Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice

Parkinson’s disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson’s disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology

Inbreeding effects on immune response in free-living song sparrows (Melospiza melodia)

The consequences of inbreeding for host immunity to parasitic infection have broad implications for the evolutionary and dynamical impacts of parasites on populations where inbreeding occurs. To rigorously assess the magnitude and the prevalence of inbreeding effects on immunity, multiple components of host immune response should be related to inbreeding coefficient (f) in free-living individuals. We used a pedigreed, free-living population of song sparrows (Melospiza melodia) to test whether individual responses to widely used experimental immune challenges varied consistently with f. The patagial swelling response to phytohaemagglutinin declined markedly with f in both females and males in both 2002 and 2003, although overall inbreeding depression was greater in males. The primary antibody response to tetanus toxoid declined with f in females but not in males in both 2004 and 2005. Primary antibody responses to diphtheria toxoid were low but tended to decline with f in 2004. Overall inbreeding depression did not solely reflect particularly strong immune responses in outbred offspring of immigrant–native pairings or weak responses in highly inbred individuals. These data indicate substantial and apparently sex-specific inbreeding effects on immune response, implying that inbred hosts may be relatively susceptible to parasitic infection to differing degrees in males and females

Epidemic growth rates and host movement patterns shape management performance for pathogen spillover at the wildlife–livestock interface

Managing pathogen spillover at the wildlife–livestock interface is a key step towards improving global animal health, food security and wildlife conservation. However, predicting the effectiveness of management actions across host–pathogen systems with different life histories is an on-going challenge since data on intervention effectiveness are expensive to collect and results are system-specific.We developed a simulation model to explore how the efficacies of different management strategies vary according to host movement patterns and epidemic growth rates. The model suggested that fast-growing, fast-moving epidemics like avian influenza were best-managed with actions like biosecurity or containment, which limited and localized overall spillover risk. For fast-growing, slower-moving diseases like foot-and-mouth disease, depopulation or prophylactic vaccination were competitive management options. Many actions performed competitively when epidemics grew slowly and host movements were limited, and how management efficacy related to epidemic growth rate or host movement propensity depended on what objectivewas used to evaluatemanagement performance. This framework offers one means of classifying and prioritizing responses to novel pathogen spillover threats, and evaluating current management actions for pathogens emerging at the wildlife–livestock interface. This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’

Subthreshold PTSD and PTSD in a prospective‐longitudinal cohort of military personnel: Potential targets for preventive interventions

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146501/1/da22819_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146501/2/da22819.pd

Associations between neighborhood-level violence and individual mental disorders: results from the World Mental Health surveys in five Latin American cities

Rapidly urbanizing areas of Latin America experience elevated but unevenly distributed levels of violence. Extensive research suggests that individual exposure to violence is associated with higher odds of both internalizing (anxiety and mood) and externalizing (substance and intermittent explosive) mental disorders. Less research, however, has focused on how neighborhood-level violence, as an indicator of broader neighborhood contexts, might relate to the mental health of residents, independently of an individual’s personal exposure. We used multilevel analyses to examine associations of neighborhood-level violence with individual-level past-year mental disorders, controlling for individual-level violence exposure. We used data from 7,251 adults nested in 83 neighborhoods within five large Latin American cities as part of the WHO World Mental Health Surveys. Accounting for individual-level violence exposure, living in neighborhoods with more violence was associated with significantly elevated odds of individual-level internalizing disorders, but not externalizing disorders. Caution should be exercised when making causal inferences regarding the effects of neighborhood-level violence in the absence of experimental interventions. Nevertheless, neighborhood context, including violence, should be considered in the study of mental disorders. These findings are particularly relevant for rapidly urbanizing areas with high levels of violence, such as Latin America

Hsp72 and Nek6 cooperate to cluster amplified centrosomes in cancer cells

Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 (Plk1) and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome de-clustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukaemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in non-cancer derived cells disturb neither spindle formation nor mitotic progression. Hence, the Nek6-Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes

Examining the demographic profile and attitudes of citizens, in areas where organised crime groups proliferate

Whilst studies refer to the community impact of Organized Crime (OC), no survey currently exists to examine the views of those citizens who reside in areas where Organized Crime Groups (OCGs) proliferate. 431 questionnaires from households co-existing in high density OCGs areas were analysed in relation to: a) demographic information; b) views on the community and the police; and c) how they expected other residents to react to illegal incidents. Overall respondents thought the average citizen would refuse to intervene in 10% - 48% of illegal incidents, with the specific case influencing whether and how they would respond. The analysis then compared three communities who lived in high density OCG areas with a control community (n=343). The ‘OCG’ communities were more likely to report low collective efficacy and were least likely to expect their neighbours to confront a crime in action. Conversely, whilst the control group showed higher levels of collective efficacy and expected the average resident more likely to confront illegal behaviour, this trend did not extend to street drug dealing and serious crime associated with OC. The study discusses the unreported intimidation associated with OCGs and the challenges of policing hostile environments

Saturated Fats Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease A Prospective Cohort Study

AbstractBackgroundThe associations between dietary saturated fats and the risk of coronary heart disease (CHD) remain controversial, but few studies have compared saturated with unsaturated fats and sources of carbohydrates in relation to CHD risk.ObjectivesThis study sought to investigate associations of saturated fats compared with unsaturated fats and different sources of carbohydrates in relation to CHD risk.MethodsWe followed 84,628 women (Nurses’ Health Study, 1980 to 2010), and 42,908 men (Health Professionals Follow-up Study, 1986 to 2010) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by a semiquantitative food frequency questionnaire every 4 years.ResultsDuring 24 to 30 years of follow-up, we documented 7,667 incident cases of CHD. Higher intakes of polyunsaturated fatty acids (PUFAs) and carbohydrates from whole grains were significantly associated with a lower risk of CHD comparing the highest with lowest quintile for PUFAs (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.73 to 0.88; p trend <0.0001) and for carbohydrates from whole grains (HR: 0.90, 95% CI: 0.83 to 0.98; p trend = 0.003). In contrast, carbohydrates from refined starches/added sugars were positively associated with a risk of CHD (HR: 1.10, 95% CI: 1.00 to 1.21; p trend = 0.04). Replacing 5% of energy intake from saturated fats with equivalent energy intake from PUFAs, monounsaturated fatty acids, or carbohydrates from whole grains was associated with a 25%, 15%, and 9% lower risk of CHD, respectively (PUFAs, HR: 0.75, 95% CI: 0.67 to 0.84; p < 0.0001; monounsaturated fatty acids, HR: 0.85, 95% CI: 0.74 to 0.97; p = 0.02; carbohydrates from whole grains, HR: 0.91, 95% CI: 0.85 to 0.98; p = 0.01). Replacing saturated fats with carbohydrates from refined starches/added sugars was not significantly associated with CHD risk (p > 0.10).ConclusionsOur findings indicate that unsaturated fats, especially PUFAs, and/or high-quality carbohydrates can be used to replace saturated fats to reduce CHD risk