Negative regulation of MurZ and MurA underlies the essentiality of GpsB- and StkP-mediated protein phosphorylation in Streptococcus pneumoniae D39.

GpsB links peptidoglycan synthases to other proteins that determine the shape of the respiratory pathogen Streptococcus pneumoniae (pneumococcus; Spn) and other low-GC Gram-positive bacteria. GpsB is also required for phosphorylation of proteins by the essential StkP(Spn) Ser/Thr protein kinase. Here we report three classes of frequently arising chromosomal duplications (≈21-176 genes) containing murZ (MurZ-family homolog of MurA) or murA that suppress ΔgpsB or ΔstkP. These duplications arose from three different repeated sequences and demonstrate the facility of pneumococcus to modulate gene dosage of numerous genes. Overproduction of MurZ or MurA alone or overproduction of MurZ caused by ΔkhpAB mutations suppressed ΔgpsB or ΔstkP phenotypes to varying extents. ΔgpsB and ΔstkP were also suppressed by MurZ amino-acid changes distant from the active site, including one in commonly studied laboratory strains, and by truncation or deletion of the homolog of IreB(ReoM). Unlike in other Gram-positive bacteria, MurZ is predominant to MurA in pneumococcal cells. However, ΔgpsB and ΔstkP were not suppressed by ΔclpCP, which did not alter MurZ or MurA amounts. These results support a model in which regulation of MurZ and MurA activity, likely by IreB(Spn), is the only essential requirement for StkP-mediated protein phosphorylation in exponentially growing D39 pneumococcal cells.

Trends in emergency colorectal surgery: a 7-year retrospective single-centre cohort study.

BACKGROUND: Emergency colorectal resections carry a higher morbidity and mortality than elective surgery. The use of minimally invasive surgery has now become widespread in elective colorectal surgery, with improved patient outcomes. Laparoscopy is being increasingly used for emergency colorectal resections, but its role is still being defined. Our aim was to observe the uptake of laparoscopy for emergency colorectal surgery in our centre. METHOD: A retrospective single-centre cohort study was performed using local National Emergency Laparotomy Audit data from January 2014-December 2020. All patients who had a colorectal resection were included. Trends in the number and type of resections were recorded. Primary outcome was the proportion of cases started and completed laparoscopically. Secondary outcomes included rate of conversion to open, length of stay and 30-day mortality. RESULTS: A total 523 colorectal resections were performed. The number of cases attempted and completed laparoscopically steadily increased over the study period (28.3% to 63.3% and 16.3% to 35.4%, respectively). The mean rate of conversion to open was 43.8%. The greatest expansion in laparoscopy was for cases of intestinal obstruction, perforation and peritonitis, and for those undergoing Hartmann's procedure and right hemicolectomy. 30­day mortality for cases completed laparoscopically was much lower than those converted or started with open surgery (2.1% vs 11.7% and 17.5%, respectively). Laparoscopic approach was independently associated with reduced length of stay. CONCLUSION: Laparoscopy has been successfully adopted for emergency colorectal resections in our centre, with half of cases felt to be suitable for minimally invasive surgery.

Medicare beneficiary barriers to genetic counselor services: Implications for patient policy, decision-making, and care.

If passed, the "Access to Genetic Counselor Services Act" will authorize genetic counselors to provide services under Medicare part B. We assert that Medicare policy should be updated through the enactment of this legislation to provide Medicare beneficiaries with direct access to genetic counselor services. In this article, we discuss the background, history, and some recent research relevant to patient access to genetic counselors to provide context and perspective regarding the rationale, justification, and potential results of the proposed legislation. We outline the potential impact of Medicare policy reform, including the effect on access to genetic counselors in high-demand areas or underserved communities. Although the proposed legislation pertains only to Medicare, we argue that private systems will also be impacted by passage as this may lead to an increase in hiring and retention of genetic counselors by health systems, thereby improving access to genetic counselors across the US.

