Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

TorsinA and the TorsinA-Interacting Protein Printor Have No Impact on Endoplasmic Reticulum Stress or Protein Trafficking in Yeast

Early-onset torsion dystonia is a severe, life-long disease that leads to loss of motor control and involuntary muscle contractions. While the molecular etiology of the disease is not fully understood, a mutation in an AAA+ ATPase, torsinA, has been linked to disease onset. Previous work on torsinA has shown that it localizes to the endoplasmic reticulum, where there is evidence that it plays roles in protein trafficking, and potentially also protein folding. Given the high level of evolutionary conservation among proteins involved in these processes, the ability of human such proteins to function effectively in yeast, as well as the previous successes achieved in examining other proteins involved in complex human diseases in yeast, we hypothesized that Saccharomyces cerevisiae might represent a useful model system for studying torsinA function and the effects of its mutants. Since torsinA is proposed to function in protein homeostasis, we tested cells for their ability to respond to various stressors, using a fluorescent reporter to measure the unfolded protein response, as well as their rate of protein secretion. TorsinA did not impact these processes, even after co-expression of its recently identified interacting partner, printor. In light of these findings, we propose that yeast may lack an additional cofactor necessary for torsinA function or proteins required for essential post-translational modifications of torsinA. Alternatively, torsinA may not function in endoplasmic reticulum protein homeostasis. The strains and assays we describe may provide useful tools for identifying and investigating these possibilities and are freely available.Howard Hughes Medical InstituteBachmann-Strauss Dystonia and Parkinson Foundatio

Motor Deficits and Decreased Striatal Dopamine Receptor 2 Binding Activity in the Striatum-Specific Dyt1 Conditional Knockout Mice

DYT1 early-onset generalized dystonia is a hyperkinetic movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Recently, significant progress has been made in studying pathophysiology of DYT1 dystonia using targeted mouse models. Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 knock-down (KD) mice exhibit motor deficits and alterations of striatal dopamine metabolisms, while Dyt1 knockout (KO) and Dyt1 ΔGAG homozygous KI mice show abnormal nuclear envelopes and neonatal lethality. However, it has not been clear whether motor deficits and striatal abnormality are caused by Dyt1 mutation in the striatum itself or the end results of abnormal signals from other brain regions. To identify the brain region that contributes to these phenotypes, we made a striatum-specific Dyt1 conditional knockout (Dyt1 sKO) mouse. Dyt1 sKO mice exhibited motor deficits and reduced striatal dopamine receptor 2 (D2R) binding activity, whereas they did not exhibit significant alteration of striatal monoamine contents. Furthermore, we also found normal nuclear envelope structure in striatal medium spiny neurons (MSNs) of an adult Dyt1 sKO mouse and cerebral cortical neurons in cerebral cortex-specific Dyt1 conditional knockout (Dyt1 cKO) mice. The results suggest that the loss of striatal torsinA alone is sufficient to produce motor deficits, and that this effect may be mediated, at least in part, through changes in D2R function in the basal ganglia circuit

Neighborhood deprivation and biomarkers of health in Britain: The mediating role of the physical environment

Background: Neighborhood deprivation has been consistently linked to poor individual health outcomes; however, studies exploring the mechanisms involved in this association are scarce. The objective of this study was to investigate whether objective measures of the physical environment mediate the association between neighborhood socioeconomic deprivation and biomarkers of health in Britain. Methods: We linked individual-level biomarker data from Understanding Society: The UK Household Longitudinal Survey (2010-2012) to neighborhood-level data from different governmental sources. Our outcome variables were forced expiratory volume in 1 s (FEV1%; n=16,347), systolic blood pressure (SBP; n=16,846), body mass index (BMI; n=19,417), and levels of C-reactive protein (CRP; n=11,825). Our measure of neighborhood socioeconomic deprivation was the Carstairs index, and the neighborhood-level mediators were levels of air pollutants (sulphur dioxide [SO2], particulate matter [PM10], nitrogen dioxide [NO2], and carbon monoxide [CO]), green space, and proximity to waste and industrial facilities. We fitted a multilevel mediation model following a multilevel structural equation framework in MPlus v7.4, adjusting for age, gender, and income. Results: Residents of poor neighborhoods and those exposed to higher pollution and less green space had worse health outcomes. However, only SO2exposure significantly and partially mediated the association between neighborhood socioeconomic deprivation and SBP, BMI, and CRP. Conclusion: Reducing air pollution exposure and increasing access to green space may improve population health but may not decrease health inequalities in Britain

Altered Dendritic Morphology of Purkinje cells in Dyt1 ΔGAG Knock-In and Purkinje Cell-Specific Dyt1 Conditional Knockout Mice

BACKGROUND: DYT1 early-onset generalized dystonia is a neurological movement disorder characterized by involuntary muscle contractions. It is caused by a trinucleotide deletion of a GAG (ΔGAG) in the DYT1 (TOR1A) gene encoding torsinA; the mouse homolog of this gene is Dyt1 (Tor1a). Although structural and functional alterations in the cerebellum have been reported in DYT1 dystonia, neuronal morphology has not been examined in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we examined the morphology of the cerebellum in Dyt1 ΔGAG knock-in (KI) mice. Golgi staining of the cerebellum revealed a reduction in the length of primary dendrites and a decrease in the number of spines on the distal dendrites of Purkinje cells. To determine if this phenomenon was cell autonomous and mediated by a loss of torsinA function in Purkinje cells, we created a knockout of the Dyt1 gene only in Purkinje cells of mice. We found the Purkinje-cell specific Dyt1 conditional knockout (Dyt1 pKO) mice have similar alterations in Purkinje cell morphology, with shortened primary dendrites and decreased spines on the distal dendrites. CONCLUSION/SIGNIFICANCE: These results suggest that the torsinA is important for the proper development of the cerebellum and a loss of this function in the Purkinje cells results in an alteration in dendritic structure

