Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders

Impact of insulin signaling and proteasomal activity on physiological 2 output of a neuronal circuit in aging D. melanogaster

The insulin family of growth factors plays an important role in development and function of the nervous system. Reduced insulin and insulin-growth-factor signaling (IIS), however, can improve symptoms of neurodegenerative diseases in laboratory model organisms and protect against age-associated decline in neuronal function. Recently, we showed that chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber escape response circuit. Here, we expand our initial findings by demonstrating that reduced functional output in the giant fiber system of aging flies can be prevented by increasing proteasomal activity within the circuit. Manipulations of IIS in neurons can also affect longevity, underscoring the relevance of the nervous system for aging

Inhibition of apoptosis and NF-κB activation by vaccinia protein N1 occur via distinct binding surfaces and make different contributions to virulence.

Vaccinia virus (VACV) protein N1 is an intracellular virulence factor and belongs to a family of VACV B-cell lymphoma (Bcl)-2-like proteins whose members inhibit apoptosis or activation of pro-inflammatory transcription factors, such as interferon (IFN) regulatory factor-3 (IRF-3) and nuclear factor-κB (NF-κB). Unusually, N1 inhibits both apoptosis and NF-κB activation. To understand how N1 exerts these different functions, we have mutated residues in the Bcl-2-like surface groove and at the interface used to form N1 homodimers. Mutagenesis of the surface groove abolished only the N1 anti-apoptotic activity and protein crystallography showed these mutants differed from wild-type N1 only at the site of mutation. Conversely, mutagenesis of the dimer interface converted N1 to a monomer and affected only inhibition of NF-κB activation. Collectively, these data show that N1 inhibits pro-inflammatory and pro-apoptotic signalling using independent surfaces of the protein. To determine the relative contribution of each activity to virus virulence, mutant N1 alleles were introduced into a VACV strain lacking N1 and the virulence of these viruses was analysed after intradermal and intranasal inoculation in mice. In both models, VACV containing a mutant N1 unable to inhibit apoptosis had similar virulence to wild-type virus, whereas VACV containing a mutant N1 impaired for NF-κB inhibition induced an attenuated infection similar to that of the N1-deleted virus. This indicates that anti-apoptotic activity of N1 does not drive virulence in these in vivo models, and highlights the importance of pro-inflammatory signalling in the immune response against viral infections

Implementation and evaluation of a harm-reduction model for clinical care of substance using pregnant women

<p>Abstract</p> <p>Background</p> <p>Methamphetamine (MA) use during pregnancy is associated with many pregnancy complications, including preterm birth, small for gestational age, preeclampsia, and abruption. Hawaii has lead the nation in MA use for many years, yet prior to 2007, did not have a comprehensive plan to care for pregnant substance-using women. In 2006, the Hawaii State Legislature funded a pilot perinatal addiction clinic. The Perinatal Addiction Treatment Clinic of Hawaii was built on a harm-reduction model, encompassing perinatal care, transportation, child-care, social services, family planning, motivational incentives, and addiction medicine. We present the implementation model and results from our first one hundred three infants (103) seen over 3 years of operation of the program.</p> <p>Methods</p> <p>Referrals came from community health centers, hospitals, addiction treatment facilities, private physician offices, homeless outreach services and self-referral through word-of-mouth and bus ads. Data to describe sample characteristics and outcome was obtained prospectively and retrospectively from chart abstraction and delivery data. Drug use data was obtained from the women's self-report and random urine toxicology during the pregnancy, as well as urine toxicology at the time of birth on mothers, and urine and meconium toxicology on the infants. Post-partum depression was measured in mothers with the Edinburgh Post-Partum depression scale. Data from Path clinic patients were compared with a representative cohort of women delivering at Kapiolani Medical Center for Women and Children during the same time frame, who were enrolled in another study of pregnancy outcomes. Ethical approval for this study was obtained through the University of Hawaii Committee for Human Studies.</p> <p>Results</p> <p>Between April 2007 and August 2010, 213 women with a past or present history of addiction were seen, 132 were pregnant and 97 delivered during that time. 103 live-born infants were delivered. There were 3 first-trimester Spontaneous Abortions, two 28-week intrauterine fetal deaths, and two sets of twins and 4 repeat pregnancies. Over 50% of the women had lost custody of previous children due to substance use. The majority of women who delivered used methamphetamine (86%), either in the year before pregnancy or during pregnancy. Other drugs include marijuana (59.8%), cocaine (33%), opiates (9.6%), and alcohol (15.2%). Of the women served, 85% smoked cigarettes upon enrollment. Of the 97 women delivered during this period, all but 4 (96%) had negative urine toxicology at the time of delivery. Of the 103 infants, 13 (12.6%) were born preterm, equal to the state and national average, despite having many risk factors for prematurity, including poverty, poor diet, smoking and polysubstance use. Overwhelmingly, the women are parenting their children, > 90% retained custody at 8 weeks. Long-term follow-up showed that women who maintained custody chose long-acting contraceptive methods; while those who lost custody had a very high (> 50%) repeat pregnancy rate at 9 months post delivery.</p> <p>Conclusion</p> <p>Methamphetamine use during pregnancy doesn't exist is isolation. It is often combined with a multitude of other adverse circumstances, including poverty, interpersonal violence, psychiatric comorbidity, polysubstance use, nutritional deficiencies, inadequate health care and stressful life experiences. A comprehensive harm reduction model of perinatal care, which aims to ameliorate some of these difficulties for substance-using women without mandating abstinence, provides exceptional birth outcomes and can be implemented with limited resources.</p

