The YAC128 mouse recapitulates many of the clinical features of Huntington disease (HD), including selective neuropathology with neuronal loss. Here we investigate whether differences in neuroanatomy ...could be detected using high-resolution magnetic resonance (MR) imaging earlier than the previously defined 9-month age of onset of striatal neuropathology. The striatum is significantly decreased in volume (3.4%,
p
<<
0.02) at 8 months of age. A subset of the brains was also analyzed using stereology, and the MR measures were found to be more robust at separating the two groups of mice. Striatal degeneration was found to be asymmetric, with the dorsal and lateral aspects of the striatum being most affected. Non-striatal changes in neuroanatomy were also investigated, revealing regions of expansion as well as atrophy. Our findings suggest that MR imaging can be used to detect and monitor subtle anatomical differences throughout the whole brain and at early time points in the YAC128 mouse-model of HD.
Fires are the major natural disturbance in the boreal forest, and their frequency and intensity will likely increase as the climate warms. Terrestrial nutrients released by fires may be transported ...to boreal lakes, stimulating increased primary productivity, which may radiate through multiple trophic levels. Using a before-after-control-impact (BACI) design, with pre- and postfire data from burned and unburned areas, we examined effects of a natural fire across several trophic levels of boreal lakes, from nutrient and chlorophyll levels, to macroinvertebrates, to waterbirds. Concentrations of total nitrogen and phosphorus were not affected by the fire. Chlorophyll
a
levels were also unaffected, likely reflecting the stable nutrient concentrations. For aquatic invertebrates, we found that densities of three functional feeding groups did not respond to the fire (filterers, gatherers, scrapers), while two groups increased (shredders, predators). Amphipods accounted for 98% of shredder numbers, and we hypothesize that fire-mediated habitat changes may have favored their generalist feeding and habitat ecology. This increase in amphipods may, in turn, have driven increased predator densities, as amphipods were the most numerous invertebrate in our lakes and are commonly taken as prey. Finally, abundance of waterbird young, which feed primarily on aquatic invertebrates, was not affected by the fire. Overall, ecosystems of our study lakes were largely resilient to forest fires, likely due to their high initial nutrient concentrations and small catchment sizes. Moreover, this resilience spanned multiple trophic levels, a significant result for ecologically similar boreal regions, especially given the high potential for increased fires with future climate change.
Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms ...of efficacy.
Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, with assessment window of 21 days from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumor and host determinants of response.
Fifteen patients were included in the safety and efficacy population: 73% had nonviral cirrhosis; median age was 72 years. Child-Pugh class was A in 14 patients. Median tumor size was 4 cm. Ten patients (67%) received pembrolizumab after one TACE; 5 patients after two (33%). Pembrolizumab yielded no synergistic toxicity nor dose-limiting toxicities post-TACE. Treatment-related adverse events occurred in 93% of patients, most commonly skin rash (40%), fatigue, and diarrhea (27%). After a median follow-up of 38.5 months, objective response rate 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months 95% confidence interval (CI): 7.30-NE (not estimable). Median duration of response was 7.3 months (95% CI: 6.3-8.3). Median overall survival was 33.5 months (95% CI: 11.6-NE). Dynamic changes in peripheral T-cell subsets, circulating tumor DNA, serum metabolites, and in stool bacterial profiles highlight potential mechanisms of action of multimodal therapy.
TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.
We investigated the in vivo function of the B7 family member B7-H3 (also known as B7RP-2) by gene targeting. B7-H3 inhibited T cell proliferation mediated by antibody to T cell receptor or allogeneic ...antigen-presenting cells. B7-H3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which T helper cells differentiated toward type 1 (T(H)1) rather than type 2 (T(H)2). B7-H3 expression was consistently enhanced by interferon-gamma but suppressed by interleukin 4 in dendritic cells. B7-H3-deficient mice developed experimental autoimmune encephalomyelitis several days earlier than their wild-type littermates, and accumulated higher concentrations of autoantibodies to DNA. Thus, B7-H3 is a negative regulator that preferentially affects T(H)1 responses.
Losses in lake area have been observed for several Arctic and Subarctic regions in recent decades, with unknown consequences for lake ecosystems. These reductions are primarily attributed to two ...climate‐sensitive mechanisms, both of which may also cause changes in water chemistry: (i) increased imbalance of evaporation relative to inflow, whereby increased evaporation and decreased inflow act to concentrate solutes into smaller volumes; and (ii) accelerated permafrost degradation, which enhances sublacustrine drainage while simultaneously leaching previously frozen solutes into lakes. We documented changes in nutrients total nitrogen (TN), total phosphorus (TP) and ions (calcium, chloride, magnesium, sodium) over a 25 year interval in shrinking, stable, and expanding Subarctic lakes of the Yukon Flats, Alaska. Concentrations of all six solutes increased in shrinking lakes from 1985–1989 to 2010–2012, while simultaneously undergoing little change in stable or expanding lakes. This created a present‐day pattern, much weaker or absent in the 1980s, in which shrinking lakes had higher solute concentrations than their stable or expanding counterparts. An imbalanced evaporation‐to‐inflow ratio (E/I) was the most likely mechanism behind such changes; all four ions, which behave semiconservatively and are prone to evapoconcentration, increased in shrinking lakes and, along with TN and TP, were positively related to isotopically derived E/I estimates. Moreover, the most conservative ion, chloride, increased >500% in shrinking lakes. Conversely, only TP concentration was related to probability of permafrost presence, being highest at intermediate probabilities. Overall, the substantial increases of nutrients (TN >200%, TP >100%) and ions (>100%) may shift shrinking lakes towards overly eutrophic or saline states, with potentially severe consequences for ecosystems of northern lakes.
Post-exposure vaccination with vaccinia virus (VACV) has been suggested to be effective in minimizing death if administered within four days of smallpox exposure. While there is anecdotal evidence ...for efficacy of post-exposure vaccination this has not been definitively studied in humans. In this study, we analyzed post-exposure prophylaxis using several attenuated recombinant VACV in a mouse model. A recombinant VACV expressing murine interferon gamma (IFN-γ) was most effective for post-exposure protection of mice infected with VACV and ectromelia virus (ECTV). Untreated animals infected with VACV exhibited severe weight loss and morbidity leading to 100% mortality by 8 to 10 days post-infection. Animals treated one day post-infection had milder symptoms, decreased weight loss and morbidity, and 100% survival. Treatment on days 2 or 3 post-infection resulted in 40% and 20% survival, respectively. Similar results were seen in ECTV-infected mice. Despite the differences in survival rates in the VACV model, the viral load was similar in both treated and untreated mice while treated mice displayed a high level of IFN-γ in the serum. These results suggest that protection provided by IFN-γ expressed by VACV may be mediated by its immunoregulatory activities rather than its antiviral effects. These results highlight the importance of IFN-γ as a modulator of the immune response for post-exposure prophylaxis and could be used potentially as another post-exposure prophylaxis tool to prevent morbidity following infection with smallpox and other orthopoxviruses.
Shrinking lakes were recently observed for several Arctic and Subarctic regions due to increased evaporation and permafrost degradation. Along with lake drawdown, these processes often boost aquatic ...chemical concentrations, potentially impacting trophic dynamics. In particular, elevated chemical levels may impact primary productivity, which may in turn influence populations of primary and secondary consumers. We examined trophic dynamics of 18 shrinking lakes of the Yukon Flats, Alaska, that had experienced pronounced increases in nutrient (>200 % total nitrogen, >100 % total phosphorus) and ion concentrations (>100 % for four major ions combined) from 1985–1989 to 2010–2012, versus 37 stable lakes with relatively little chemical change over the same period. We found that phytoplankton stocks, as indexed by chlorophyll concentrations, remained unchanged in both shrinking and stable lakes from the 1980s to 2010s. Moving up the trophic ladder, we found significant changes in invertebrate abundance across decades, including decreased abundance of five of six groups examined. However, these decadal losses in invertebrate abundance were not limited to shrinking lakes, occurring in lakes with stable surface areas as well. At the top of the food web, we observed that probabilities of lake occupancy for ten waterbird species, including adults and chicks, remained unchanged from the period 1985–1989 to 2010–2012. Overall, our study lakes displayed a high degree of resilience to multi-trophic cascades caused by rising chemical concentrations. This resilience was likely due to their naturally high fertility, such that further nutrient inputs had little impact on waters already near peak production.