The Outer Surface Protease, SepM, Is Required for blp Locus Activation in Three of the Four Most Common Pherotypes of Streptococcus pneumoniae.

Streptococcus pneumoniae (pneumococcus) is an important human pathogen that primarily resides in the nasopharynx. To persist in this polymicrobial environment, pneumococcus must compete with other members of the bacterial community. Competition is mediated in part by the action of the blp locus, which encodes a variable array of bacteriocins and their associated immunity proteins. The locus is controlled by a two-component regulatory system that senses the extracellular concentration of the peptide pheromone, BlpC. There are four major pherotypes of BlpC that can be found in most pneumococcal genomes. Here, we show that the protease SepM is required for activation of three of the four major pherotypes. The only SepM-independent BlpC type is 9 amino acids shorter than the SepM-dependent peptides, consistent with a cleavage event at the C-terminal end. The processing event occurs following secretion, and removal of the C-terminal region is required for binding to the histidine kinase receptor. Synthetic truncated peptides or full-length peptides preincubated with SepM-expressing bacteria can upregulate the blp locus independent of SepM. We show that naturally secreted SepM-independent peptides accumulate in the supernatant of secreting cells at low levels, suggesting a role for the tail in peptide secretion, stability, or solubility and demonstrating a significant trade-off for SepM-independence. IMPORTANCE Streptococcus pneumoniae is an important cause of disease in humans that occurs when the bacteria in the nasopharynx bypasses host defenses to invade deeper tissues. Colonization fitness thus represents an important initial step in pathogenesis. S. pneumoniae produces antimicrobial peptides called bacteriocins that provide a competitive advantage over neighboring bacteria in the nasopharynx. The blp locus encodes a variable array of bacteriocins that participate in competition. Here, we demonstrate that activation of the blp locus requires a surface protease that activates the blp signal peptide. There are naturally occurring signal peptides that do not require cleavage, but these are characterized by poor secretion. We describe an additional, previously unappreciated activation step in the control of bacteriocin production in S. pneumoniae.

Health and economic outcomes of newborn screening for infantile-onset Pompe disease.

PURPOSE: To estimate health and economic outcomes associated with newborn screening (NBS) for infantile-onset Pompe disease in the United States. METHODS: A decision analytic microsimulation model simulated health and economic outcomes of a birth cohort of 4 million children in the United States. Universal NBS and treatment was compared with clinical identification and treatment of infantile-onset Pompe disease. Main outcomes were projected cases identified, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) over the life course. RESULTS: Universal NBS for Pompe disease and confirmatory testing was estimated to cost an additional $26 million annually. Additional medication costs associated with earlier treatment initiation were $181 million; however, $8 million in medical care costs for other services were averted due to delayed disease progression. Infants with screened and treated infantile-onset Pompe disease experienced an average lifetime increase of 11.66 QALYs compared with clinical detection. The ICER was $379,000/QALY from a societal perspective and $408,000/QALY from the health-care perspective. Results were sensitive to the cost of enzyme replacement therapy. CONCLUSION: Newborn screening for Pompe disease results in substantial health gains for individuals with infantile-onset Pompe disease, but with additional costs.

The dynamic course of psychological outcomes following the Victorian Black Saturday bushfires.