The Thermoanaerobacter Glycobiome Reveals Mechanisms of Pentose and Hexose Co-Utilization in Bacteria

Author Summary Renewable liquid fuels derived from lignocellulosic biomass could alleviate global energy shortage and climate change. Cellulose and hemicellulose are the main components of lignocellulosic biomass. Therefore, the ability to simultaneously utilize pentose and hexose (i.e., co-utilization) has been a crucial challenge for industrial microbes producing lignocellulosic biofuels. Certain thermoanaerobic bacteria demonstrate this unusual talent, but the genetic foundation and molecular mechanism of this process remain unknown. In this study, we reconstructed the structure and dynamics of the first genome-wide carbon utilization network of thermoanaerobes. This transcriptome-based co-expression network reveals that glucose, xylose, fructose, and cellobiose catabolism are each featured on distinct functional modules. Furthermore, the dynamics of the network suggests a distinct yet collaborative nature between glucose and xylose catabolism. In addition, we experimentally demonstrated that these novel network-derived features can be rationally exploited for product-yield enhancement via optimized timing and balanced loading of the carbon supply in a substrate-specific manner. Thus, the newly discovered modular and precisely regulated network elucidates unique features of thermoanaerobic glycobiomes and reveals novel perturbation strategies and targets for the enhanced thermophilic production of lignocellulosic biofuels.Yeshttp://www.plosgenetics.org/static/editorial#pee

Write, draw, show, and tell: a child-centred dual methodology to explore perceptions of out-of-school physical activity

Background Research to increase children’s physical activity and inform intervention design has, to date, largely underrepresented children’s voices. Further, research has been limited to singular qualitative methods that overlook children’s varied linguistic ability and interaction preference. The aim of this study was to use a novel combination of qualitative techniques to explore children’s current views, experiences and perceptions of out-of-school physical activity as well as offering formative opinion about future intervention design. Methods Write, draw, show and tell (WDST) groups were conducted with 35 children aged 10–11 years from 7 primary schools. Data were analysed through a deductive and inductive process, firstly using the Youth Physical Activity Promotion Model as a thematic framework, and then inductively to enable emergent themes to be further explored. Pen profiles were constructed representing key emergent themes. Results The WDST combination of qualitative techniques generated complimentary interconnected data which both confirmed and uncovered new insights into factors relevant to children’s out-of-school physical activity. Physical activity was most frequently associated with organised sports. Fun, enjoyment, competence, and physical activity provision were all important predictors of children’s out-of-school physical activity. Paradoxically, parents served as both significant enablers (i.e. encouragement) and barriers (i.e. restricting participation) to physical activity participation. Some of these key findings would have otherwise remained hidden when compared to more traditional singular methods based approaches. Conclusions Parents are in a unique position to promote health promoting behaviours serving as role models, physical activity gatekeepers and choice architects. Given the strong socialising effect parents have on children’s physical activity, family-based physical activity intervention may offer a promising alternative compared to traditional school-based approaches. Parents' qualitative input is important to supplement children’s voices and inform future family-based intervention design. The WDST method developed here is an inclusive, interactive and child-centred methodology which facilitates the exploration of a wide range of topics and enhances data credibility

Obesity prevention in child care: A review of U.S. state regulations

<p>ABSTRACT</p> <p>Objective</p> <p>To describe and contrast individual state nutrition and physical activity regulations related to childhood obesity for child care centers and family child care homes in the United States.</p> <p>Methods</p> <p>We conducted a review of regulations for child care facilities for all 50 states and the District of Columbia. We examined state regulations and recorded key nutrition and physical activity items that may contribute to childhood obesity. Items included in this review were: 1) Water is freely available; 2) Sugar-sweetened beverages are limited; 3) Foods of low nutritional value are limited; 4) Children are not forced to eat; 5) Food is not used as a reward; 6) Support is provided for breastfeeding and provision of breast milk; 7) Screen time is limited; and 8) Physical activity is required daily.</p> <p>Results</p> <p>Considerable variation exists among state nutrition and physical activity regulations related to obesity. Tennessee had six of the eight regulations for child care centers, and Delaware, Georgia, Indiana, and Nevada had five of the eight regulations. Conversely, the District of Columbia, Idaho, Nebraska and Washington had none of the eight regulations. For family child care homes, Georgia and Nevada had five of the eight regulations; Arizona, Mississippi, North Carolina, Oregon, Tennessee, Texas, Vermont, and West Virginia had four of the eight regulations. California, the District of Columbia, Idaho, Iowa, Kansas, and Nebraska did not have any of the regulations related to obesity for family child care homes.</p> <p>Conclusion</p> <p>Many states lack specific nutrition and physical activity regulations related to childhood obesity for child care facilities. If widely implemented, enhancing state regulations could help address the obesity epidemic in young children in the United States.</p

Regulating STING in health and disease.

The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named "STimulator of INterferon Genes (STING)". STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases