Genetic and environmental factors responsible for numerous neurodegenerative diseases vary between disorders, yet age remains a universal risk factor. Age-associated decline in protein homeostasis, ...or proteostasis, enables disease-linked proteins to adopt aberrant tertiary structures, accumulate as higher-ordered aggregates, and cause a myriad of cellular dysfunctions and neuronal death. However, recent findings suggest that the assembly of disease proteins into tightly ordered aggregates can significantly delay proteotoxic onset. Furthermore, manipulation of metabolic pathways through key signaling components extends lifespan, bolsters proteostasis networks, and delays the onset of proteotoxicity. Thus, understanding the relationship between proteostasis and aging has provided important insights into neurodegeneration.
In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to ...mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2–α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other’s surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.
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► Activator BH3 domains bind the Bax canonical groove and help free the Bax BH3 ► Bax:BH3 peptide complexes reveal sequence characteristics of activator BH3 domains ► Bax activation separates its “core” domain (helices α1–α5) and “latch” (α6–α8) ► The freed core forms a symmetric BH3-in-groove dimer with a lipophilic surface
The structural transitions that set proapoptotic Bax on the pathway to forming a pore in the outer mitochondrial membrane are revealed in crystal structures of Bax bound to activator BH3 peptides.
Paleoclimate studies suggest that increased global warmth during the Eocene epoch was greatly amplified at high latitudes, a state that climate models cannot fully reproduce. However, proxy estimates ...of Eocene near-Antarctic sea surface temperatures (SSTs) have produced widely divergent results at similar latitudes, with SSTs above 20 °C in the southwest Pacific contrasting with SSTs between 5 and 15 °C in the South Atlantic. Validation of this zonal temperature difference has been impeded by uncertainties inherent to the individual paleotemperature proxies applied at these sites. Here, we present multiproxy data from Seymour Island, near the Antarctic Peninsula, that provides well-constrained evidence for annual SSTs of 10–17 °C (1σ SD) during the middle and late Eocene. Comparison of the same paleotemperature proxy at Seymour Island and at the East Tasman Plateau indicate the presence of a large and consistent middle-to-late Eocene SST gradient of ∼7 °C between these two sites located at similar paleolatitudes. Intermediate-complexity climate model simulations suggest that enhanced oceanic heat transport in the South Pacific, driven by deep-water formation in the Ross Sea, was largely responsible for the observed SST gradient. These results indicate that very warm SSTs, in excess of 18 °C, did not extend uniformly across the Eocene southern high latitudes, and suggest that thermohaline circulation may partially control the distribution of high-latitude ocean temperatures in greenhouse climates. The pronounced zonal SST heterogeneity evident in the Eocene cautions against inferring past meridional temperature gradients using spatially limited data within given latitudinal bands.
Biotic communities are shaped by adaptations from generations of exposure to selective pressures by recurrent and often infrequent events. In large rivers, floods can act as significant agents of ...change, causing considerable physical and biotic disturbance while often enhancing productivity and diversity. We show that the relative balance between these seemingly divergent outcomes can be explained by the rhythmicity, or predictability of the timing and magnitude, of flood events. By analyzing biological data for large rivers that span a gradient of rhythmicity in the Neotropics and tropical Australia, we find that systems with rhythmic annual floods have higher fish species richness, more stable avian populations, and elevated rates of riparian forest production compared with those with arrhythmic flood pulses. Intensification of the hydrological cycle driven by climate change, coupled with reductions in runoff due to water extractions for human use and altered discharge from impoundments, is expected to alter the hydrologic rhythmicity of floodplain rivers with significant consequences for both biodiversity and productivity.
Significance The Terminal Classic decline of the Maya civilization represents a key example of ancient societal collapse that may have been caused by climate change, but there are inconsistencies ...between paleoclimate and archaeological evidence regarding the spatial distribution of droughts and sociopolitical disintegration. We conducted a new analysis of regional drought intensity that shows drought was most severe in the region with the strongest societal collapse. We also found that an earlier drought interval coincided with agricultural intensification, suggesting that the ancient Maya adapted to previous episodes of climate drying, but could not cope with the more extreme droughts of the Terminal Classic.
Paleoclimate records indicate a series of severe droughts was associated with societal collapse of the Classic Maya during the Terminal Classic period (∼800–950 C.E.). Evidence for drought largely derives from the drier, less populated northern Maya Lowlands but does not explain more pronounced and earlier societal disruption in the relatively humid southern Maya Lowlands. Here we apply hydrogen and carbon isotope compositions of plant wax lipids in two lake sediment cores to assess changes in water availability and land use in both the northern and southern Maya lowlands. We show that relatively more intense drying occurred in the southern lowlands than in the northern lowlands during the Terminal Classic period, consistent with earlier and more persistent societal decline in the south. Our results also indicate a period of substantial drying in the southern Maya Lowlands from ∼200 C.E. to 500 C.E., during the Terminal Preclassic and Early Classic periods. Plant wax carbon isotope records indicate a decline in C ₄ plants in both lake catchments during the Early Classic period, interpreted to reflect a shift from extensive agriculture to intensive, water-conservative maize cultivation that was motivated by a drying climate. Our results imply that agricultural adaptations developed in response to earlier droughts were initially successful, but failed under the more severe droughts of the Terminal Classic period.
