Abstract Huntington's disease is a neurodegenerative disorder, caused by an elongation of CAG repeats in the huntingtin gene. Mice with an insertion of an expanded polyglutamine repeat in the mouse ...huntingtin gene (knock-in mice) most closely model the disease because the mutation is expressed in the proper genomic and protein context. However, few knock-in mouse lines have been extensively characterized and available data suggest marked differences in the extent and time course of their behavioral and pathological phenotype. We have previously described behavioral anomalies in the open field as early as 1 month of age, followed by the appearance at 2 months of progressive huntingtin neuropathology, in a mouse carrying a portion of human exon 1 with approximately 140 CAG repeats inserted into the mouse huntingtin gene. Here we extend these observations by showing that early behavioral anomalies exist in a wide range of motor (climbing, vertical pole, rotarod, and running wheel performance) and non-motor functions (fear conditioning and anxiety) starting at 1–4 months of age, and are followed by progressive gliosis and decrease in dopamine and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP32) (12 months) and a loss of striatal neurons at 2 years. At this age, mice also present striking spontaneous behavioral deficits in their home cage. The data show that this line of knock-in mice reproduces canonical characteristics of Huntington's disease, preceded by deficits which may correspond to the protracted pre-manifest phase of the disease in humans. Accordingly, they provide a useful model to elucidate early mechanisms of pathophysiology and the progression to overt neurodegeneration.
Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of ...resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.
White matter (WM) integrity declines with normal aging. Physical activity may attenuate age-related WM integrity changes and improve cognitive function. This study examined brain WM integrity in ...Masters athletes who have engaged in life-long aerobic exercise training. We tested the hypothesis that life-long aerobic training is associated with improved brain WM integrity in older adults.
Ten Masters athletes (3 females, age=72.2±5.3years, endurance training >15years) and 10 sedentary older adults similar in age and educational level (2 females, age=74.5±4.3years) participated. MRI fluid-attenuated-inversion-recovery (FLAIR) images were acquired to assess white matter hyperintensities (WMH) volume. Diffusion tensor imaging (DTI) was performed to evaluate the WM microstructural integrity with a DTI-derived metric, fractional anisotropy (FA) and mean diffusivity (MD).
After normalization to whole-brain volume, Masters athletes showed an 83% reduction in deep WMH volume relative to their sedentary counterparts (0.05±0.05% vs. 0.29±0.29%, p<0.05). In addition, we found an inverse relationship between aerobic fitness (VO2max) and deep WMH volume (r=−0.78, p<0.001). Using TBSS, Masters athletes showed higher FA values in the right superior corona radiata (SCR), both sides of superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFO), and left inferior longitudinal fasciculus (ILF). In addition, Masters athletes also showed lower MD values in the left posterior thalamic radiation (PTR) and left cingulum hippocampus.
These findings suggest that life-long exercise is associated with reduced WMH and may preserve WM fiber microstructural integrity related to motor control and coordination in older adults.
•We showed the effect of life-long exercise on brain white matter hyperintensities.•We showed the relationship between aerobic fitness and brain health.•We showed white matter tracts that are likely associated with exercise benefits.
Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal ...cancer following a diagnosis of colorectal cancer in mutation carriers.
We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.
Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval CI = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).
Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
Considerable uncertainty surrounds the fate of Amazon rainforests in response to
climate change.
Here, carbon (C) flux predictions of five terrestrial biosphere models (Community
Land Model version ...3.5 (CLM3.5), Ecosystem Demography model version 2.1 (ED2),
Integrated BIosphere Simulator version 2.6.4 (IBIS), Joint UK Land Environment
Simulator version 2.1 (JULES) and Simple Biosphere model version 3 (SiB3)) and a
hydrodynamic terrestrial ecosystem model (the
Soil–Plant–Atmosphere (SPA) model) were evaluated against
measurements from two large-scale Amazon drought experiments.
Model predictions agreed with the observed C fluxes in the control plots of both
experiments, but poorly replicated the responses to the drought treatments. Most
notably, with the exception of ED2, the models predicted negligible reductions
in aboveground biomass in response to the drought treatments, which was in
contrast to an observed c. 20% reduction at both sites.
