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Heinrich Stadial 4 during the last glacial period was marked by severe cooling at northern high latitudes along with the attendant changes in Asian Monsoon (Chinese Stadial 4) and South American Monsoon (South American Stadial 4). Here we present improved constraints on timings of Heinrich/Chinese/South American Stadial 4 onset and termination at sub-centennial precision based on speleothem records. We show that their initial onsets were essentially synchronous (40.20 ± 0.08 thousand years ago) and led the Antarctic warming by ~300 years. The Heinrich/Chinese Stadial 4 termination commenced at 38.34 ± 0.07 thousand years ago following a centennial-scale reduction in the Amazon River runoff and a poleward shift of the Southern Westerly wind belt. These two precursor events may have contributed to a reduced Amazon Plume Region and an enhanced Agulhas salt/heat leakage that led to an abrupt resumption of the Atlantic Meridional Ocean Circulation eventually triggering the Heinrich/Chinese Stadial 4 termination. Severe cooling at high northern latitudes, which marked the onset of Heinrich Stadial 4, was synchronous with changes in tropical monsoon systems and preceded Antarctic warming by around 300 years, according to a compilation of speleothem and ice core records.

Regulatory T (Treg) cells have an essential role in maintaining immune homeostasis, in part by suppressing effector T cell functions. Phosphoinositide-dependent kinase 1 (PDK1) is a pleiotropic kinase that acts as a key effector downstream of PI3K in many cell types. In T cells, PDK1 has been shown to be critical for activation of NF-κB and AKT signaling upon TCR ligation and is therefore essential for effector T cell activation, proliferation, and cytokine production. Using Treg cell–specific conditional deletion, we now demonstrate that PDK1 is also essential for Treg cell suppressive activity in vivo. Ablation of Pdk1 specifically in Treg cells led to systemic, lethal, scurfy-like inflammation in mice. Genome-wide analysis confirmed that PDK1 is essential for the regulation of key Treg cell signature gene expression and, further, suggested that PDK1 acts primarily to control Treg cell gene expression through regulation of the canonical NF-κB pathway. Consistent with these results, the scurfy-like phenotype of mice lacking PDK1 in Treg cells was rescued by enforced activation of NF-κB downstream of PDK1. Therefore, PDK1-mediated activation of the NF-κB signaling pathway is essential for regulation of Treg cell signature gene expression and suppressor function.

The Asian summer monsoon (ASM) is a vast climate system, whose variability is critical to the livelihoods of billions of people across the Asian continent. During the past half-century, much progress has been made in understanding variations on a wide range of timescales, yet several significant issues remain unresolved. Of note are two long-standing problems concerning orbital-scale variations of the ASM. (1) Chinese loess magnetic susceptibility records show a persistent glacial-interglacial dominated ~100 kyr (thousand years) periodicity, while the cave oxygen-isotope (δ18O) records reveal periodicity in an almost pure precession band (~20 kyr periodicity)—the “Chinese 100 kyr problem”. (2) ASM records from the Arabian Sea and other oceans surrounding the Asian continent show a significant lag of 8–10 kyr to Northern Hemisphere summer insolation (NHSI), whereas the Asian cave δ18O records follow NHSI without a significant lag—a discrepancy termed the “sea-land precession-phase paradox”. How can we reconcile these differences? Recent and more refined model simulations now provide spatial patterns of rainfall and wind across the precession cycle, revealing distinct regional divergences in the ASM domain, which can well explain a large portion of the disparities between the loess, marine, and cave proxy records. Overall, we also find that the loess, marine, and cave records are indeed complementary rather than incompatible, with each record preferentially describing a certain aspect of ASM dynamics. Our study provides new insight into the understanding of different hydroclimatic proxies and largely reconciles the “Chinese 100 kyr problem“ and “sea-land precession-phase paradox”.

