Leucine-rich repeat kinase 2 (LRRK2) is a complex kinase and mutations in LRRK2 are perhaps the most common genetic cause of Parkinson's disease (PD). However, the identification of the normal ...physiological function of LRRK2 remains elusive. Here, we show that LRRK2 protects neurons against apoptosis induced by the Drosophila genes grim, hid and reaper. Genetic dissection reveals that Akt is the critical downstream kinase of LRRK2 that phosphorylates and inhibits FOXO1, and thereby promotes survival. Like human LRRK2, Drosophila lrrk also promotes neuron survival; lrrk loss-of-function mutant displays reduced cell numbers, which can be rescued by LRRK2 expression. Importantly, LRRK2 G2019S and LRRK2 R1441C mutants impair the ability of LRRK2 to activate Akt, and fail to prevent apoptotic death. Ectopic expression of a constitutive active form of Akt hence is sufficient to rescue this functional deficit. These data establish that LRRK2 can protect neurons from apoptotic insult through a survival pathway in which LRRK2 signals to activate Akt, and then inhibits FOXO1. These results might indicate that a LRRK-Akt therapeutic pathway to promote neuron survival and to prevent neurodegeneration in Parkinson's disease.
Hope is a goal-directed thought that reflects the sense of control over uncertainties and can promote adjustment to chronic illness. This study aimed to assess the level of hope among patients on ...peritoneal dialysis and evaluate the association of hope with health-related quality of life and psychological distress. This cross-sectional study included 134 Chinese patients receiving peritoneal dialysis in Hong Kong. Patients’ level of hope was assessed using the Adult Trait Hope Scale. Participants who were employed, had a higher income, and received automated peritoneal dialysis reported a higher hope score. Hope was found to have significant correlations with age and social support. A higher hope score was associated with better mental well-being and less severe depressive symptoms. Specific relationships between agency/pathway thinking and these outcomes were identified. The patient subgroups at risk for losing hope need to be identified and received early interventions to prevent adverse outcomes.
Responses of primary hippocampal and cortical neurons derived from male and female rats to cellular stressors were studied. It is demonstrated that 17β-estradiol (E2), a potent neuroprotectant, ...protected the female neurons but had no effects on the male neurons from CoCl
2
- and glutamate-induced toxicity. Agonists of the estrogen receptor (ER) subtypes ERα and ERβ, DPN and PPT, respectively, had similar effects to E2. By contrast, effects of E2 were abolished by the ER antagonist ICI-182780, further corroborating the neuroprotective role of ERs. In male neurons, CoCl
2
predominately activated the apoptosis-inducing factor (AIF)-dependent pathway and AIF translocation from the cytosol to the nucleus. In comparison, CoCl
2
activated the caspase pathway and cytochrome c release in female neurons. The inhibitors of these pathways, namely DiQ for AIF and zVAD for caspase, specifically rescued CoCl
2
-induced cell death in male and female neurons, respectively. When zVAD and ICI-182780, and E2 were applied in combination, it was demonstrated E2 acted on the caspase pathway leading to female-specific neuroprotection. Furthermore, the PI3 kinase (PI3K) inhibitor blocked the rescue effects of DiQ and zVAD on the male and female neurons, respectively, suggesting that PI3K is a common upstream regulator for both pathways. The present study suggested that both sex-specific and nonspecific mechanisms played a role in neuronal responses to stressors and protective reagents.
