The disconnect between animal models of sepsis and human sepsis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141189/1/jlb0137.pd

Innervation of gonadotropin-releasing hormone neurons by peptidergic neurons conveying circadian or energy balance information in the mouse

Background: Secretion of gonadotropin-releasing hormone (GnRH) produced in neurons in the basal forebrain is the primary regulator of reproductive maturation and function in mammals. Peptidergic signals relating to circadian timing and energy balance are an important influence on the reproductive axis. The aim of this study was to investigate the innervation of GnRH neurons by peptidergic neurons. Methodology/Principal Findings: Immunohistochemistry and confocal microscopy were used to detect appositions of peptidergic fibers (NPY, β-endorphin, MCH) associated with energy balance and metabolic status in transgenic mice expressing a green fluorescent protein reporter construct in GnRH neurons. The frequency of these appositions was compared to those of vasoactive intestinal peptide (VIP), a hypothalamic neuropeptide likely to convey circadian timing information to the GnRH secretory system. The majority of GnRH neurons (73-87%) were closely apposed by fibers expressing NPY, β-endorphin, or MCH, and a significant proportion of GnRH neurons (28%) also had close contacts with VIP-ir fibers. Conclusions/Significance: It is concluded that GnRH neurons in the mouse receive a high frequency of direct modulatory inputs from multiple hypothalamic peptide systems known to be important in conveying circadian information and signalling energy balance. © 2009 Ward et al

Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition.

Autophagy is a lysosomal degradation pathway that eliminates aggregated proteins and damaged organelles to maintain cellular homeostasis. A major route for activating autophagy involves inhibition of the mTORC1 kinase, but current mTORC1-targeting compounds do not allow complete and selective mTORC1 blockade. Here, we have coupled screening of a covalent ligand library with activity-based protein profiling to discover EN6, a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase, which activates mTORC1 via the Rag guanosine triphosphatases. EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling

Not all developmental assets are related to positive health outcomes in college students

<p>Abstract</p> <p>Background</p> <p>The purpose of this investigation was to model the relationships between developmental assets, life satisfaction, and health-related quality of life (HRQOL) among a stratified, random sample (<it>n </it>= 765, 56% response rate) of college students.</p> <p>Methods</p> <p>Structural equation modeling techniques were employed to test the relationships using Mplus v4.21; Model evaluations were based on 1) theoretical salience, 2) global fit indices (chi-square goodness of fit, comparative fit index: CFI and Tucker-Lewis Index: TLI), 3) microfit indices (parameter estimates, root mean squared error of approximation: RMSEA and residuals) and 4) parsimony.</p> <p>Results</p> <p>The model fit the data well: χ²(<it>n </it>= 581, 515) = 1252.23, CFI = .94, TLI = .93 and RMSEA = .05. First, participants who reported increased Family Communication also reported higher levels of life satisfaction. Second, as participants reported having more Non-Parental Role Models, life satisfaction decreased and poor mental HRQOL days increased. Finally increased Future Aspirations was related to increased poor mental HRQOL days. Results were variant across gender.</p> <p>Conclusions</p> <p>Preliminary results suggest not all developmental assets are related to positive health outcomes among college students, particularly mental health outcomes. While the findings for Family Communication were expected, the findings for Non-Parental Role Models suggest interactions with potential role models in college settings may be naturally less supportive. Future Aspirations findings suggest college students may harbor a greater temporal urgency for the rigors of an increasingly competitive work world. In both cases, these assets appear associated with increased poor mental HRQOL days.</p

The Use of Public Funds for Private Benefit: An Examination of the Relationship between Public Stadium Funding and Ticket Prices in the National Football League

During the past decade there has been a proliferation of sports stadia being built in America’s municipal districts. While it used to be common for the public to fully fund stadium construction projects, over the past 20 years factors such as political motives, tax reform, and increased public awareness of tax equity have forced sports teams to share increasing amounts of the financial burden (Crompton, Howard, & Var, 2003). As public funding for stadia construction has decreased, franchises have continued to strive for maximized profits. Concurrently, the cost of attending events in sports stadia has increased for consumers in terms of higher ticket prices even though changes in fixed costs should not affect pricing (Leeds & von Allmen, 2004). The purpose of this study was to examine the relationship between the use of public funds to build stadia and the profit maximizing goals of National Football League (NFL) franchises. A hypothesis was formulated that stated the impact of the public share of the construction cost would have no effect on relative ticket prices for those that consume the product. The cross-sectional data for a ticket price model, which consisted of seasonal data from every NFL team to play from 1991 through 2003, was investigated. The results showed an increase in public funding by 10% lowers ticket prices by 42 cents. As shown, the bulk of the variation in ticket prices was due to a general increase over time and MSA per capita income