The understanding of pore characteristics is the basis for studying the macroscopic physical properties of wood. Herein, mercury intrusion porosimetry (MIP) was analyzed in detail as a function of pressure to analyze wood samples. Additionally, fractal analysis was performed from the MIP derived data to establish the relationship between the fractal dimension and the structural parameters. The results demonstrate that in spite of the large variability of the MIP data from different wood species, the overall trend can be approximated. The aperture size ranged from 2.0 nm to 350 µm with a corresponding porosity ranging from 44.26 to 73.18%. The threshold pressure, average pore radius and pore-to-throat ratio extracted from the MIP data can be used as a valid parameter to evaluate the structural characteristics. The fractal dimension values in the corresponding macropore, mesopore and micropore aperture range intervals are 2.978, 2.827 and 2.438, respectively, which indicate a higher degree of pore complexity for larger pores. Negative correlations are observed between the fractal dimension and porosity with R2 values of 0.85, and in addition, positive correlations are observed between the fractal dimension and the average pore radius and pore-to-throat ratio with corresponding R2 values of 0.66 and 0.52, respectively.

The elastic strain of wood reflects the nature (stretching or compression) and the magnitude of the drying stress at that time during the conventional drying process. The accurate prediction of strain is important to optimize the drying process and to improve drying speed and quality. In this work, the elastic strain was measured in real time, and moisture content was measured by periodic weighing during the drying process. Using these data, the GM (1,1) grey prediction model was used to predict moisture content in adjacent periods in the future. Based on the moisture content predicted by GM (1,1), a BP neural network was constructed to predict the development trend of elastic strain in the surface layer and core layer. The prediction results of the GM-BP combination model showed that the fitting error range of the prediction of the surface layer elastic strain was [-5×10-3~5×10-3], with a mean square error (MSE) of 2.31×10-7. The elastic strain of the core layer was [-2×10-3~2×10-3], and the MSE was 3.86×10-8. Thus, the GM-BP model achieved high accuracy for predicting the development trend of elastic strain. It can provide a new method and innovative thinking for the optimization and control of wood drying process.

The microscopic pore structure of wood is an important factor that affects its macroscopic properties. In this study, an oak sample was used for pore structure characterization. X-ray computed tomography imaging was carried out, and the scanning results (a multi-layer two-dimensional planar image) were rendered using Avizo software (a three-dimensional stereo image). A digital image processing method was used to identify the characteristics of the three-dimensional pore structure features and to calculate the characteristic parameters, i.e., the porosity (volume/surface), pore area and volume, pore size distribution, and the connectivity. The 27 mm3 oak sample had the following characteristics: a pore size which ranged from 8.56 µm to 1262.84 µm; a pore volume of 1.01 × 1010 µm3; a pore area and volume porosity of 1.12 × 109 µm2 and 37.6%, respectively; a surface porosity range of approximately 36.1% to 39.1%; a pore diameter for axial connection ranging from approximately 164.57 µm to 1262.84 µm; and had corresponding proportions of the pore area and volume of approximately 74.4% and 67.3%, respectively. This information provided useful structural data for the construction of future models.

Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.

The NLRP3 inflammasome, as an important component of the innate immune system, plays vital roles in various metabolic disorders. It has been reported that the NLRP3 inflammasome can be activated by a broad range of distinct stimuli, such as K+ efflux, mitochondrial dysfunction, lysosomal disruption and trans-Golgi disassembly, etc. However, there has been no well-established model for NLRP3 inflammasome activation so far, especially the underlying mechanisms for mitochondria in NLRP3 inflammasome activation remain elusive. Given that K+ efflux is a widely accepted nexus for triggering activation of NLRP3 inflammasome in most previous studies, we sought to elucidate the role of mitochondria in K+ efflux-induced NLRP3 inflammasome activation. Here, we demonstrated that inflammation activation by LPS evoked the expression of genes that involved in mitochondrial biogenesis and mitophagy, subsequently mitochondrial mass and mitochondrial membrane potential were also elevated, suggesting the contribution of mitochondria in inflammatory responses. Moreover, we inhibited mitochondrial biogenesis by silencing Tfam and genetic ablation of Tfam abolished the NLRP3 inflammasome activation induced by K+ efflux via release of mitochondrial DNA (mtDNA), as deprivation of cellular mtDNA by EtBr treatment could reverse inflammasome activation induced by K+ efflux. Collectively, we reveal that mtDNA release induced by K+ efflux in macrophages activates NLRP3 inflammasome, and propose that mitochondria may serve as a potential therapeutic target for NLRP3 inflammasome-related diseases.

