Depression and HIV infection: Risk factors for cardiovascular disease

Depression, a common mental health disorder, is associated with higher risk of cardiovascular disease (CVD). Adults with HIV infection are often burdened with depression. Although both depression and HIV infection are risk factors for CVD, previous studies have not explored how co-occurring depression and HIV are associated with CVD outcomes or underlying physiology. The aim of this dissertation was to (i) measure the risk of incident heart failure (HF) with co-occurring major depressive disorder (MDD) and HIV infection; (ii) measure biomarkers of inflammation, coagulation, monocyte activation, and metabolism with depression and HIV infection; and (iii) provide a comprehensive biomarker profile associated with symptoms of major depression in HIV+ and HIV- participants. We analyzed data from the Veterans Aging Cohort Study (VACS), a prospective study of HIV+ and HIV- veterans matched on age, sex, race/ethnicity, and geographical region. In a sample of 81,427 participants, we found that those with co-occurring HIV infection and MDD had significantly higher risk of incident HF compared to HIV- participants without MDD, after adjusting for covariates. In a subset of 2,099 participants, we determined that depression was associated with higher concentrations of interleukin-6 and soluble CD14 (biomarkers for inflammation and monocyte activation) in HIV- participants but not HIV+ participants. HIV+ participants had higher concentrations of glucose and triglycerides and lower concentrations of high-density lipoprotein cholesterol with depression. In a smaller sample with more extensive biomarker data, we found a significant association between depression and lower concentrations of vascular endothelial growth factor in HIV+ participants. Neither biomarker study supported the hypothesis that co-occurring depressive symptoms and HIV infection would interact and produce excessively high concentrations of these biomarkers. The findings from this dissertation are significant for public health research and practice. Depression is extremely common and is a risk factor for CVD. In the future, investigators must elucidate specific mechanisms driving CVD risk with depression and identify effective therapies for preventing depression-related CVD morbidity and mortality in both HIV- and HIV+ adults. Meanwhile, clinicians must remain vigilant in identifying and managing depressive symptoms, especially among those who are at heightened risk for CVD due to HIV infection

The Impact of Host Diet on Wolbachia Titer in Drosophila

While a number of studies have identified host factors that influence endosymbiont titer, little is known concerning environmental influences on titer. Here we examined nutrient impact on maternally transmitted Wolbachia endosymbionts in Drosophila. We demonstrate that Drosophila reared on sucrose- and yeast-enriched diets exhibit increased and reduced Wolbachia titers in oogenesis, respectively. The yeast-induced Wolbachia depletion is mediated in large part by the somatic TOR and insulin signaling pathways. Disrupting TORC1 with the small molecule rapamycin dramatically increases oocyte Wolbachia titer, whereas hyper-activating somatic TORC1 suppresses oocyte titer. Furthermore, genetic ablation of insulin-producing cells located in the Drosophila brain abolished the yeast impact on oocyte titer. Exposure to yeast-enriched diets altered Wolbachia nucleoid morphology in oogenesis. Furthermore, dietary yeast increased somatic Wolbachia titer overall, though not in the central nervous system. These findings highlight the interactions between Wolbachia and germline cells as strongly nutrient-sensitive, and implicate conserved host signaling pathways by which nutrients influence Wolbachia titer.Florida International University, National Institutes of Health, Minority Access to Research Careers program: (GMS-2T34GM007910), National Science Foundation grant: (MCB-1122252)

Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer

BACKGROUND: Long intergenic non-coding RNAs (lncRNAs) represent an emerging and under-studied class of transcripts that play a significant role in human cancers. Due to the tissue- and cancer-specific expression patterns observed for many lncRNAs it is believed that they could serve as ideal diagnostic biomarkers. However, until each tumor type is examined more closely, many of these lncRNAs will remain elusive. RESULTS: Here we characterize the lncRNA landscape in lung cancer using publicly available transcriptome sequencing data from a cohort of 567 adenocarcinoma and squamous cell carcinoma tumors. Through this compendium we identify over 3,000 unannotated intergenic transcripts representing novel lncRNAs. Through comparison of both adenocarcinoma and squamous cell carcinomas with matched controls we discover 111 differentially expressed lncRNAs, which we term lung cancer-associated lncRNAs (LCALs). A pan-cancer analysis of 324 additional tumor and adjacent normal pairs enable us to identify a subset of lncRNAs that display enriched expression specific to lung cancer as well as a subset that appear to be broadly deregulated across human cancers. Integration of exome sequencing data reveals that expression levels of many LCALs have significant associations with the mutational status of key oncogenes in lung cancer. Functional validation, using both knockdown and overexpression, shows that the most differentially expressed lncRNA, LCAL1, plays a role in cellular proliferation. CONCLUSIONS: Our systematic characterization of publicly available transcriptome data provides the foundation for future efforts to understand the role of LCALs, develop novel biomarkers, and improve knowledge of lung tumor biology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-014-0429-8) contains supplementary material, which is available to authorized users