OBJECTIVES: To profile the long-term mental health outcomes of those affected by the 2009 Black Saturday bushfires and to document the course of mental health since the disaster. METHOD: The longitudinal Beyond Bushfires study included 1017 respondents (Wave 1; 3-4 years after the fires), 736 (76.1%) at Wave 2 (5 years after the fires) and 525 (51.6%) at Wave 3 (10 years after the fires). The survey indexed fire-related and subsequent stressful events, probable posttraumatic stress disorder, major depressive disorder, alcohol use, severe distress and receipt of health services for mental health problems. RESULTS: Relative to their status 3-4 years after the fires, there were reduced rates of fire-related posttraumatic stress disorder (6.2% vs 12.2%), general posttraumatic stress disorder (14.9% vs 18.7%) and severe distress (4.4% vs 7.5%) at 10 years. There were comparable rates between Wave 1 and Wave 3 for depression (10.9% vs 8.3%) and alcohol abuse (21.8% vs 18.5%). Of people in high-affected regions, 22.1% had posttraumatic stress disorder, depression or severe distress at Wave 3. One-third to one-half of participants who reported probable posttraumatic stress disorder or depression at any assessment did not display the disorder at the next assessment. Worsening of mental health at Wave 3 was associated with the extent of property loss, exposure to recent traumatic events or recent stressful life events. Only 24.6% of those with a probable disorder had sought professional help for this in the previous 6 months. CONCLUSION: Approximately one-fifth of people from high-affected areas have a probable psychological disorder a decade after the fires. Mental health appears to fluctuate for those who are not consistently resilient, apparently as a result of ongoing stressors. The observation that most people with probable disorder are not receiving care highlights the need for further planning about managing long-term mental health needs of disaster-affected communities.

S1 Domain RNA-Binding Protein CvfD Is a New Posttranscriptional Regulator That Mediates Cold Sensitivity, Phosphate Transport, and Virulence in Streptococcus pneumoniae D39.

Posttranscriptional gene regulation often involves RNA-binding proteins that modulate mRNA translation and/or stability either directly through protein-RNA interactions or indirectly by facilitating the annealing of small regulatory RNAs (sRNAs). The human pathogen Streptococcus pneumoniae D39 (pneumococcus) does not encode homologs to RNA-binding proteins known to be involved in promoting sRNA stability and function, such as Hfq or ProQ, even though it contains genes for at least 112 sRNAs. However, the pneumococcal genome contains genes for other RNA-binding proteins, including at least six S1 domain proteins: ribosomal protein S1 (rpsA), polynucleotide phosphorylase (pnpA), RNase R (rnr), and three proteins with unknown functions. Here, we characterize the function of one of these conserved, yet uncharacterized, S1 domain proteins, SPD_1366, which we have renamed CvfD (conserved virulence factor D), since loss of the protein results in attenuation of virulence in a murine pneumonia model. We report that deletion of cvfD impacts the expression of 144 transcripts, including the pst1 operon, encoding phosphate transport system 1 in S. pneumoniae We further show that CvfD posttranscriptionally regulates the PhoU2 master regulator of the pneumococcal dual-phosphate transport system by binding phoU2 mRNA and impacting PhoU2 translation. CvfD not only controls expression of phosphate transporter genes but also functions as a pleiotropic regulator that impacts cold sensitivity and the expression of sRNAs and genes involved in diverse cellular functions, including manganese uptake and zinc efflux. Together, our data show that CvfD exerts a broad impact on pneumococcal physiology and virulence, partly by posttranscriptional gene regulation.IMPORTANCE Recent advances have led to the identification of numerous sRNAs in the major human respiratory pathogen S. pneumoniae However, little is known about the functions of most sRNAs or RNA-binding proteins involved in RNA biology in pneumococcus. In this paper, we characterize the phenotypes and one target of the S1 domain RNA-binding protein CvfD, a homolog of general stress protein 13 identified, but not extensively characterized, in other Firmicutes species. Pneumococcal CvfD is a broadly pleiotropic regulator, whose absence results in misregulation of divalent cation homeostasis, reduced translation of the PhoU2 master regulator of phosphate uptake, altered metabolism and sRNA amounts, cold sensitivity, and attenuation of virulence. These findings underscore the critical roles of RNA biology in pneumococcal physiology and virulence.

There's nowhere to go: counting the costs of extreme weather to the homeless community.