Description, Floods and megadroughts affected the Neolithic cultures in the Yangtze River Delta between 4300 and 4000 years ago., The Liangzhu culture in the Yangtze River Delta (YRD) was among the world’s most advanced Neolithic cultures. Archeological evidence suggests that the Liangzhu ancient city was abandoned, and the culture collapsed at ~4300 years ago. Here, we present speleothem records from southeastern China in conjunction with other paleoclimatic and archeological data to show that the Liangzhu culture collapsed within a short and anomalously wet period between 4345 ± 32 and 4324 ± 30 years ago, supporting the hypothesis that the city was abandoned after large-scale flooding and inundation. We further show that the demise of Neolithic cultures in the YRD occurred within an extended period of aridity that started at ~4000 ± 45 years ago. We suggest that the major hydroclimatic changes between 4300 and 3000 years ago may have resulted from an increasing frequency of the El Niño–Southern Oscillation in the context of weakened Northern Hemisphere summer insolation.

The relationships between free shrinkage and actual shrinkage of different layers in Mongolian Scotch pine (Pinus sylvestris var. mongolica Litv.) were explored to provide basic data for the further study of drying shrinkage properties. The free shrinkage coefficients at different temperatures and the actual shrinkage strain of each layer were examined under conventional drying. The results showed high precision of free drying shrinkage of corresponding layers of thin small test strips in each layer of sawn timber. The free shrinkage increased linearly as moisture content declined. At the same temperature, the free shrinkage coefficient reached the largest values for the first layer (above 0.267%), while the smallest values were recorded for the ninth layer (below 0.249%). Except for the ninth layer, the free shrinkage coefficients in width directions of other representative layers decreased as temperature increased. At constant temperature, the difference in free shrinkage coefficient of test materials in the length direction of sawn timber was small for the first layer, but slightly larger and changed irregularly in the fifth and ninth layer direction. At the end of conventional drying, the plastic deformation of each layer in the early stage of drying showed a reducing trend or even reversal due to the effects of reverse stress and later damp heat. In sum, these findings look promising for future optimization of wood drying process.

Large-section boxed-heart square timber is prone to surface and radial cracks during the drying process. A high-temperature setting pretreatment could prevent cracking in boxed-heart timber. The pretreatment process is primarily determined by the preheating time. To determine the preheating time of the test material, a mathematical model for the internal temperature distribution of Mongolian pine (Pinus sylvestris var. mongolica Litv.) boxed-heart square timber in the preheating stage was established by the finite element method. The model viability was verified by tests that showed that the model simulation results were stable and non-fluctuating. For the prediction error of the temperature change, the early-period error was large, while the later predicted values and measured values tended to be consistent. For the prediction error of the temperature distribution, the core-layer error was smallest, while that of the surface layer was greatest. For the prediction error of the preheating time, greater preheating temperatures exhibited greater error, and the minimum error was 10 min, at 90 °C. Overall, the predicted values were close to the measured values and can be referenced for subsequent pretreatment process research.