Geological evidence indicates that grounded ice sheets reached sea level at all latitudes during two long-lived Cryogenian (58 and ≥5 My) glaciations. Combined uranium-lead and rhenium-osmium dating ...suggests that the older (Sturtian) glacial onset and both terminations were globally synchronous. Geochemical data imply that CO
was 10
PAL (present atmospheric level) at the younger termination, consistent with a global ice cover. Sturtian glaciation followed breakup of a tropical supercontinent, and its onset coincided with the equatorial emplacement of a large igneous province. Modeling shows that the small thermal inertia of a globally frozen surface reverses the annual mean tropical atmospheric circulation, producing an equatorial desert and net snow and frost accumulation elsewhere. Oceanic ice thickens, forming a sea glacier that flows gravitationally toward the equator, sustained by the hydrologic cycle and by basal freezing and melting. Tropical ice sheets flow faster as CO
rises but lose mass and become sensitive to orbital changes. Equatorial dust accumulation engenders supraglacial oligotrophic meltwater ecosystems, favorable for cyanobacteria and certain eukaryotes. Meltwater flushing through cracks enables organic burial and submarine deposition of airborne volcanic ash. The subglacial ocean is turbulent and well mixed, in response to geothermal heating and heat loss through the ice cover, increasing with latitude. Terminal carbonate deposits, unique to Cryogenian glaciations, are products of intense weathering and ocean stratification. Whole-ocean warming and collapsing peripheral bulges allow marine coastal flooding to continue long after ice-sheet disappearance. The evolutionary legacy of Snowball Earth is perceptible in fossils and living organisms.
We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders ...(PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial.
There is growing interest in developing spatially resolved methane
(CH4) isotopic source signatures to aid in geographic source
attribution of CH4 emissions. CH4 hydrogen isotope measurements
...(δ2H–CH4) have the potential to be a powerful tool for
geographic differentiation of CH4 emissions from freshwater
environments, as well as other microbial sources. This is because microbial
δ2H–CH4 values are partially dependent on the δ2H of environmental water (δ2H–H2O), which exhibits
large and well-characterized spatial variability globally. We have refined
the existing global relationship between δ2H–CH4 and
δ2H–H2O by compiling a more extensive global dataset of
δ2H–CH4 from freshwater environments, including wetlands,
inland waters, and rice paddies, comprising a total of 129 different sites,
and compared these with measurements and estimates of δ2H–H2O, as well as δ13C-CH4 and δ13C–CO2 measurements. We found that estimates of δ2H–H2O explain approximately 42 % of the observed variation in
δ2H–CH4, with a flatter slope than observed in previous
studies. The inferred global δ2H–CH4 vs. δ2H–H2O regression relationship is not sensitive to using either
modelled precipitation δ2H or measured δ2H–H2O as the predictor variable. The slope of the global
freshwater relationship between δ2H–CH4 and δ2H–H2O is similar to observations from incubation experiments
but is different from pure culture experiments. This result is consistent
with previous suggestions that variation in the δ2H of acetate,
controlled by environmental δ2H–H2O, is important in
determining variation in δ2H–CH4. The relationship between
δ2H–CH4 and δ2H–H2O leads to significant
differences in the distribution of freshwater δ2H–CH4
between the northern high latitudes (60–90∘ N), relative to
other global regions. We estimate a flux-weighted global freshwater δ2H–CH4 of −310 ± 15 ‰, which is higher
than most previous estimates. Comparison with δ13C measurements
of both CH4 and CO2 implies that residual δ2H–CH4 variation is the result of complex interactions between
CH4 oxidation, variation in the dominant pathway of methanogenesis, and
potentially other biogeochemical variables. We observe a significantly
greater distribution of δ2H–CH4 values, corrected for
δ2H–H2O, in inland waters relative to wetlands, and
suggest this difference is caused by more prevalent CH4 oxidation in
inland waters. We used the expanded freshwater CH4 isotopic dataset to
calculate a bottom-up estimate of global source δ2H–CH4
and δ13C-CH4 that includes spatially resolved isotopic
signatures for freshwater CH4 sources. Our bottom-up global source
δ2H–CH4 estimate (−278 ± 15 ‰) is
higher than a previous estimate using a similar approach, as a result of the
more enriched global freshwater δ2H–CH4 signature derived
from our dataset. However, it is in agreement with top-down estimates of
global source δ2H–CH4 based on atmospheric measurements
and estimated atmospheric sink fractionations. In contrast our bottom-up
global source δ13C-CH4 estimate is lower than top-down
estimates, partly as a result of a lack of δ13C-CH4 data
from C4-plant-dominated ecosystems. In general, we find there is a
particular need for more data to constrain isotopic signatures for
low-latitude microbial CH4 sources.
The gut microbiome community structure and development are associated with several health outcomes in young children. To determine the household influences of gut microbiome structure, we assessed ...microbial sharing within households in western Kenya by sequencing 16S rRNA libraries of fecal samples from children and cattle, cloacal swabs from chickens, and swabs of household surfaces. Among the 156 households studied, children within the same household significantly shared their gut microbiome with each other, although we did not find significant sharing of gut microbiome across host species or household surfaces. Higher gut microbiome diversity among children was associated with lower wealth status and involvement in livestock feeding chores. Although more research is necessary to identify further drivers of microbiota development, these results suggest that the household should be considered as a unit. Livestock activities, health and microbiome perturbations among an individual child may have implications for other children in the household.
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