wed, 09/28/2016 - 11:26am

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/Homo sapiens-tc/THA/2014/SV0127-14 and Zika virus/H. sapiens-tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage.

Associations of Peripubertal Serum Dioxin and Polychlorinated Biphenyl Concentrations with Pubertal Timing among Russian Boys

Wed, 09/28/2016 - 11:26am

BACKGROUND: Dioxins, furans, and polychlorinated biphenyls (PCBs), dioxin-like and nondioxin-like, have been linked to alterations in puberty.

OBJECTIVES: We examined the association of peripubertal serum levels of these compounds (and their toxic equivalents (TEQs)) with pubertal onset and maturity among Russian boys enrolled at ages 8-9 years and followed prospectively through ages 17-18 years.

METHODS: At enrollment, 473 boys had serum dioxin-like compounds and PCBs measured. At the baseline visit and annually until age 17-18 years, a physician performed pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV)]. 315 subjects completed the follow-up visit at 17-18 years of age. Pubertal onset was defined as TV > 3 mL, G2, or P2. Sexual maturity was defined as TV > /=20 mL, G5, or P5. Multivariable interval-censored models were used to evaluate associations of lipid-standardized concentrations with pubertal timing.

RESULTS: Medians (interquartile ranges) of the sum of dioxin-like compounds, TEQs, and nondioxin-like-PCBs were 362 pg/g lipid (279-495), 21.1 pg TEQ/g lipid (14.4-33.2), and 250 ng/g lipid (164-395), respectively. In adjusted models, the highest compared to lowest TEQ quartile was associated with later pubertal onset (months; 95% CI) [TV 11.6 (3.8, 19.4); G2 10.1 (1.4, 18.8)] and sexual maturity [TV 11.6 (5.7, 17.6); G5 9.7 (3.1, 16.2)]. However, the highest compared to the lowest quartile of nondioxin-like-PCBs, when co-adjusted by TEQs, was associated with earlier pubertal onset [TV -8.3 (-16.2, -0.3)] and sexual maturity [TV -6.3 (-12.2, -0.3); G5 -7.2 (-13.8, -0.6)]; the nondioxin-like-PCB associations were only significant when adjusted for TEQs. TEQs and PCBs were not significantly associated with pubic hair development.

CONCLUSIONS: Our results suggest that TEQs may delay, while nondioxin-like-PCBs advance, the timing of male puberty.

Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity

Wed, 09/28/2016 - 11:26am

Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins.

The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

Wed, 09/28/2016 - 11:26am

Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.

Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses

Wed, 09/28/2016 - 11:26am

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.

Whole exome sequencing links dental tumor to an autosomal-dominant mutation in ANO5 gene associated with gnathodiaphyseal dysplasia and muscle dystrophies

Wed, 09/28/2016 - 11:26am

Tumors of the jaws may represent different human disorders and frequently associate with pathologic bone fractures. In this report, we analyzed two affected siblings from a family of Russian origin, with a history of dental tumors of the jaws, in correspondence to original clinical diagnosis of cementoma consistent with gigantiform cementoma (GC, OMIM: 137575). Whole exome sequencing revealed the heterozygous missense mutation c.1067G > A (p.Cys356Tyr) in ANO5 gene in these patients. To date, autosomal-dominant mutations have been described in the ANO5 gene for gnathodiaphyseal dysplasia (GDD, OMIM: 166260), and multiple recessive mutations have been described in the gene for muscle dystrophies (OMIM: 613319, 611307); the same amino acid (Cys) at the position 356 is mutated in GDD. These genetic data and similar clinical phenotypes demonstrate that the GC and GDD likely represent the same type of bone pathology. Our data illustrate the significance of mutations in single amino-acid position for particular bone tissue pathology. Modifying role of genetic variations in another gene on the severity of the monogenic trait pathology is also suggested. Finally, we propose the model explaining the tissue-specific manifestation of clinically distant bone and muscle diseases linked to mutations in one gene.

Prevalent presence of periodic actin-spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species

Wed, 09/28/2016 - 11:26am

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal- and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.

Crave-Out: A Distraction/Motivation Mobile Game to Assist in Smoking Cessation

Wed, 09/28/2016 - 11:26am

BACKGROUND: Smoking is still the number one preventable cause of death. Cravings-an intense desire or longing for a cigarette-are a major contributor to quit attempt failure. New tools to help smokers' manage their cravings are needed.

OBJECTIVE: To present a case study of the development process and testing of a distraction/motivation game (Crave-Out) to help manage cravings.

METHODS: We used a phased approach: in Phase 1 (alpha testing), we tested and refined the game concept, using a Web-based prototype. In Phase 2 (beta testing), we evaluated the distraction/motivation potential of the mobile game prototype, using a prepost design. After varying duration of abstinence, smokers completed the Questionnaire of Smoking Urge-Brief (QSU-Brief) measurement before and after playing Crave-Out. Paired t tests were used to compare pregame and postgame QSU-Brief levels. To test dissemination potential, we released the game on the Apple iTunes App Store and tracked downloads between December 22, 2011, and May 5, 2014.

RESULTS: Our concept refinement resulted in a multilevel, pattern memory challenge game, with each level increasing in difficulty. Smokers could play the game as long as they wanted. At the end of each level, smokers were provided clear goals for the next level and rewards (positive reinforcement using motivational tokens that represented a benefit of quitting smoking). Negative reinforcement was removed in alpha testing as smokers felt it reminded them of smoking. Measurement of QSU-Brief (N=30) resulted in a pregame mean of 3.24 (SD 1.65) and postgame mean of 2.99 (SD 1.40) with an overall decrease of 0.25 in cravings (not statistically significant). In a subset analysis, the QSU-Brief decrease was significant for smokers abstinent for more than 48 hours (N=5) with a pregame mean of 2.84 (SD 1.16) and a postgame mean of 2.0 (SD 0.94; change=0.84; P =.03). Between December 22, 2011, and May 29, 2014, the game was downloaded 3372 times from the App-Store, with 1526 smokers visiting the online resource linked to the game.

CONCLUSIONS: Overall, playing the game resulted in small, but nonsignificant decreases in cravings, with changes greater for those had already quit for more than 48 hours. Lessons learned can inform further development. Future research could incorporate mHealth games in multicomponent cessation interventions.

TRIAL REGISTRATION: NCT00797628; (Archived by WebCite at

Single molecule analysis reveals reversible and irreversible steps during spliceosome activation

Wed, 09/28/2016 - 11:26am

The spliceosome is a complex machine composed of small nuclear ribonucleoproteins (snRNPs) and accessory proteins that excises introns from pre-mRNAs. After assembly the spliceosome is activated for catalysis by rearrangement of subunits to form an active site. How this rearrangement is coordinated is not well-understood. During activation, U4 must be released to allow U6 conformational change, while Prp19 complex (NTC) recruitment is essential for stabilizing the active site. We used multi-wavelength colocalization single molecule spectroscopy to directly observe the key events in Saccharomyces cerevisiae spliceosome activation. Following binding of the U4/U6.U5 tri-snRNP, the spliceosome either reverses assembly by discarding tri-snRNP or proceeds to activation by irreversible U4 loss. The major pathway for NTC recruitment occurs after U4 release. ATP stimulates both the competing U4 release and tri-snRNP discard processes. The data reveal the activation mechanism and show that overall splicing efficiency may be maintained through repeated rounds of disassembly and tri-snRNP reassociation.

Tanning bed burns reported on Twitter: over 15,000 in 2013

Wed, 09/28/2016 - 11:26am

Few surveillance tools exist for monitoring tanning bed injuries. Twitter data were examined to identify and describe reports of tanning bed-caused burns. Tweets sent in 2013 containing keywords for tanning bed use and burning were content analyzed to determine whether a burn caused by a tanning bed was described, and additional data on tanning behavior and burn characteristics were extracted. After content assessment, 15,178 (64 %) tweets were found to describe a tanning bed-caused burn. Sites most reportedly burnt were buttocks (n = 3117), face/head (n = 1020), and chest/breast (n = 546). Alarmingly, 200 burns to the eyes/eyelids were mentioned. A total of 456 tweets described burning > 1 time from a tanning bed. A total of 211 tweets mentioned falling asleep inside the tanning bed. In 2013, over 15,000 tweets reported tanning bed-caused burns. Twitter data provides unique insight into tanning behaviors and injuries not captured through traditional public health surveillance.

Interest in a Twitter-delivered weight loss program among women of childbearing age

Wed, 09/28/2016 - 11:26am

Weight management through the childbearing years is important, yet few women have access to efficacious weight loss programs. Online social network-delivered programs may increase reach and thus impact. The aim of this study was to gauge interest in a Twitter-based weight loss intervention among women of childbearing age and the feasibility of recruitment via Twitter. We recruited English-speaking women aged 18-45 years (N = 63) from Twitter to complete an anonymous online survey including open-ended questions about program advantages and concerns. Forty percent of participants were obese and 83 % were trying to lose weight. Eighty-one percent were interested in a Twitter-delivered weight loss program. Interest was high in all subgroups (62-100 %). Participants (59 %) cited program advantages, including convenience, support/accountability, and privacy. Concerns (59 %) included questions about privacy, support/accountability, engagement, efficacy, and technology barriers. Research is needed to develop and evaluate social media-delivered interventions, and to develop methods for recruiting participants directly from Twitter.

An exploration of the role of religion/spirituality in the promotion of physicians' wellbeing in Emergency Medicine

Wed, 09/28/2016 - 11:26am

BACKGROUND: Burnout is highly prevalent among Emergency Medicine (EM) physicians and has significant impact on quality of care and workforce retention. The objective of this study was to determine whether higher religion/spirituality (R/S) is associated with a lower prevalence of burnout among EM physicians (primary outcome). A history of malpractice lawsuits and maladaptive behaviors were the secondary outcomes.

METHODS: This was a cross-sectional, survey-based study conducted among a random sample of physicians from the Massachusetts College of Emergency Physicians mailing list. Burnout was measured using a validated 2-item version of the Maslach Burnout Inventory. Maladaptive behaviors (smoking, drinking, and substance use) and medical malpractice were self-reported. R/S measures included organized religiosity, religious affiliation, private R/S practice, self-rated spirituality, religious rest, and religious commitment. Logistic regression was used to model study outcomes as a function of R/S predictors.

RESULTS: Of 422 EM physicians who received the invitation to participate, 138 completed the survey (32.7%). The prevalence of burnout was 27%. No significant associations were observed between burnout and R/S indicators. Maladaptive behaviors (adjusted OR = 0.42, CI: 0.19 to 0.96; p = 0.039) and history of medical malpractice (adjusted OR = 0.32; CI: 0.11 to 0.93; p = 0.037) were less likely among physicians reporting to be more involved in organized religious activity and to observe a day of rest for religious reasons, respectively.

CONCLUSION: This study provides preliminary evidence for a possible protective association of certain dimensions of R/S on maladaptive behaviors and medical malpractice among EM physicians.

Leishmania amazonensis Engages CD36 to Drive Parasitophorous Vacuole Maturation

Wed, 09/28/2016 - 11:26am

Leishmania amastigotes manipulate the activity of macrophages to favor their own success. However, very little is known about the role of innate recognition and signaling triggered by amastigotes in this host-parasite interaction. In this work we developed a new infection model in adult Drosophila to take advantage of its superior genetic resources to identify novel host factors limiting Leishmania amazonensis infection. The model is based on the capacity of macrophage-like cells, plasmatocytes, to phagocytose and control the proliferation of parasites injected into adult flies. Using this model, we screened a collection of RNAi-expressing flies for anti-Leishmania defense factors. Notably, we found three CD36-like scavenger receptors that were important for defending against Leishmania infection. Mechanistic studies in mouse macrophages showed that CD36 accumulates specifically at sites where the parasite contacts the parasitophorous vacuole membrane. Furthermore, CD36-deficient macrophages were defective in the formation of the large parasitophorous vacuole typical of L. amazonensis infection, a phenotype caused by inefficient fusion with late endosomes and/or lysosomes. These data identify an unprecedented role for CD36 in the biogenesis of the parasitophorous vacuole and further highlight the utility of Drosophila as a model system for dissecting innate immune responses to infection.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group

Wed, 09/28/2016 - 11:25am

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset 21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease

Wed, 09/28/2016 - 11:25am

OBJECTIVE: Normal adipose tissue growth and function is critical to maintaining metabolic homeostasis and its excess (e.g. obesity) or absence (e.g. lipodystrophy) is associated with severe metabolic disease. The goal of this study was to understand the mechanisms maintaining healthy adipose tissue growth and function.

METHODS: Adipose tissue senses and responds to systemic changes in growth factor and nutrient availability; in cells mTORC1 regulates metabolism in response to growth factors and nutrients. Thus, mTORC1 is poised to be a critical intracellular regulator of adipocyte metabolism. Here, we investigate the role of mTORC1 in mature adipocytes by generating and characterizing mice in which the Adiponectin-Cre driver is used to delete floxed alleles of Raptor, which encodes an essential regulatory subunit of mTORC1.

RESULTS: Raptor (Adipoq-cre) mice have normal white adipose tissue (WAT) mass for the first few weeks of life, but soon thereafter develop lipodystrophy associated with hepatomegaly, hepatic steatosis, and insulin intolerance. Raptor (Adipoq-cre) mice are also resistant to becoming obese when consuming a high fat diet (HFD). Resistance to obesity does not appear to be due to increased energy expenditure, but rather from failed adipose tissue expansion resulting in severe hepatomegaly associated with hyperphagia and defective dietary lipid absorption. Deleting Raptor in WAT also decreases C/EBPalpha expression and the expression of its downstream target adiponectin, providing one possible mechanism of mTORC1 function in WAT.

CONCLUSIONS: mTORC1 activity in mature adipocytes is essential for maintaining normal adipose tissue growth and its selective loss in mature adipocytes leads to a progressive lipodystrophy disorder and systemic metabolic disease that shares many of the hallmarks of human congenital generalized lipodystrophy.