This study was based on the finite element method to construct a high-frequency heating temperature field simulation model. In the model, the bending length and angle of top plate were changed upwards. The heating uniformity of test material was then analyzed under different conditions (bending length and angle) to identify the best improvement scheme and carry out the experimental verification. The results showed that when the bending length and angle of top plate were 200mm and 45°, the heating uniformity was the best. Comparison of temperature distribution along the width direction of test material before and after improvement, it was concluded that the temperature distribution was more uniform after improvement. Comparison the temperature difference between the center of test material and its length, width and thickness direction measurement point before and after improvement, the temperature difference was reduced by 7.6 ℃ , 1.7 ℃ , 3.4 ℃ , respectively, which effectively improved the heating uniformity. Comparison of the changes in the electromagnetic field distributions between plates before and after improvement revealed an increase in distribution uniformity from 0.631 to 0.811. This indicated that the electromagnetic field distribution after improvement was more uniform with ideal heating effect. Overall, the improvement in bending length and angle of top plate could change the distribution of electromagnetic fields between the plates and enhance temperature distribution uniformity of wood during high-frequency heating.

Speleothem records have radically changed our understanding of the paleo Asian monsoon (AM), but explanations for Asian summer monsoon (ASM) variations in the Holocene period are usually based on single proxy records, such as oxygen isotope (δ18O). The application of multi-proxy records to the study of the forcing mechanism and internal structure of climate events is more comprehensive and accurate in the analysis of paleoclimates than using single proxy records. Therefore, a multi-proxy speleothem record of weak ASM events in 8.0–7.0 BP from Chongqing, which showed a dry southwestern China during weak ASM episodes, was reported. The analysis of multi-proxy records of SMY2 stalagmite indicated that the beginning of the ‘7.2 ka event’ was at 7.29 ± 0.03 ka BP, and its culmination was at 7.1 ± 0.04 ka BP. Thus, this event lasted nearly 200 a, and the main drought period lasted 50 a. Power spectrum analysis showed a significant 61 a cycle signal during the study period in the δ18O record of SMY2, which coincided with the Atlantic multidecadal oscillation activity (AMOC) cycle. This study demonstrates that the ASM during 8.0–7.0 ka BP is strongly correlated with the changes in solar activity and also sensitive to the southward shift of Intertropical Convergence Zone (ITCZ) and AMOC cycle.

Stalagmite is one kind of secondary carbonates formed in limestone caves (speleothem). After cave water droplets containing Ca2+ and $$\rm{HCO}_3^-$$ drip onto floor, carbonate in the water might become supersaturated due to CO2 degassing under certain conditions, resulting in the formation of stalagmite in a process year after year. Stalagmite is one of important geological archives for paleoclimate research. The advantages include wide spatial distribution, suitable for U-Th and U-Pb dating, enriched in climate proxies, continuity, long time span, comparability and lower sampling cost etc. These factors have propelled stalagmite paleoclimate research to the forefront of global paleoclimatology with an irreplaceable role. The stalagmite paleoclimate study started in the western countries, mainly in Europe and America in 1960s–1970s, while the relevant research in China was progressively developed in the 1980s–1990s after the Reform and Opening up. Although there was a huge gap between the overall research level in China and western countries, a solid research foundation, as well as a number of talent teams were established during the period. In the 21st century, starting from the publication of stalagmite records from Hulu Cave in Nanjing in 2001, the stalagmite paleoclimate research in China has ushered in a flourishing development and a real leap on the basis of international cooperation, resulting in significant international impacts. The landmark achievements, including establishment of the world’s longest (640000 years) East Asian monsoon stalagmite record, as well as the longest Indian monsoon (280000 years), South American monsoon (250000 years), North American westerly climate (330000 years), Central Asian westerly climate (135000 years), and northwestern China westerly climate (500000 years), have laid a milestone in the paleoclimate study in these climate domains. Importantly, these stalagmite records have revealed the relationship of Asian monsoon variations with solar insolation climate change in polar regions, and the South American monsoon changes on orbital-suborbital timescales, which have provided new geological observations for the development of orbital-suborbital climate theory; elaborated coupling and differentiation relationships between the Asian monsoon and the westerly climate; reconstructed the history of Asian monsoon changes in the Holocene in detail, and thus the hydrological and climate variances behind Chinese and Indian civilization-cultural evolutions. Furthermore, a large number of high-resolution stalagmite records over the past 2000 years have been reconstructed, which are important for understanding short-term climate variability and magnitude, events, cycles, and thus the future climate projection. The achievements have also involved the improvements of a number of important techniques, such as U-Th dating method, the establishments of various hydroclimatic proxies, as well as the contributions to the reconstruction of the atmosphere 14C variation history over the past ∼54000 years. On the perspective of the future, the Chinese stalagmite community should continue to develop key techniques, further clarify the hydroclimatic significance of stalagmite proxies, impel the integration of related disciplines, and concentrate on key scientific issues in global climate change and major social demands.

