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The 8.2 ka event is the most significant global climate anomaly of the Holocene epoch, but a lack of records from Mainland Southeast Asia (MSEA) currently limits our understanding of the spatial and temporal extent of the climate response. A newly developed speleothem record from Tham Doun Mai Cave, Northern Laos provides the first high‐resolution record of this event in MSEA. Our multiproxy record (δ18O, δ13C, Mg/Ca, Sr/Ca, and petrographic data), anchored in time by 9 U‐Th ages, reveals a significant reduction in local rainfall amount and weakening of the monsoon at the event onset at ∼8.29 ± 0.03 ka BP. This response lasts for a minimum of ∼170 years, similar to event length estimates from other speleothem δ18O monsoon records. Interestingly, however, our δ13C and Mg/Ca data, proxies for local hydrology, show that abrupt changes to local rainfall amounts began decades earlier (∼70 years) than registered in the δ18O. Moreover, the δ13C and Mg/Ca also show that reductions in rainfall continued for at least ∼200 years longer than the weakening of the monsoon inferred from the δ18O. Our interpretations suggest that drier conditions brought on by the 8.2 ka event in MSEA were felt beyond the temporal boundaries defined by δ18O‐inferred monsoon intensity, and an initial wet period (or precursor event) may have preceded the local drying. Most existing Asian Monsoon proxy records of the 8.2 ka event may lack the resolution and/or multiproxy information necessary to establish local and regional hydrological sensitivity to abrupt climate change. Plain Language Summary: The most significant global climate event in the last ∼11,000 years occurred ∼8,200 years ago (the "8.2 ka event"). Many globally distributed records of past climate (paleoclimate) document significant changes during the event, but there are few from Mainland Southeast Asia available to reconstruct the climate impacts in this region. We present a new speleothem (cave sample) record from Tham Doun Mai Cave, Northern Laos that uses multiple geochemical and physical signals (proxies) to document local and regional climate effects of the 8.2 ka event at a high resolution. Using oxygen isotopes, we find that the 8.2 ka event weakened regional monsoon intensity for at least ∼170 years, which resembles findings from other studies. However, other proxies suggest local rainfall changed abruptly decades before the signal of monsoon weakening. Additionally, local drying may have lasted much longer than current estimates of 8.2 ka event responses. Most proxy records of the 8.2 ka event in monsoon regions lack similar multiproxy information and/or do not have high enough resolution to fully capture the climatic response. Additional records like ours from monsoon regions may assist in establishing how sensitive local and regional rainfall is to abrupt climate change. Key Points: High‐resolution speleothem record of the 8.2 ka event in northern Laos shows weakened monsoon intensity and reduced local rainfall amountsMultiproxy data suggest the disruption to local rainfall amounts started decades before the weakened monsoon intensity inferred from δ18OPrevious monsoon records of the event lack the resolution and/or multiproxy dimensions needed to reconstruct local hydrologic changes [ABSTRACT FROM AUTHOR]

Introduction: The classification and management of pulmonary hypertension (PH) is challenging due to clinical heterogeneity of patients. We sought to identify distinct multimorbid phenogroups of patients with PH that are at particularly high-risk for adverse events. Methods: A hospital-based cohort of patients referred for right heart catheterization between 2005–2016 with PH were included. Key exclusion criteria were shock, cardiac arrest, cardiac transplant, or valvular surgery. K-prototypes was used to cluster patients into phenogroups based on 12 clinical covariates. Results: Among 5208 patients with mean age 64±12 years, 39% women, we identified 5 distinct multimorbid PH phenogroups with similar hemodynamic measures yet differing clinical outcomes: (1) "young men with obesity", (2) "women with hypertension", (3) "men with overweight", (4) "men with cardiometabolic and cardiovascular disease", and (5) "men with structural heart disease and atrial fibrillation." Over a median follow-up of 6.3 years, we observed 2182 deaths and 2002 major cardiovascular events (MACE). In age- and sex-adjusted analyses, phenogroups 4 and 5 had higher risk of MACE (HR 1.68, 95% CI 1.41–2.00 and HR 1.52, 95% CI 1.24–1.87, respectively, compared to the lowest risk phenogroup 1). Phenogroup 4 had the highest risk of mortality (HR 1.26, 95% CI 1.04–1.52, relative to phenogroup 1). Conclusions: Cluster-based analyses identify patients with PH and specific comorbid cardiometabolic and cardiovascular disease burden that are at highest risk for adverse clinical outcomes. Interestingly, cardiopulmonary hemodynamics were similar across phenogroups, highlighting the importance of multimorbidity on clinical trajectory. Further studies are needed to better understand comorbid heterogeneity among patients with PH. [ABSTRACT FROM AUTHOR]

Background: Men are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known. Study design and methods: We examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression. Results: Initial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04–2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29–19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52–5.18, p = 0.009 in women, Pinteraction = 0.02). Conclusions: In a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection. [ABSTRACT FROM AUTHOR]

