Attempts to model inherited human prion disorders such as familial Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically ...modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease-specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8-kDa proteinase K-resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity.
Recovery of Interdependent Networks Di Muro, M A; La Rocca, C E; Stanley, H E ...
Scientific reports,
03/2016, Letnik:
6, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Recent network research has focused on the cascading failures in a system of interdependent networks and the necessary preconditions for system collapse. An important question that has not been ...addressed is how to repair a failing system before it suffers total breakdown. Here we introduce a recovery strategy for nodes and develop an analytic and numerical framework for studying the concurrent failure and recovery of a system of interdependent networks based on an efficient and practically reasonable strategy. Our strategy consists of repairing a fraction of failed nodes, with probability of recovery γ, that are neighbors of the largest connected component of each constituent network. We find that, for a given initial failure of a fraction 1 - p of nodes, there is a critical probability of recovery above which the cascade is halted and the system fully restores to its initial state and below which the system abruptly collapses. As a consequence we find in the plane γ - p of the phase diagram three distinct phases. A phase in which the system never collapses without being restored, another phase in which the recovery strategy avoids the breakdown, and a phase in which even the repairing process cannot prevent system collapse.
Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense ...and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.
Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of ...genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (r
= 0.24, p = 1.8 × 10
versus r
= -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10
). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.
Hamstring muscle injury is highly prevalent in sports involving repeated maximal sprinting. Although neuromuscular fatigue is thought to be a risk factor, the mechanisms underlying the fatigue ...response to repeated maximal sprints are unclear. Here, we show that repeated maximal sprints induce neuromuscular fatigue accompanied with a prolonged strength loss in hamstring muscles. The immediate hamstring strength loss was linked to both central and peripheral fatigue, while prolonged strength loss was associated with indicators of muscle damage. The kinematic changes immediately after sprinting likely protected fatigued hamstrings from excess elongation stress, while larger hamstring muscle physiological cross-sectional area and lower myoblast:fibroblast ratio appeared to protect against fatigue/damage and improve muscle recovery within the first 48 h after sprinting. We have therefore identified novel mechanisms that likely regulate the fatigue/damage response and initial recovery following repeated maximal sprinting in humans.
Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this ...association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.
To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.
This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier PRESSO) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.
MDD and physical activity.
GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio OR, 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).
Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.
All organisms have evolved to cope with changes in environmental conditions, ensuring the optimal combination of proliferation and survival. In yeast, exposure to a mild stress leads to an increased ...tolerance for other stresses. This suggests that yeast uses information from the environment to prepare for future threats. We used the yeast knockout collection to systematically investigate the genes and functions involved in severe stress survival and in the acquisition of stress (cross-) tolerance. Besides genes and functions relevant for survival of heat, acid, and oxidative stress, we found an inverse correlation between mutant growth rate and stress survival. Using chemostat cultures, we confirmed that growth rate governs stress tolerance, with higher growth efficiency at low growth rates liberating the energy for these investments. Cellular functions required for stress tolerance acquisition, independent of the reduction in growth rate, were involved in vesicular transport, the Rpd3 histone deacetylase complex, and the mitotic cell cycle. Stress resistance and acquired stress tolerance in Saccharomyces cerevisiae are governed by a combination of stress-specific and general processes. The reduction of growth rate, irrespective of the cause of this reduction, leads to redistribution of resources toward stress tolerance functions, thus preparing the cells for impending change.
Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these ...animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.
We present a simple, automated method for high-throughput formation of droplet interface bilayers (DIBs) in a microfluidic device. We can form complex DIB networks that are able to fill predefined ...three dimensional architectures. Moreover, we demonstrate the flexibility of the system by using a variety of lipids including 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).
Please cite this paper as: Robinson M, Oddy W, McLean N, Jacoby P, Pennell CE, de Klerk N, Zubrick S, Stanley F, Newnham J. Low–moderate prenatal alcohol exposure and risk to child behavioural ...development: a prospective cohort study. BJOG 2010;117:1139–1152.
Objective To examine the association of fetal alcohol exposure during pregnancy with child and adolescent behavioural development.
Design The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnancies (1989–91) and the 14‐year follow up was conducted between 2003 and 2006.
Setting Tertiary obstetric hospital in Perth, Western Australia.
Population The women in the study provided data at 18 and 34 weeks of gestation on weekly alcohol intake: no drinking, occasional drinking (up to one standard drink per week), light drinking (2–6 standard drinks per week), moderate drinking (7–10 standard drinks per week), and heavy drinking (11 or more standard drinks per week).
Methods Longitudinal regression models were used to analyse the effect of prenatal alcohol exposure on Child Behaviour Checklist (CBCL) scores over 14 years, assessed by continuous z‐scores and clinical cutoff points, after adjusting for confounders.
Main outcome measure Their children were followed up at ages 2, 5, 8, 10 and 14 years. The CBCL was used to measure child behaviour.
Results Light drinking and moderate drinking in the first 3 months of pregnancy were associated with child CBCL z‐scores indicative of positive behaviour over 14 years after adjusting for maternal and sociodemographic characteristics. These changes in z‐score indicated a clinically meaningful reduction in total, internalising and externalising behavioural problems across the 14 years of follow up.
Conclusions Our findings do not implicate light–moderate consumption of alcohol in pregnancy as a risk factor in the epidemiology of child behavioural problems.
PDF