The negative correlation between the local precipitation and speleothem $$ \delta^{18} {\text{O}} $$ is used extensively in the study of monsoon variability. However, the correlation coefficient between them do not always pass the significance test, which makes it difficult to interpret the monsoon variability using speleothem $$ \delta^{18} {\text{O}} $$ . In this study, regression analysis and corresponding significance test method are employed to investigate the relationship between the Asian summer monsoon circulation and speleothem $$ \delta^{18} {\text{O}} $$ of Xiaobailong cave using CERA-20C, speleothem $$ \delta^{18} {\text{O}} $$ of Xiaobailong cave, and precipitation and temperature data from 8 meteorological stations around the cave. Diagnostic results indicate that the speleothem $$ \delta^{18} {\text{O}} $$ of Xiaobailong cave can reflect the variability of Asian summer monsoon circulation via the rainout effect from the nearest upstream sources to destination. The stronger (weaker) ASM circulation causes isotopically depleted (enriched) water vapor via enhancing (reducing) the Rayleigh distillation processes during the transport of water vapor from the northern Bay of Bengal and the northern South China Sea to the region around the cave. The lower (higher) isotope value in water vapor further leads to depleted (enriched) speleothem $$ \delta^{18} {\text{O}} $$ of Xiaobailong cave. The numerical experiments using isotope-incorporated spectral model substantiate the key physical process revealed in the observational analysis. These results provide an efficient way for reconstructing the paleomonsoon circulation with $$ \delta^{18} {\text{O}} $$ in speleothems, ice cores, and tree ring cellulose.

The knowledge of moisture content (MC) and drying stress are crucial parameters to control the drying process and maintain the quality of dried wood. Herein, we investigated the pattern of moisture...

Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. Hepatic ischemia-reperfusion injury (HIRI) causes acute-on-chronic liver failure and induces transformation of acute to chronic injury. HIRI model of mice was established by a semi-hepatic blocking method and treated with Ghrelin. This process is involved in inflammation, oxidative stress damage and apoptosis, and is associated with the expansion and activation of fibrotic haematopoietic stem cells (HSCs) which express and secrete high levels of collagen that induces liver fibrosis. Therefore, we investigated the effects of Ghrelin during transformation of HIRI to liver fibrosis, and explored the molecular mechanism of Ghrelin's action based on Smad and ERK pathways.Hepatic injury was detected by plasma ALT levels. The hepatic histology and collagen were elucidated by HE staining and Masson staining, respectively. Liver inflammation levels and inflammatory cell counts were assessed by MPO and HE staining, respectively. The antioxidant capacity of plasma was evaluated based on the levels of SOD, MDA, and XOD. The mRNA or protein expression levels of genes related to apoptosis, fibrosis, Smad, and ERK pathways were assessed by real-time quantitative PCR (RT-qPCR), ELISA, or western blotting.The HIRI model was established to investigate the effects of the liver injury transformed to liver fibrosis. Ghrelin exhibited good hepatic protection by ameliorating liver histological changes and decreasing plasma ALT levels. Ghrelin significantly decreased the expression of MPO than that in model group, suggesting that Ghrelin blocked the inflammatory response in the HIRI liver tissue; this supports the anti-inflammatory effects of Ghrelin. Ghrelin significantly decreased apoptosis (enhanced Bcl-2 expression, and down-regulated Bax and Caspase 3). Ghrelin exhibited anti-oxidative effects as it inhibited plasma MDA levels, and promoted plasma SOD and XOD levels. Moreover, Ghrelin inhibited activation of hepatic stellate cells, blocked traditional fibrotic Smad and ERK signalling pathways, and reduced hepatic fibrosis by stimulating degradation of extracellular matrices (ECMs; such as collagen I, collagen III, HA, and LN).This study demonstrates that Ghrelin delays the transformation of HIRI to liver fibrosis process which is correlated to its anti-apoptotic, anti-inflammatory, and anti-oxidative effects. Moreover, Ghrelin alleviates HIRI-mediated liver fibrosis, inhibits activation of HSCs, and reduces accumulation of ECM via inhibition of Smad and ERK signalling pathways.