People experiencing homelessness are vulnerable to extreme weather in unique ways. The entrenched inequalities that underpin disaster vulnerability are compounded by extreme isolation and the stress of transient living on mental and physical health. However, the impacts of extreme weather on the homeless in Australia are largely undocumented and rarely incorporated in emergency planning. Interviews with and surveys of emergency and homeless services and service users revealed that the primary ramifications of losing shelter and worsening mental health deepen the cycle of homelessness and trauma. Consequently, homeless shelter losses, such as tents, should be included in pre- and post-event impact statistics and subsequent recovery support. Extreme weather response plans should include early triggers and strategies for 'non-severe' weather events, as the homeless community is affected earlier and by a wider range of meteorological conditions. Moreover, this study also explores the benefits of a trauma-informed response to extreme weather when working with the homeless.

Psychosocial mediators of dietary change among Hispanic/Latina breast cancer survivors in a culturally tailored dietary intervention.

OBJECTIVE: To examine psychosocial mediators of the effect of a culturally tailored dietary intervention on dietary change among Hispanic/Latina breast cancer survivors. METHODS: Hispanic/Latina breast cancer survivors (n = 70) were randomized to receive either a 12-week theory-based and culturally tailored dietary change program (intervention group, n = 34), or standard-of-care printed recommendations (control group, n = 36) (ClinicalTrials.gov NCT01414062). Fruit/vegetable intake (F/V), % calories from fat, and hypothesized psychosocial mediators were assessed at baseline, 6 and 12 months. Analysis of covariance assessed intervention effects on psychosocial mediators at 6 and 12 months. Mediation analysis using the bootstrap method evaluated the indirect intervention effects on dietary intake at 6 and 12 months through changes in psychosocial mediators at 6 and 12 months. RESULTS: Compared with controls, at 6 and 12 months, the intervention group reported greater improvements in stages of change (P < .001, P < .001, respectively), self-efficacy (P = .009, P = .002, respectively), snack preference for F/snack preference for F/V (P = .045, P = .002, respectively); at 12 months, the intervention group reported a decrease in chance-oriented external locus of control (P = .02). At 6 months, mediation analysis showed that the intervention effect was associated with an increase of 1.0 (95% CI, -0.1-2.4) serving/day of F/V, compared with the control group, although no indirect effect through the hypothesized psychosocial mediators was observed. At 12 months, the intervention was associated with an increase in 0.5 serving/day F/V through improved taste/snack preference for F/V at 6 and 12 months (95% CIs, 0.1-1.3, 0.0-1.4, respectively). CONCLUSIONS: Future programs can target improving taste/snack preference for F/V to promote dietary change in Hispanic/Latina breast cancer survivors.

Chlorpyrifos interacts with other agricultural stressors to alter stream communities in laboratory microcosms.

Chlorpyrifos is one of the most widely used agricultural insecticides in the world, but to date there is limited empirical information about its potential to interact with other common agricultural stressors. We conducted a 15-d, community-level, microcosm experiment evaluating individual and combined effects of chlorpyrifos, nutrient enrichment, and sedimentation on stream invertebrate communities (abundance, biomass, richness, size structure, composition) and ecosystem processes (primary productivity and leaf decomposition). We found that sedimentation was the most detrimental stressor, with significant negative impacts on most invertebrate community and ecosystem function variables. Even though chlorpyrifos did not cause significant invertebrate mortality in the microcosms, it still altered ecosystem function by lowering leaf decomposition rates, probably through sublethal inhibition of invertebrate shredders. Furthermore, we observed a significant reversal interaction between chlorpyrifos and sediment for small-sized invertebrates collected in gravel (abundance in sediment × insecticide microcosms was 2.4 times lower than predicted by additivity), as well as an antagonistic interaction with nutrients on invertebrate richness in the same microhabitat (richness in nutrient × insecticide microcosms was 1.6 times higher than predicted by additivity). Our results suggest that chlorpyrifos has the potential to alter freshwater ecosystem function and interact non-additively with other common agricultural stressors. These findings are in keeping with a growing body of research highlighting that multiple stressor interactions and ecosystem processes should be considered when evaluating the impacts of organic toxicants on freshwater ecosystems.