Mutations in VCP (Valosin-containing protein), an AAA ATPase critical for ER-associated degradation, are linked to IBMPFD (Inclusion body myopathy with Paget disease and frontotemporal dementia). ...Using a Drosophila IBMPFD model, we have identified the ER protein Derlin-1 as a modifier of pathogenic TER94 (the fly VCP homolog) mutants. Derlin-1 binds to TER94 directly, and this interaction is essential for Derlin-1 overexpression to suppress the pathogenic TER94-induced neurodegeneration. Derlin-1 overexpression reduces the elevated ATPase activity of pathogenic TER94, implying that IBMPFD is caused by ATPase hyper-activation. Under physiological condition, Derlin-1 expression is increased upon ER stress to recruit TER94 to the ER. However, in response to severe ER stress, Derlin-1 is required for activating apoptosis to eliminate damaged cells. This pro-apoptotic response is mimicked by Derlin-1 overexpression, which elicits acute ER stress and triggers apoptosis via a novel C-terminal motif (α). As this Derlin-1-dependent cell death is negated by TER94 overexpression, we propose that while Derlin-1 and VCP work cooperatively in ER stress response, their imbalance has a role in removing cells suffering prolonged ER stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 3-D morphological change has gained increasing significance in recent investigations on human fetal brains. This study uses a pair of new indices, the shape index (SI) and curvedness index (CVD), ...to quantify 3-D morphological changes in developing brains from 22 to 33 weeks of gestation. The SI was used to automatically locate the gyral nodes and sulcal pits, and the CVD was used to measure the degree of deviation of cortical shapes from a flat plane. The CVD values of classified regions were compared with two traditional biomarkers: cerebral volume and cortical surface area. Because the fetal brains dramatically deform with age, the age effect was controlled during the comparison between morphological changes and volume and surface area. The results show that cerebral volume, the cortical surface area, and the CVD values of gyral nodes and sulcal pits increased with gestational age. However, with age controlled, the CVD values of gyral nodes and sulcal pits did not correlate with cerebral volume, but the CVD of gyral nodes increased slightly with the cortical surface area. These findings suggest that the SI, in conjunction with the CVD, provides developmental information distinct from the brain volumetry. This approach provides additional insight into 3-D cortical morphology in the assessment of fetal brain development.
Abstract
Geological isolation with limited gene flow can shape phenotypic diversification among different populations or species. From Luzon northward to Taiwan lies a series of isolated volcanic ...islands (the Taiwan–Luzon volcanic belt) where three Pachyrhynchus species P. sarcitis (Behrens, 1887), P. nobilis (Heller, 1912) and P. semperi (Heller, 1912) (Coleoptera: Curculionidae: Entiminae: Pachyrhynchini) are sympatrically distributed. With intraspecific color variation across different islands, these three weevil species provide a unique opportunity to study genetic divergence associated with geographic isolation and/or phenotypic differences. In this study, genome-wide single nucleotide polymorphism (SNP) data derived from ddRAD-seq was used to reconstruct the speciation history and to delimit species within each of the three species. Our results indicate all three species have ancient diversification histories in southern islands of the Taiwan–Luzon volcanic belt instead of more recent diversification histories in northern islands. Ancestral effective population size estimations also support a scenario of a series of founder colonization events from southern to northern islands in the volcanic belt. Most island populations are monophyletic, and early-divergent populations with deep genetic structures are supported statistically as distinct species. However, color variations could occur between populations with very recent diversification, indicating a fast-evolving rate in the change of coloration, possibly due to müllerian mimicry or founder effects across this region.
Spatial orientation memory plays a crucial role in animal navigation. Recent studies of tethered
Drosophila melanogaster
(fruit fly) in a virtual reality setting showed that the head direction is ...encoded in the form of an activity bump, i.e., localized neural activity, in the torus-shaped ellipsoid body (EB). However, how this system is involved in orientation working memory is not well understood. We investigated this question using free moving flies (
D. melanogaster
) in a spatial orientation memory task by manipulating two EB subsystems, C and P circuits, which are hypothesized for stabilizing and updating the activity bump, respectively. To this end, we suppressed or activated two types of inhibitory ring neurons (EIP and P) which innervate EB, and we discovered that manipulating the two inhibitory neuron types produced distinct behavioral deficits, suggesting specific roles of the inhibitory neurons in coordinating the stabilization and updating functions of the EB circuits. We further elucidate the neural mechanisms underlying such control circuits using a connectome-constrained spiking neural network model.
Trace amount (0.3 wt%) of scandium is added to Al-5.6Mg-0.7Mn alloy to form uniformly distributed Al
3
Sc precipitates for producing a fine-grained and stable microstructure at high temperature ...through cross-channel extrusion process. Superplasticity and hot workability of the Sc-containing Al-5.6Mg-0.7Mn alloy, after extrusion, are also examined. The result indicates that Al-5.6Mg-0.7Mn alloys with and without 0.3 wt% Sc after extrusion of six passes at 300°C, fine-grained structures were observed with grain sizes of 1-2 µm and improvement of mechanical properties. Furthermore, Al
3
Sc phase can effectively retard recrystallization to increase the thermal stability and remain equiaxed. The elongation of Al-5.6Mg-0.7Mn alloy with Sc addition to failure is extended to 873% maximum at high temperature of 450°C at strain rate of 1 × 10
−1
s
−1
after six passes in the CCEP.
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