We thank Stuchlik et al. for their comments (1) on our paper (2). First, for the sake of clarity, we note that Stuchlik et al. may have inadvertently stated “δ18O records in several ice cores from Greenland and Antarctica that were originally dated by the radiocarbon method.” This is obviously incorrect, as ice-core δ18O series are not radiocarbon-dated. We are also intrigued by their comment that “the authors refer to several papers dealing with the Laacher See volcanic eruption (LSVE)” (1), because we neither discussed the LSVE nor cited any papers related to the LSVE (2). We stress that one of the key issues discussed in our paper was evaluating the extraterrestrial impact (3 … [↵][1]1To whom correspondence may be addressed. Email: cheng021{at}xjtu.edu.cn. [1]: #xref-corresp-1-1

Human activities within the context of a drying trend triggered the megafaunal extinctions in Madagascar and Mascarene Islands., Madagascar and the Mascarene Islands of Mauritius and Rodrigues underwent catastrophic ecological and landscape transformations, which virtually eliminated their entire endemic vertebrate megafauna during the past millennium. These ecosystem changes have been alternately attributed to either human activities, climate change, or both, but parsing their relative importance, particularly in the case of Madagascar, has proven difficult. Here, we present a multimillennial (approximately the past 8000 years) reconstruction of the southwest Indian Ocean hydroclimate variability using speleothems from the island of Rodrigues, located ∼1600 km east of Madagascar. The record shows a recurring pattern of hydroclimate variability characterized by submillennial-scale drying trends, which were punctuated by decadal-to-multidecadal megadroughts, including during the late Holocene. Our data imply that the megafauna of the Mascarenes and Madagascar were resilient, enduring repeated past episodes of severe climate stress, but collapsed when a major increase in human activity occurred in the context of a prominent drying trend.

The Younger Dryas (YD), arguably the most widely studied millennialscale extreme climate event, was characterized by diverse hydroclimate shifts globally and severe cooling at high northern latitudes that abruptly punctuated the warming trend from the last glacial to the present interglacial. To date, a precise understanding of its trigger, propagation, and termination remains elusive. Here, we present speleothem oxygen-isotope data that, in concert with other proxy records, allow us to quantify the timing of the YD onset and termination at an unprecedented subcentennial temporal precision across the North Atlantic, Asian Monsoon-Westerlies, and South American Monsoon regions. Our analysis suggests that the onsets of YD in the North Atlantic (12,870 ± 30 B.P.) and the Asian Monsoon- Westerlies region are essentially synchronous within a few decades and lead the onset in Antarctica, implying a north-to-south climate signal propagation via both atmospheric (decadal-time scale) and oceanic (centennial-time scale) processes, similar to the Dansgaard- Oeschger events during the last glacial period. In contrast, the YD termination may have started first in Antarctica at ~11,900 B.P., or perhaps even earlier in the western tropical Pacific, followed by the North Atlantic between ~11,700 ± 40 and 11,610 ± 40 B.P. These observations suggest that the initial YD termination might have originated in the Southern Hemisphere and/or the tropical Pacific, indicating a Southern Hemisphere/tropics to North Atlantic-Asian Monsoon-Westerlies directionality of climatic recovery., This work was supported by grants from National Nature Science Foundation of China (NSFC 41888101 and 41731174 to H.C.) and US NSF Grant (1702816 to R.L.E. and H.C.)