The Salmonella effector SseJ disrupts microtubule dynamics when ectopically expressed in Normal Rat Kidney cells

Salmonella effector protein SseJ is secreted by Salmonella into the host cell cytoplasm where it can then modify host cell processes. Whilst host cell small GTPase RhoA has previously been shown to activate the acyl-transferase activity of SseJ we show here an un-described effect of SseJ protein production upon microtubule dynamism. SseJ prevents microtubule collapse and this is independent of SseJ's acyl-transferase activity. We speculate that the effects of SseJ on microtubules would be mediated via its known interactions with the small GTPases of the Rho family

Assessment of carbon in woody plants and soil across a vineyard-woodland landscape

<p>Abstract</p> <p>Background</p> <p>Quantification of ecosystem services, such as carbon (C) storage, can demonstrate the benefits of managing for both production and habitat conservation in agricultural landscapes. In this study, we evaluated C stocks and woody plant diversity across vineyard blocks and adjoining woodland ecosystems (wildlands) for an organic vineyard in northern California. Carbon was measured in soil from 44 one m deep pits, and in aboveground woody biomass from 93 vegetation plots. These data were combined with physical landscape variables to model C stocks using a geographic information system and multivariate linear regression.</p> <p>Results</p> <p>Field data showed wildlands to be heterogeneous in both C stocks and woody tree diversity, reflecting the mosaic of several different vegetation types, and storing on average 36.8 Mg C/ha in aboveground woody biomass and 89.3 Mg C/ha in soil. Not surprisingly, vineyard blocks showed less variation in above- and belowground C, with an average of 3.0 and 84.1 Mg C/ha, respectively.</p> <p>Conclusions</p> <p>This research demonstrates that vineyards managed with practices that conserve some fraction of adjoining wildlands yield benefits for increasing overall C stocks and species and habitat diversity in integrated agricultural landscapes. For such complex landscapes, high resolution spatial modeling is challenging and requires accurate characterization of the landscape by vegetation type, physical structure, sufficient sampling, and allometric equations that relate tree species to each landscape. Geographic information systems and remote sensing techniques are useful for integrating the above variables into an analysis platform to estimate C stocks in these working landscapes, thereby helping land managers qualify for greenhouse gas mitigation credits. Carbon policy in California, however, shows a lack of focus on C stocks compared to emissions, and on agriculture compared to other sectors. Correcting these policy shortcomings could create incentives for ecosystem service provision, including C storage, as well as encourage better farm stewardship and habitat conservation.</p