The energetic consequences of habitat structure for forest stream salmonids.

Increasing habitat availability (i.e. habitat suitable for occupancy) is often assumed to elevate the abundance or production of mobile consumers; however, this relationship is often nonlinear (threshold or unimodal). Identifying the mechanisms underlying these nonlinearities is essential for predicting the ecological impacts of habitat change, yet the functional forms and ultimate causation of consumer-habitat relationships are often poorly understood. Nonlinear effects of habitat on animal abundance may manifest through physical constraints on foraging that restrict consumers from accessing their resources. Subsequent spatial incongruence between consumers and resources should lead to unimodal or saturating effects of habitat availability on consumer production if increasing the area of habitat suitable for consumer occupancy comes at the expense of habitats that generate resources. However, the shape of this relationship could be sensitive to cross-ecosystem prey subsidies, which may be unrelated to recipient habitat structure and result in more linear habitat effects on consumer production. We investigated habitat-production relationships for juveniles of stream-rearing Pacific salmon and trout (Oncorhynchus spp.), which typically forage in low-velocity pool habitats, while their prey (drifting benthic invertebrates) are produced upstream in high-velocity riffles. However, juvenile salmonids also consume subsidies of terrestrial invertebrates that may be independent of pool-riffle structure. We measured salmonid biomass production in 13 experimental enclosures each containing a downstream pool and upstream riffle, spanning a gradient of relative pool area (14%-80% pool). Increasing pool relative to riffle habitat area decreased prey abundance, leading to a nonlinear saturating effect on fish production. We then used bioenergetics model simulations to examine how the relationship between pool area and salmonid biomass is affected by varying levels of terrestrial subsidy. Simulations indicated that increasing terrestrial prey inputs linearized the effect of habitat availability on salmonid biomass, while decreasing terrestrial inputs exaggerated a "hump-shaped" effect. Our results imply that nonlinear effects of habitat availability on consumer production can arise from trade-offs between habitat suitable for consumer occupancy and habitat that generates prey. However, cross-ecosystem prey subsidies can effectively decouple this trade-off and modify consumer-habitat relationships in recipient systems.

The use of high definition colonoscopy versus standard definition: does it affect polyp detection rate?

BACKGROUND: Polyp detection rate (PDR) during lower gastrointestinal endoscopy (LGIE) is of clinical importance. Detecting adenomatous polyps early in the adenoma-carcinoma sequence can halt disease progression, enabling treatment at a favourable stage. High definition colonoscopy (HDC) has been used in our hospital alongside standard definition equipment since 2011. We aim to determine what affect the use of HDC has on PDR. METHODS: Post-hoc analysis of a prospectively maintained database on all patients undergoing LGIE was performed (01/01/2012-31/12/2015), n = 15,448. Analysis tested the primary outcome of HD's effect on PDR across LGIE and secondary outcome stratified this by endoscopist group (Physician (PE), Surgeon (SE) and Nurse Endoscopist (NE)). RESULTS: Of 15,448 patients, 1353 underwent HDC. Unmatched analysis showed PDR increased by 5.3% in this group (p < 0.001). Matched analysis considered 2288 patients from the total cohort (1144 HDC) and showed an increase of 1% in PDR with HDC (p = 0.578). Further unmatched analysis stratified by endoscopist groups showed a PDR increase of 1.8% (p = 0.375), 5.4% (p = 0.008) and 4.6% (p = 0.021) by PE, SE and NE respectively. Matched analysis demonstrated an increase of 1% (p = 0.734) and 1.5% (p = 0.701) amongst PE and NE, with a decrease of 0.6% (p = 0.883) by SE. CONCLUSION: The introduction of HDC increased PDR across all LGIE in our hospital, though this was not clinically significant. This marginal benefit was present across all endoscopist groups with no group benefiting over another in matched analysis.

