NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum homeostasis

Many metabolic diseases disrupt endoplasmic reticulum (ER) homeostasis, but little is known about how metabolic activity is communicated to the ER. Here, we show in hepatocytes and other metabolically active cells that decreasing the availability of substrate for the tricarboxylic acid (TCA) cycle diminished NADPH production, elevated glutathione oxidation, led to altered oxidative maturation of ER client proteins, and attenuated ER stress. This attenuation was prevented when glutathione oxidation was disfavored. ER stress was also alleviated by inhibiting either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity increased NADPH production, glutathione reduction, and ER stress. Validating these findings, deletion of the Mitochondrial Pyruvate Carrier-which is known to decrease TCA cycle activity and protect the liver from steatohepatitis-also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. Together, our results demonstrate a novel pathway by which mitochondrial metabolic activity is communicated to the ER through the relay of redox metabolites

Extended Functional Connectivity of Convergent Structural Alterations Among Individuals with PTSD: A Neuroimaging Meta-Analysis

Background: Post-traumatic stress disorder (PTSD) is a debilitating disorder defined by the onset of intrusive, avoidant, negative cognitive or affective, and/or hyperarousal symptoms after witnessing or experiencing a traumatic event. Previous voxel-based morphometry studies have provided insight into structural brain alterations associated with PTSD with notable heterogeneity across these studies. Furthermore, how structural alterations may be associated with brain function, as measured by task-free and task-based functional connectivity, remains to be elucidated. Methods: Using emergent meta-analytic techniques, we sought to first identify a consensus of structural alterations in PTSD using the anatomical likelihood estimation (ALE) approach. Next, we generated functional profiles of identified convergent structural regions utilizing resting-state functional connectivity (rsFC) and meta-analytic co-activation modeling (MACM) methods. Finally, we performed functional decoding to examine mental functions associated with our ALE, rsFC, and MACM brain characterizations. Results: We observed convergent structural alterations in a single region located in the medial prefrontal cortex. The resultant rsFC and MACM maps identified functional connectivity across a widespread, whole-brain network that included frontoparietal and limbic regions. Functional decoding revealed overlapping associations with attention, memory, and emotion processes. Conclusions: Consensus-based functional connectivity was observed in regions of the default mode, salience, and central executive networks, which play a role in the tripartite model of psychopathology. Taken together, these findings have important implications for understanding the neurobiological mechanisms associated with PTSD

Pathways to Belonging and Engagement: Testing a Tailored Social Belonging Intervention for University Students

Background Prominent theories of motivation suggest that belonging plays a critical role in student success (Connell & Wellborn, 1991). Social-belonging interventions have been shown to improve student belonging, well-being, engagement, and more—especially those from traditionally disadvantaged backgrounds (Walton & Brady, 2017). The current study aimed to explore the effects of a tailored social-belonging intervention delivered in introductory classes at VCU on students’ belonging, engagement, persistence, and achievement. Methods A diverse sample of first-year undergraduate students at VCU participated. To create authentic intervention materials, we collaborated with a diverse group of upper-level undergraduate student researchers who wrote narratives to present vivid stories of how they personally experienced and overcame struggles to belong. Prior to and following the intervention, students completed a survey that assessed student belonging, engagement, and social and academic fit. We also collected student demographics, achievement, and additional data from institutional records. Results Following the implementation of the belonging intervention, data was collected on students’ sense of belonging, their social and academic fit at the university, and other related outcomes. While most students felt as though they belonged at VCU and had the potential to succeed, there were still some students who worried whether they belonged in college. Conclusions From students’ responses, faculty and advisors of first-year students were given an overview on students’ current states of belonging at VCU. As an implication for future research, we argue that including diverse upper-level students as fellow researchers in this work strengthens the authenticity and effectiveness of the belonging intervention.https://scholarscompass.vcu.edu/gradposters/1171/thumbnail.jp

Hunters and Their Perceptions of Public Access: A View from Afield

Declining hunter participation threatens cultural traditions and public support for conservation, warranting examination of the forces behind the downward trajectory. Access to lands for hunting, an often-cited reason for non participation, may play a critical role in the retention and recruitment of hunters. Meeting the access needs of a diverse hunting constituency requires understanding how hunters use and perceive access opportunities, particularly public-access sites. Given that perceptions of access are entirely place based and degrade with time, traditional postseason survey methods may fail to adequately quantify the value of public access to the hunting constituency. To overcome the potential limitations of postseason surveys, we conducted on-site assessments of hunter perceptions of habitat quality, game abundance, ease of access, and crowding as well as whether the experience met the hunters’ expectations and their likelihood to return to hunt. Over 3 y, we interviewed 3,248 parties of which 71.5% were hunting. Most parties (65.9%) reported having no private access within the region of Nebraska where they were interviewed. Parties (67.6%) were largely limited to two or fewer hunters, most of whom were adult males (84.3%) who were, on average, 41.2 y old. The perception of public-access sites was generally positive, but 43.1% of parties indicated that game abundance was below average despite 59.2% of parties seeing game and 37.3% harvesting at least one animal. Similar to other explorations of hunter satisfaction, we found game abundance, and in particular harvest success, had the most consistent relationship with hunter perception of public access. By surveying multiple types of hunters across sites that encompass a range of social and ecological conditions, we gained a broader understanding of how hunters perceive public access in real time, which will help to inform future management decisions to foster and improve public-access programs

ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress

Neural Systems Underlying RDoC Social Constructs: An Activation Likelihood Estimation Meta-Analysis

Neuroscientists have sought to identify the underlying neural systems supporting social processing that allow interaction and communication, forming social relationships, and navigating the social world. Through the use of NIMH’s Research Domain Criteria (RDoC) framework, we evaluated consensus among studies that examined brain activity during social tasks to elucidate regions comprising the “social brain”. We examined convergence across tasks corresponding to the four RDoC social constructs, including Affiliation and Attachment, Social Communication, Perception and Understanding of Self, and Perception and Understanding of Others. We performed a series of coordinate-based meta-analyses using the activation likelihood estimate (ALE) method. Meta-analysis was performed on whole-brain coordinates reported from 864 fMRI contrasts using the NiMARE Python package, revealing convergence in medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, temporoparietal junction, bilateral insula, amygdala, fusiform gyrus, precuneus, and thalamus. Additionally, four separate RDoC-based meta-analyses revealed differential convergence associated with the four social constructs. These outcomes highlight the neural support underlying these social constructs and inform future research on alterations among neurotypical and atypical populations

DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma

DEAD-Box Helicase 3 X-Linked (DDX3X) is frequently mutated in the Wingless (WNT) and Sonic hedghog (SHH) subtypes of medulloblastoma—the commonest malignant childhood brain tumor, but whether DDX3X functions as a medulloblastoma oncogene or tumor suppressor gene is not known. Here, we show that Ddx3x regulates hindbrain patterning and development by controlling Hox gene expression and cell stress signaling. In mice predisposed to Wnt- or Shh medulloblastoma, Ddx3x sensed oncogenic stress and suppressed tumor formation. WNT and SHH medulloblastomas normally arise only in the lower and upper rhombic lips, respectively. Deletion of Ddx3x removed this lineage restriction, enabling both medulloblastoma subtypes to arise in either germinal zone. Thus, DDX3X is a medulloblastoma tumor suppressor that regulates hindbrain development and restricts the competence of cell lineages to form medulloblastoma subtypes

The NEWFIRM Medium-band Survey: Photometric Catalogs, Redshifts and the Bimodal Color Distribution of Galaxies out to z~3

We present deep near-infrared (NIR) medium-bandwidth photometry over the wavelength range 1-1.8 microns in the All-wavelength Extended Groth strip International Survey (AEGIS) and Cosmic Evolution Survey (COSMOS) fields. The observations were carried out as part of the NEWFIRM Medium-Band Survey (NMBS), an NOAO survey program on the Mayall 4m telescope on Kitt Peak using the NOAO Extremely Wide-Field Infrared Imager (NEWFIRM). In this paper, we describe the full details of the observations, data reduction and photometry for the survey. We also present a public K-selected photometric catalog, along with accurate photometric redshifts. The redshifts are computed with 37 (20) filters in the COSMOS (AEGIS) fields, combining the NIR medium-bandwidth data with existing ultraviolet (UV; Galaxy Evolution Explorer), visible and NIR (Canada-France-Hawaii Telescope and Subaru) and mid-IR (Spitzer/IRAC) imaging. We find excellent agreement with publicly available spectroscopic redshifts, with sigma_z/(1+z)~1-2% for ~4000 galaxies at z=0-3. The NMBS catalogs contain ~13,000 galaxies at z>1.5 with accurate photometric redshifts and rest-frame colors. Due to the increased spectral resolution obtained with the five NIR medium-band filters, the median 68% confidence intervals of the photometric redshifts of both quiescent and star-forming galaxies are a factor of ~2 times smaller when comparing catalogs with medium-band NIR photometry to NIR broadband photometry. We show evidence for a clear bimodal color distribution between quiescent and star-forming galaxies that persists to z~3, a higher redshift than has been probed so far.Comment: All NMBS data products and a high resolution version of paper are available for download at http://www.astro.yale.edu/nmbs; Accepted for publication in ApJ; 24 pages, 21 figures, 4 table