ER-to-Golgi trafficking of procollagen in the absence of large carriers

AbstractSecretion and assembly of collagen is fundamental to the function of the extracellular matrix. Defects in the assembly of a collagen matrix lead to pathologies including fibrosis and osteogenesis imperfecta. Owing to the size of fibril-forming procollagen molecules it is assumed that they are transported from the endoplasmic reticulum to the Golgi in specialised large COPII-dependent carriers. Here, analysing endogenous procollagen and a new engineered GFP-tagged form, we show that transport to the Golgi occurs in the absence of large carriers. Large GFP-positive structures are observed occasionally but these are non-dynamic, are not COPII-positive, and label with markers of the ER. We propose a “short-loop” model of COPII-dependent ER-to-Golgi traffic that, while consistent with models of ERGIC-dependent expansion of COPII carriers, does not invoke long-range trafficking of large vesicular structures. Our findings provide an important insight into the process of procollagen trafficking and reveal a short-loop pathway from the ER to the Golgi, without the use of large carriers.SummaryTrafficking of procollagen is essential for normal cell function. Here, imaging of GFP-tagged type I procollagen reveals that it is transported from the endoplasmic reticulum to the Golgi, without the use of large carriers.</jats:sec

ZnT2 Is Critical for TLR4-Mediated Cytokine Expression in Colonocytes and Modulates Mucosal Inflammation in Mice

A wide range of microbial pathogens can enter the gastrointestinal tract, causing mucosal inflammation and infectious colitis and accounting for most cases of acute diarrhea. Severe cases of infectious colitis can persist for weeks, and if untreated, may lead to major complications and death. While the molecular pathogenesis of microbial infections is often well-characterized, host-associated epithelial factors that affect risk and severity of infectious colitis are less well-understood. The current study characterized functions of the zinc (Zn) transporter ZnT2 (SLC30A2) in cultured HT29 colonocytes and determined consequences of ZnT2 deletion in mice on the colonic response to enteric infection with Citrobacter rodentium. ZnT2 in colonocytes transported Zn into vesicles buffering cytoplasmic Zn pools, which was important for Toll-like receptor 4 (TLR4) expression, activation of pathogen-stimulated NF-&kappa;&beta; translocation and cytokine expression. Additionally, ZnT2 was critical for lysosome biogenesis and bacterial-induced autophagy, both promoting robust host defense and resolution mechanisms in response to enteric pathogens. These findings reveal that ZnT2 is a novel regulator of mucosal inflammation in colonocytes and is critical to the response to infectious colitis, suggesting that manipulating the function of ZnT2 may offer new therapeutic strategies to treat specific intestinal infections

The relative age effect in the Gaelic Athletic Association (GAA): a mixed methods approach

Background: In the Gaelic Athletic Association (GAA), Talent Academies (TAs) and senior teams cater for high-performing players. However, only two previous studies have quantified the relative age effect (RAE; i.e., a selection bias favouring those born near the beginning of the cut-off date) in these cohorts. Additionally, no studies have explored stakeholder understanding of the RAE using qualitative methods. Aim This study aimed to: (a) quantify the RAE in TAs and senior teams, and (b) investigate stakeholder perspectives of the talent development environment, providing practical insight into the RAE. Methods A mixed methods sequential explanatory study design was employed. Phase one involved a retrospective analysis of longitudinal data for the frequency and distribution of births using TA (n = 12,445) and senior (n = 8,752) players. Phase two comprised two focus groups of key stakeholders [coaches (n = 4) and Talent Development Leaders (n = 4)] at TA and senior level. Results Analysis revealed a significant difference between TA birth quarter (BQ) distributions compared with expected distributions (P < 0.001; BQ1 = 30.4% vs. BQ4 = 17.6%), whereas at senior level, there were no significant differences observed (χ2 (df = 3) = 3.812, P = 0.282). In phase two, inductive analysis revealed three higher-order themes: (a) understanding of the RAE, (b) selection criteria, and (c) player characteristics. Conclusion The GAA are encouraged to reflect on the practice of chronological age band grouping, investigate possible solutions to limit the effects of the RAE, and offer support programmes to educate key stakeholders