With the discovery of magnetoreceptor mechanisms in animals, it materialized the novel applications of controlling cell and animal behaviors using magnetic fields. T cells have shown to be sensitive to magnetic fields. Here, we reported that exposure to moderate SMFs (static magnetic fields) led to increased granule and cytokine secretion as well as ATP production and mitochondrial respiration from CD8+ T cells. These effects were inhibited by knocking down the Uqcrb and Ndufs6 genes of mitochondrial respiratory chain, whose transcriptions were regulated by candidate magnetoreceptor genes Isca1 and Cry1/Cry2. SMF exposure also promoted CD8+ T cell granule and cytokine secretion and repressed tumor growth in vivo. SMFs enhanced CD8+ T cell cytotoxicity, and the adoptive transfer into tumor-bearing mice resulted in enhanced antitumor effects. Collectively, our study suggests that moderate SMFs enhance CD8+ T cell cytotoxicity by promoting mitochondrial respiration and promoted the antitumor function of CD8+ T cells.

Hydroclimatic variability over the Volga River watershed (western Russia) strongly influences agricultural production, forest and grassland ecology, Caspian Sea level, and associated economic stability. Climate model forecasts of these variables suggest long-term increases in crop shortfalls and over-basin evaporation in the Volga and Caspian regions, respectively, but these projections currently lack validation from high-quality paleoclimate data. We present decadal-scale geochemical proxy data (δ13C, Mg/Ca, Sr/Ca) from 230Th-dated stalagmites retrieved from four caves along a 640-km north-south gradient in the Ural Mountains, which collectively cover the entire Holocene (11.7 ka to present). Orbital trends in δ13C and Mg/Ca are broadly coherent between Ural speleothems and suggest that following Early Holocene aridity, warm-season precipitation was paced by summer insolation and has gradually declined since ~8 ka, consistent with model hindcasting. Centennial-scale variability, which is exceptionally well replicated between the Southern (Kinderlinskaya Cave) and Central (Geologov-3 Cave) Ural sites, supports a dynamic link between Volga hydroclimate and sea-surface temperature in the northeastern North Atlantic and Barents Sea. Important discrepancies exist, however, with data from the southernmost cave sites, which may be related to past migration of a strong latitudinal precipitation gradient that characterizes the modern basin and approximates the limit of North Atlantic influence. Finally, we conduct model-data comparisons and review our composite dataset in light of pollen- and soil-based proxies from across the Volga region, as well as reconstructions of Caspian Sea level. Our results provide a temporally well-constrained and spatially coherent portrait of Holocene hydroclimate for the Volga River watershed, thus constituting an important metric for future modeling studies.

Regulatory T (Treg) cells have an essential role in maintaining immune homeostasis, in part by suppressing effector T (Teff) cell functions. Phosphoinositide-dependent kinase 1 (PDK1) is a pleiotropic kinase that acts as a key effector downstream of phosphatidylinositol-3-OH kinase (PI3K) in many cell types. In T cells, PDK1 has been shown to be critical for activation of NF-κB and AKT signaling upon T cell receptor ligation and is, therefore, essential for Teff cell activation, proliferation and cytokine production. Using Treg-specific conditional deletion, we now demonstrate that PDK1 is also essential for Treg suppressive activity in vivo. Ablation of Pdk1 specifically in Treg cells led to systemic, lethal, scurfy-like inflammation in mice. Genome-wide analysis confirmed that PDK1 is essential for the regulation of key Treg signature gene expression and, further, suggested that PDK1 acts primarily to control Treg gene expression through regulation of the canonical NF-κB pathway. Consistent with these results, the scurfy-like phenotype of mice lacking PDK1 in Treg cells was rescued by enforced activation of NF-κB downstream of PDK1. Therefore, PDK1-mediated activation of the NF-κB signaling pathway is essential for regulation of Treg signature gene expression and suppressor function.