Risk Factors for Triple-Negative Breast Cancer in Women Under Age 45

Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use >/=1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (Pheterogeneity = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (Pheterogeneity = 0.02 and 0.01, respectively). Among women /=1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women </=40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology

Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) affects over 200000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined. METHODS: Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls. MAIN RESULTS: Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis. CONCLUSIONS: We demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then 'deprime' and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.This work was supported by the Wellcome Trust, MRC (UK), Papworth Hospital R&D, Intensive Care Society and NIHR Cambridge Biomedical Research Centre.This is the final published version, also available from http://thorax.bmj.com/content/early/2014/04/04/thoraxjnl-2013-204742.full

Cue-Evoked Dopamine Release Rapidly Modulates D2 Neurons in the Nucleus Accumbens During Motivated Behavior

Dopaminergic neurons that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) fire in response to unpredicted rewards or to cues that predict reward delivery. Although it is well established that reward-related events elicit dopamine release in the NAc, the role of rapid dopamine signaling in modulating NAc neurons that respond to these events remains unclear. Here, we examined dopamine's actions in the NAc in the rat brain during an intracranial self-stimulation task in which a cue predicted lever availability for electrical stimulation of the VTA. To distinguish actions of dopamine at select receptors on NAc neurons during the task, we used a multimodal sensor that probes three aspects of neuronal communication simultaneously: neurotransmitter release, cell firing, and identification of dopamine receptor type. Consistent with prior studies, we first show dopamine release events in the NAc both at cue presentation and after lever press (LP). Distinct populations of NAc neurons encode these behavioral events at these same locations selectively. Using our multimodal sensor, we found that dopamine-mediated responses after the cue involve exclusively a subset of D2-like receptors (D2Rs), whereas dopamine-mediated responses proximal to the LP are mediated by both D1-like receptors (D1R) and D2Rs. These results demonstrate for the first time that dopamine-mediated responses after cues that predict reward availability are specifically linked to its actions at a subset of neurons in the NAc containing D2Rs

Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

Type I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection. However, the role of astrocytes in innate immune responses of the BBB during viral infection of the CNS remains to be fully elucidated. Here, we have demonstrated that type I IFNAR signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Mice with astrocyte-specific loss of IFNAR signaling showed decreased survival after West Nile virus infection. Accelerated mortality was not due to expanded viral tropism or increased replication. Rather, viral entry increased specifically in the hindbrain of IFNAR-deficient mice, suggesting that IFNAR signaling critically regulates BBB permeability in this brain region. Pattern recognition receptors and IFN-stimulated genes had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes than did cerebral cortical astrocytes, suggesting that IFNAR signaling has brain region–specific roles in CNS immune responses. Taken together, our data identify cerebellar astrocytes as key responders to viral infection and highlight the existence of distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS

The Relationship Between Intermittent Limit Cycles and Postural Instability Associated with Parkinson’s Disease

Background: Many disease-specifc factors such as muscular weakness, increased muscle stiffness, varying postural strategies, and changes in postural refexes have been shown to lead to postural instability and fall risk in people with Parkinson’s disease (PD). Recently, analytical techniques, inspired by the dynamical systems perspective on movement control and coordination, have been used to examine the mechanisms underlying the dynamics of postural declines and the emergence of postural instabilities in people with PD. Methods: A wavelet-based technique was used to identify limit cycle oscillations (LCOs) in the anterior–posterior (AP) postural sway of people with mild PD (n = 10) compared to age-matched controls (n = 10). Participants stood on a foam and on a rigid surface while completing a dual task (speaking). Results: There was no signifcant difference in the root mean square of center of pressure between groups. Three out of 10 participants with PD demonstrated LCOs on the foam surface, while none in the control group demonstrated LCOs. An inverted pendulum model of bipedal stance was used to demonstrate that LCOs occur due to disease-specifc changes associated with PD: time-delay and neuromuscular feedback gain. Conclusion: Overall, the LCO analysis and mathematical model appear to capture the subtle postural instabilities associated with mild PD. In addition, these fndings provide insights into the mechanisms that lead to the emergence of unstable posture in patients with PD