Impact of Telephone-Based Problem-Solving Treatment on the Use of Medical and Psychological Services in the Military.

OBJECTIVE: To explore the impact of problem-solving treatment (PST) for mild traumatic brain injury in active duty service members on the use of medical and psychological services. PARTICIPANTS: Service members who had a mild traumatic brain injury during their last deployment and enrolled in the CONcussion Treatment After Combat Trauma (CONTACT) study. DESIGN: Secondary analysis of a randomized clinical trial. Participants were assigned to telephone-based PST, or e-mailed or mailed education only over the course of 6 months. MAIN MEASURE: Self-reported health service utilization from months 4 through 6 and 10 through 12 after initiation of treatment, using the Cornell Service Index. RESULTS: In months 4 to 6, participants receiving PST had 6.17 times the odds of an emergency department visit or hospitalization than those receiving education only (95% confidence interval = 1.92-19.8; P value = .0023). These estimates, however, were not significant using a conservative Bonferroni correction (P value threshold < .0014). There were no other significant differences for other medical or psychological services received in months 4 to 6 or 10 to 12. CONCLUSION: Telephone-based PST was designed to complement clinical care, and this study showed that it may increase emergency department utilization. Future evaluations of PST with more accurate and complete measures of health service utilization are needed.

Longitudinal study of changing psychological outcomes following the Victorian Black Saturday bushfires.

OBJECTIVES: To map the changing prevalence and predictors of psychological outcomes in affected communities 5 years following the Black Saturday bushfires in Victoria. METHOD: Follow-up assessment of longitudinal cohort study in high, medium and non-affected communities in Victoria, Australia. Participants included 1017 respondents (Wave 1) interviewed via telephone and web-based survey between December 2011 and January 2013, and 735 (76.1%) eligible participants were retested between July and November 2014 (Wave 2). The survey included measures of fire-related and subsequent stressful events, probable posttraumatic stress disorder, major depressive episode, alcohol use and severe distress. RESULTS: There were reduced rates of fire-related posttraumatic stress disorder (8.7% vs 12.1%), general posttraumatic stress disorder (14.7% vs 18.2%), major depressive episode (9.0% vs 10.9%) and serious mental illness (5.4% vs 7.8%). Rates of resilience increased over time (81.8% vs 77.1%), and problem alcohol use remained high across Wave 1 (22.1%) and Wave 2 (21.4%). The most robust predictor of later development of fire-related posttraumatic stress disorder (odds ratio: 2.11; 95% confidence interval: [1.22, 3.65]), general posttraumatic stress disorder (odds ratio: 3.15; 95% confidence interval: [1.98, 5.02]), major depressive episode (odds ratio: 2.86; 95% confidence interval: [1.74, 4.70]), serious mental illness (odds ratio: 2.67; 95% confidence interval: [0.57, 1.72]) or diminished resilience (odds ratio: 2.01; 95% confidence interval: [1.32, 3.05]) was extent of recent life stressors. CONCLUSION: Although rates of mental health problems diminished over time, they remained higher than national levels. Findings suggest that policy-makers need to recognize that the mental health consequences of disasters can persist for many years after the event and need to allocate resources towards those who are most at risk as a result of substantive losses and ongoing life stressors.

Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults.

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.

Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy.