Wolf (Canis lupus) kill rates are fundamental to understanding predation, but are not well known at low moose (Alces alces) densities. We investigated kill rates of 6 wolf packs (2–10 wolves/pack) ...during 2 winters on the Yukon Flats, a region of eastern Interior Alaska where moose were the sole ungulate prey of wolves occurring at densities <0.2 moose/km2. Our objectives were to compare kill rates with those from areas of greater moose densities, and to determine potential trends in kill rates across the winter. We located moose killed by wolves in February–March 2009, and November 2009–March 2010 using aerial tracking techniques and global positioning system (GPS) location clusters. Wolves killed more moose in early than late winter (βMONTH = −0.02 moose/pack/day, 95% CI = −0.01 to −0.04), and kill rate estimates (mean, 95% CI) were greatest in November (0.033 moose/wolf/day, 0.011–0.055) and least in February (0.011, 0.002–0.02). Kill rates were similar between February and March 2009 (0.019 moose/wolf/day, 0.01–0.03) and 2010 (0.018, 0.01–0.03). Prey composition was primarily adult females (39%) and young-of-the-year (35%). We attribute an elevated kill rate in early winter to predation on more vulnerable young-of-the-year. Kill rates in our study were similar to those from other studies where moose occurred at greater densities. We suggest that very few, if any, wolf–moose systems in Alaska and the Yukon experience a density-dependent phase in the functional response, and instead wolves respond numerically to changes in moose density or availability in the absence of alternative prey. Through a numerical response, wolf predation rates may approximate the annual growth potential of the moose population, contributing to persistent low densities of moose and wolves on the Yukon Flats. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Identification of ecological factors that drive animal distributions allows us to understand why distributions vary temporally and spatially, and to develop models to predict future changes to ...populationsvital tools for effective wildlife management and conservation. For waterbird broods in the boreal forest, distributions are likely driven by factors affecting quality of nesting and brood-rearing habitats, and the influence of these factors may extend beyond singles species, affecting the entire waterbird community. We used occupancy models to assess factors influencing species richness of waterbird broods on 72 boreal lakes, along with brood distributions of 3 species of conservation concern: lesser scaup (Aythya affinis), whitewinged scoters (Melanitta fusca), and horned grebe (Podiceps auritus). Factors examined included abundance of invertebrate foods (Amphipoda, Diptera, Gastropoda, Hemiptera, Odonata), physical lake attributes (lake area, emergent vegetation), water chemistry (nitrogen, phosphorus, chlorophyll a concentrations), and nesting habitats (water edge, non-forest cover). Of the 5 invertebrates, only amphipod density was related to richness and occupancy, consistently having a large and positive relationship. Despite this importance to waterbirds, amphipods were the most patchily distributed invertebrate, with 17% of the study lakes containing 70% of collected amphipods. Lake area was the only other covariate that strongly and positively influenced species richness and occupancy of scaup, scoters, and grebes. All 3 water chemistry covariates, which provided alternative measures of lake productivity, were positively related to species richness but had little effect on scaup, scoter, and grebe occupancy. Conversely, emergent vegetation was negatively related to richness, reflecting avoidance of overgrown lakes by broods. Finally, nesting habitats had no influence on richness and occupancy, indicating that, at a broad spatial scale, brood distributions are largely driven by the presence of quality brood-rearing lakes, not nesting habitats. Our findings are relevant to generating conservation plans or management goals; specifically, boreal lakes with abundant amphipods and surface areas >25 ha are important habitat for waterbird broods and merit conservation, especially given the patchy distribution of amphipods. Moreover, these high quality brood-rearing lakes are much rarer, and thus more constraining, than are quality nesting habitats, which are likely abundant in the boreal.
In the deep, cooler layers of clear, nutrient-poor, stratified water bodies, phytoplankton often accumulate to form a thin band or "deep chlorophyll maximum" (DCM) of ecological importance. Under ...such conditions, these photosynthetic microorganisms may be close to their physiological compensation points and to the boundaries of their ecological tolerance. To grow and survive any resulting energy limitation, DCM species are thought to exhibit highly specialised or flexible acclimation strategies. In this study, we investigated several of the adaptable ecophysiological strategies potentially employed by one such species, Chlamydomonas acidophila: a motile, unicellular, phytoplanktonic flagellate that often dominates the DCM in stratified, acidic lakes. Physiological and behavioural responses were measured in laboratory experiments and were subsequently related to field observations. Results showed moderate light compensation points for photosynthesis and growth at 22°C, relatively low maintenance costs, a behavioural preference for low to moderate light, and a decreased compensation point for photosynthesis at 8°C. Even though this flagellated alga exhibited a physiologically mediated diel vertical migration in the field, migrating upwards slightly during the day, the ambient light reaching the DCM was below compensation points, and so calculations of daily net photosynthetic gain showed that survival by purely autotrophic means was not possible. Results suggested that strategies such as low-light acclimation, small-scale directed movements towards light, a capacity for mixotrophic growth, acclimation to low temperature, in situ exposure to low O 2 , high CO 2 and high P concentrations, and an avoidance of predation, could combine to help overcome this energetic dilemma and explain the occurrence of the DCM. Therefore, corroborating the deceptive ecophysiological complexity of this and similar organisms, only a suite of complementary strategies can facilitate the survival of C. acidophila in this DCM.
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