On the origin of seismic anisotropy in the shallow crust of the Northern Volcanic Zone, Iceland

Title: Authors: Conor Andrew Bacon, Jessica Helen Johnson, Robert Stephen White, Nicholas Rawlinson Journal: Journal of Geophysical Research: Solid Earth Plain Language Summary Iceland is well known for its earthquakes and volcanoes, which have helped to produce an awe-inspiring primordial landscape over the last 20 million years or so. The emergence of Iceland in the North Atlantic Ocean can be attributed to the interaction of the Mid-Atlantic Ridge, where new oceanic crust forms by rifting between the North American and Eurasian plates, and a rising conduit of hot mantle from deep in the Earth, known as a mantle plume. The confluence of these two phenomena has produced excessive melting of mantle rocks, with the resultant melt accreted and cooled to form the Icelandic crust. We investigate how extensional stresses related to the divergence of the two tectonic plates have influenced the upper 3–4 km of the crust around Askja volcano, in the deep interior of Iceland. To do so, we exploit information contained in recordings of earthquakes from the neighborhood of Askja, which suggests that cracks formed parallel to the Mid-Atlantic Ridge, which permeate the upper crust, gradually close with depth. This relationship between the regional stress field associated with rifting and brittle deformation in the uppermost crust breaks down around Askja itself, where magmatic processes likely cause local changes in the stress field. Abstract The Icelandic crust is a product of its unique tectonic setting, where the interaction of an ascending mantle plume and the Mid-Atlantic Ridge has caused elevated mantle melting, with the melt accreted and cooled in the crust to form an oceanic plateau. We investigate the strength and orientation of seismic anisotropy in the upper crust of the Northern Volcanic Zone using local earthquake shear-wave splitting, with a view to understanding how the contemporary stress field may influence sub-wavelength structure and processes. This is achieved using a data set comprising urn:x-wiley:21699313:media:jgrb55395:jgrb55395-math-000150,000 earthquakes located in the top 10 km of the crust, recorded by up to 70 stations over a 9 year period. We find that anisotropy is largely confined to the top 3–4 km of the crust, with an average delay time of 0.10 ± 0.05 s, and an average orientation of the fast axis of anisotropy of N014°E ± 27°, which is perpendicular to the spreading direction of the Eurasian and North American plates (N106°E). These results are consistent with the presence of rift-parallel cracks that gradually close with depth, the preferential opening of which is controlled by the regional stress field. Lateral variations in the strength of shear wave anisotropy (SWA) reveal that regions with the highest concentrations of earthquakes have the highest SWA values (∼10%), which reflects the presence of significant brittle deformation. Disruption of the orientation of the fast axis of anisotropy around Askja volcano can be related to local stress changes caused by underlying magmatic processes

Impaired Cognitive Flexibility After Neonatal Perirhinal Lesions in Rhesus Macaques

Previous research indicated that monkeys with neonatal perirhinal lesions (Neo-PRh) were impaired on working memory (WM) tasks that generated proactive interference, but performed normally on WM tasks devoid of interference (Weiss et al., 2016). This finding suggested that the early lesions disrupted cognitive processes important for resolving proactive interference, such as behavioral inhibition and cognitive flexibility. To distinguish between these possibilities, the same Neo-PRh monkeys and their controls were tested using the Intradimensional/Extradimensional attentional set-shifting task (Roberts et al., 1988; Dias et al., 1997). Neo-PRh monkeys completed the Simple and Compound Discrimination stages, the Intradimensional Shift stage, and all Reversal stages comparably to controls, but made significantly more errors on the Extradimensional Shift stage of the task. These data indicate that impaired cognitive flexibility was the likely source of increased perseverative errors made by Neo-PRh monkeys when performing WM tasks, rather than impaired behavioral inhibition, and imply that the perirhinal cortex and its interactions with the PFC may play a unique and critical role in the development of attentional set shifting abilities