Toll-like receptor 4 (TLR4) recognizes specific structural motifs associated with microbial pathogens and also responds to certain endogenous host molecules associated with tissue damage. In Duchenne muscular dystrophy (DMD), inflammation plays an important role in determining the ultimate fate of dystrophic muscle fibers. In this study, we used TLR4-deficient dystrophic mdx mice to assess the role of TLR4 in the pathogenesis of DMD. TLR4 expression was increased and showed enhanced activation following agonist stimulation in mdx diaphragm muscle. Genetic ablation of TLR4 led to significantly increased muscle force generation in dystrophic diaphragm muscle, which was associated with improved histopathology including decreased fibrosis, as well as reduced pro-inflammatory gene expression and macrophage infiltration. TLR4 ablation in mdx mice also altered the phenotype of muscle macrophages by inducing a shift toward a more anti-inflammatory (iNOS(neg) CD206(pos)) profile. In vitro experiments confirmed that lack of TLR4 is sufficient to influence macrophage activation status in response to classical polarizing stimuli such as IFN-gamma and IL-4. Finally, treatment of dystrophic mice with glycyrrhizin, an inhibitor of the endogenous TLR4 ligand, high mobility group box (HMGB1), also pointed to involvement of the HMGB1-TLR4 axis in promoting dystrophic diaphragm pathology. Taken together, our findings reveal TLR4 and the innate immune system as important players in the pathophysiology of DMD. Accordingly, targeting either TLR4 or its endogenous ligands may provide a new therapeutic strategy to slow disease progression.

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system.

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.

A test of the effects of timing of a pulsed resource subsidy on stream ecosystems.

Spatial resource subsidies can alter bottom-up and top-down forces of community regulation across ecosystem boundaries. Most subsidies are temporally variable, and recent theory has suggested that consumer-resource dynamics can be stabilized if the peak timing of a subsidy is desynchronized with that of prey productivity in the recipient ecosystem. However, magnitude of consumer responses per se could depend on the subsidy timing, which may be a critical component for community dynamics and ecosystem processes. The aim of this study was to test (i) whether a recipient consumer (cutthroat trout) responds differently to a resource subsidy occurring early in its growing season than to a subsidy occurring late in the season and, if this is the case, (ii) whether the timing-dependent consumer response has cascading effects on communities and ecosystem functions in streams. To test those hypotheses, we conducted a large-scale field experiment, in which we directly manipulated the timing of augmentation of the terrestrial invertebrates that enter stream (i.e. peak timing of June-August vs. August-October), keeping constant the total amounts of the invertebrates entered. We found large increases in the individual growth rate and population biomass of the cutthroat trout, in response to the early resource pulse, but not to the late pulse. This timing-dependent consumer response cascaded down to reduce benthic invertebrates and leaf breakdown rate, and increased water nutrient concentrations. Furthermore, the early resource pulse resulted in higher maturity rate of the cutthroat trout in the following spring, demonstrating the importance of the subsidy timing on long-term community dynamics via the consumer's numerical response. Our results emphasize the need to acknowledge timing-dependent consumer responses in understanding the effects of subsidies on communities and ecosystem processes. Elucidating the mechanisms by which consumers effectively exploit pulsed subsidies is an important avenue to better understand community dynamics in spatially coupled ecosystems.

Mental Health Following Separation in a Disaster: The Role of Attachment.

Short-term separation from close family members during a disaster is a highly salient event for those involved. Yet, its subsequent impact on mental health has received little empirical attention. One relevant factor may be attachment style, which influences patterns of support-seeking under threatening conditions. Individuals (N = 914) affected by the 2009 Victorian bushfires in southeastern Australia were assessed for disaster experiences, depression, posttraumatic stress disorder (PTSD) symptoms, and attachment style 3-4 years after the fires. Using multigroup structural equation modelling, individuals who reported separation from close family members during the bushfires (n = 471) were compared to those who reported no separation (n = 443). Cross-sectional results indicated that separated individuals had higher levels of PTSD symptoms. Furthermore, attachment anxiety was more strongly positively associated with depression among separated (b = 0.62) versus not separated individuals (b = 0.32). Unexpectedly, among separated individuals, attachment avoidance had a statistically weaker association with depression (b = 0.17 vs. b = 0.35) and with PTSD symptoms (b = 0.06 vs. b = 0.22). These results suggest that attachment anxiety amplifies a negative reaction to separation; meanwhile, for avoidant individuals, separation in times of danger may facilitate defensive cognitive processes.