Executive Function Capacities, Negative Driving Behavior and Crashes in Young Drivers

Motor vehicle crashes remain a leading cause of injury and death in adolescents, with teen drivers three times more likely to be in a fatal crash when compared to adults. One potential contributing risk factor is the ongoing development of executive functioning with maturation of the frontal lobe through adolescence and into early adulthood. Atypical development resulting in poor or impaired executive functioning (as in Attention-Deficit/Hyperactivity Disorder) has been associated with risky driving and crash outcomes. However, executive function broadly encompasses a number of capacities and domains (e.g., working memory, inhibition, set-shifting). In this review, we examine the role of various executive function sub-processes in adolescent driver behavior and crash rates. We summarize the state of methods for measuring executive control and driving outcomes and highlight the great heterogeneity in tools with seemingly contradictory findings. Lastly, we offer some suggestions for improved methods and practical ways to compensate for the effects of poor executive function (such as in-vehicle assisted driving devices). Given the key role that executive function plays in safe driving, this review points to an urgent need for systematic research to inform development of more effective training and interventions for safe driving among adolescents

Binding modes of high stoichiometry guest complexes with a Co8L12 cage uncovered by mass spectrometry

We demonstrate how different modes of guest binding with a Co8L12 cubic cage can be determined using ESI-MS. High stoichiometry guest binding was observed, with the guests preferentially binding externally, but internal guest inclusion was also seen at higher guest loading

Impact of major depression on cardiovascular outcomes for individuals with hypertension: prospective survival analysis in UK Biobank

Objectives: To assess whether a history of major depressive disorder (MDD) in middle-aged individuals with hypertension influences first-onset cardiovascular disease outcomes. Design: Prospective cohort survival analysis using Cox proportional hazards regression with a median follow-up of 63 months (702 902 person-years). Four mutually exclusive groups were compared: hypertension only (n=56 035), MDD only (n=15 098), comorbid hypertension plus MDD (n=12 929) and an unaffected (no hypertension, no MDD) comparison group (n=50 798). Setting: UK Biobank. Participants: UK Biobank participants without cardiovascular disease aged 39–70 who completed psychiatric questions relating International Classification of Diseases-10 Revision (ICD-10) diagnostic criteria on a touchscreen questionnaire at baseline interview in 2006–2010 (n=134 860). Primary and secondary outcome measures: First-onset adverse cardiovascular outcomes leading to hospital admission or death (ICD-10 codes I20–I259, I60–69 and G45–G46), adjusted in a stepwise manner for sociodemographic, health and lifestyle features. Secondary analyses were performed looking specifically at stroke outcomes (ICD-10 codes I60–69 and G45–G46) and in gender-separated models. Results: Relative to controls, adjusted HRs for adverse cardiovascular outcomes were increased for the hypertension only group (HR 1.36, 95% CI 1.22 to 1.52) and were higher still for the comorbid hypertension plus MDD group (HR 1.66, 95% CI 1.45 to 1.9). HRs for the comorbid hypertension plus MDD group were significantly raised compared with hypertension alone (HR 1.22, 95% CI 1.1 to 1.35). Interaction measured using relative excess risk due to interaction (RERI) and likelihood ratios (LRs) were identified at baseline (RERI 0.563, 95% CI 0.189 to 0.938; LR p=0.0116) but not maintained during the follow-up. Limitations: Possible selection bias in UK Biobank and inability to assess for levels of medication adherence. Conclusions: Comorbid hypertension and MDD conferred greater hazard than hypertension alone for adverse cardiovascular outcomes, although evidence of interaction between hypertension and MDD was inconsistent over time. Future cardiovascular risk prediction tools may benefit from the inclusion of questions about prior history of depressive disorders