For ED2, the timing of the decline in aboveground biomass was accurate, but the
magnitude was too high for one site and too low for the other.
Three key findings indicate critical areas for future research and model
development. First, the models predicted declines in autotrophic respiration
under prolonged drought in contrast to measured increases at one of the sites.
Secondly, models lacking a phenological response to drought introduced bias in
the sensitivity of canopy productivity and respiration to drought. Thirdly, the
phenomenological water-stress functions used by the terrestrial biosphere models
to represent the effects of soil moisture on stomatal conductance yielded
unrealistic diurnal and seasonal responses to drought.
miRNAs act as oncogenes or tumor suppressors in a wide variety of human cancers, including prostate cancer (PCa). We found a severe and consistent downregulation of miRNAs, miR-154, miR-299-5p, ...miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 region in metastatic cell lines as compared with normal prostatic epithelial cells (PrEC). In specimens of human prostate (28 normals, 99 primary tumors and 13 metastases), lower miRNA levels correlated significantly with a higher incidence of metastatic events and higher prostate specific antigen (PSA) levels, with similar trends observed for lymph node invasion and the Gleason score. We transiently transfected 10 members of the 14q32.31 cluster in normal prostatic epithelial cell lines and characterized their affect on malignant cell behaviors, including proliferation, apoptosis, migration and invasion. Finally, we identified FZD4, a gene important for epithelial-to-mesenchymal transition in (PCa), as a target of miR-377.
Abstract Purpose Despite concerted actions to streamline care transitions, the journey from hospital to home remains hazardous for patients and caregivers. Remarkably little is known about the ...patient and caregiver experience during care transitions, the services they need, or the outcomes they value. The aims of this study were to (1) describe patient and caregiver experiences during care transitions and (2) characterize patient and caregiver desired outcomes of care transitions and the health services associated with them. Methods We interviewed 138 patients and 110 family caregivers recruited from 6 health networks across the United States. We conducted 34 homogenous focus groups (103 patients, 65 caregivers) and 80 key informant interviews (35 patients, 45 caregivers). Audio recordings were transcribed and analyzed using principles of grounded theory to identify themes and the relationship between them. Results Patients and caregivers identified 3 desired outcomes of care transition services: (1) to feel cared for and cared about by medical providers, (2) to have unambiguous accountability from the health care system, and (3) to feel prepared and capable of implementing care plans. Five care transition services or provider behaviors were linked to achieving these outcomes: (1) using empathic language and gestures, (2) anticipating the patient's needs to support self-care at home, (3) collaborative discharge planning, (4) providing actionable information, and (5) providing uninterrupted care with minimal handoffs. Conclusions Clear accountability, care continuity, and caring attitudes across the care continuum are important outcomes for patients and caregivers. When these outcomes are achieved, care is perceived as excellent and trustworthy. Otherwise, the care transition is experienced as transactional and unsafe, and leaves patients and caregivers feeling abandoned by the health care system.
In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia ...(ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P<0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P=0.04), and less likely to display complex karyotype, in blast-phase disease (P<0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P<0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7-5.2), but not IDH mutational status (P=0.55; HR 1.3, 95% CI 0.5-3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P=0.04) and blast-phase MPN (P=0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes.
Capsaicin, the main pungent ingredient in 'hot chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the ...central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
Many conservation plans remain unimplemented, in part because of insufficient consideration of the social processes that influence conservation decisions. Complementing social considerations with an ...integrated understanding of the ecology of a region can result in a more complete conservation approach. We suggest that linking conservation planning to a social-ecological systems (SES) framework can lead to a more thorough understanding of human-environment interactions and more effective integration of social considerations. By characterizing SES as a set of subsystems, and their interactions with each other and with external factors, the SES framework can improve our understanding of the linkages between social and ecological influences on the environment. Using this framework can help to identify socially and ecologically focused conservation actions that will benefit ecosystems and human communities, and assist in the development of more consistent evidence for evaluating conservation actions by comparing conservation case studies.
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