The Asian monsoon region is highly dependent on boreal summer rainfall, which directly impacts the socio-economic stability and welfare of billions of people each year. Precipitation variability over East China has been extensively studied and is known to be characterized by meridional tripole and dipole precipitation structures. In contrast, few studies have focused on precipitation variability over Mainland Southeast Asia (MSEA) and the possible relationship with the variability over East China. Here we focus on how interannual precipitation variability across MSEA during 1983–2017 may be associated with the tripole or dipole patterns using an empirical orthogonal function (EOF) analysis. The first EOF shows a meridional tripole pattern in East China summer precipitation and an in-phase relationship between MSEA and South China precipitation. In contrast, the second EOF shows a meridional dipole pattern in East China precipitation and an out-of-phase relationship between MSEA and South China precipitation. We show that the first EOF mode is a delayed precipitation response to the El Niño-Southern Oscillation (ENSO), while the second EOF mode is a simultaneous precipitation response to the remote influence of the North Atlantic Oscillation (NAO). Therefore, the in-phase or out-of-phase variations in precipitation between MSEA and South China may be used to gauge the relative importance of local Pacific and remote Atlantic influences on Asian monsoon climate. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that play a wide variety of critical roles in different biological processes by post-transcriptionally regulating gene expression. They access diverse regulatory pathways during various stages of cellular differentiation, growth, and apoptosis, and can contribute to both normal and diseased functions. One important family of miRNAs involved in these functions is the miR-125 family (miR-125a and miR-125b). Investigations have been made to increasingly uncover the mechanisms by which the miR-125 family regulates normal homeostasis and growth in a variety of cell types including immune cells, and how dysregulation of miR-125a and miR-125b can lead to disease pathogenesis and tumorigenesis. In this review, we summarize what is currently known about miR-125a and miR-125b, mainly focusing on their roles in immune cell development and function as well as tumor suppression and promotion. [ABSTRACT FROM AUTHOR]

Adoptive T cell transfer, in particular TCR T cell therapy, holds great promise for cancer immunotherapy with encouraging clinical results. However, finding the right TCR T cell clone is a tedious, time-consuming, and costly process. Thus, there is a critical need for single cell technologies to conduct fast and multiplexed functional analyses followed by recovery of the clone of interest. Here, we use droplet microfluidics for functional screening and real-time monitoring of single TCR T cell activation upon recognition of target tumor cells. Notably, our platform includes a tracking system for each clone as well as a sorting procedure with 100% specificity validated by downstream single cell reverse-transcription PCR and sequencing of TCR chains. Our TCR screening prototype will facilitate immunotherapeutic screening and development of T cell therapies. [ABSTRACT FROM AUTHOR]

ABSTRACT Thirty years (1954-1983) of soil moisture data from 60 sites in Iowa are used to identify the dominant modes of spatial and temporal variability. Both soil moisture and precipitation exhibit a northwest to southeast gradient across Iowa, with wetter conditions in the southeast and drier conditions in the northwest. Climate and soil characteristics are responsible for the spatial variations in soil moisture. There is a pronounced annual soil moisture cycle that has three distinct phases: a moist phase (April-June), a drying phase (June-September), and a recharge phase (September-November). Spring soil moisture is strongly controlled by the amount of recharge during the previous fall. There is no evidence of a long-term trend in soil moisture; however there is significant interannual variability and about 20% of the variance is attributable to El Niño-Southern Oscillation (ENSO). The warm (cold) phase of ENSO is associated with above (below) average soil moisture in Iowa. The multi-decadal soil moisture record is used to analyse drought frequency and magnitude in Iowa, and to place the 2012 Midwest drought in historical context. In general, Iowa drought is more common during the latter part of the warm season (August through November), but tends to be more severe during the early part of the warm season (April-July). We find that the 2012 drought was unusual because it persisted and intensified throughout the growing season. [ABSTRACT FROM AUTHOR]

The spatiotemporal variability of the Asian Monsoon (AM) over the last two millennia has been attributed to a combination of external solar and volcanic forcing and/or internal coupled atmosphere-ocean dynamics, but the relative importance of these mechanisms remains unresolved. The present knowledge of multidecadal to centennial-scale AM variability over Mainland Southeast Asia is not well-constrained, despite substantial progress in understanding seasonal to decadal variability from tree ring records. Here we present the first high-resolution stable isotope (δ 13 C and δ 18 O) speleothem record from northern Laos spanning the Common Era (∼50 BCE to 1880 CE). The δ 13 C record reveals substantial centennial-scale fluctuations primarily driven by local water balance. Notably, the driest period at our site occurred from ∼1280 to 1430 CE, during the time of the Angkor droughts, supporting previous findings that this megadrought likely impacted much of Mainland Southeast Asia. In contrast, variations in stalagmite δ 18 O reflect changes in rainfall upstream from our study site. Interestingly, the δ 18 O record exhibits a positive correlation with solar activity that persists after 1200 CE, contrary to the findings in previous studies. Solar-forced climate model simulations reveal that these δ 18 O variations may be driven by solar-forced changes in upstream rainout over the tropical Indian Ocean, which modify the δ 18 O of moisture transported to our study site without necessarily affecting local rainfall amount. We conclude that future rainfall changes in Mainland Southeast Asia are likely to be superimposed on multidecadal to centennial-scale variations in background climate driven primarily by internal climate variability, whereas solar forcing may impact upstream rainout over the Indian Ocean. • New high-resolution speleothem record from northern Laos spanning ∼50 BCE to 1880 CE. • δ 13 C reflects local water balance and records centennial-length dry periods during the Little Ice Age. • δ 18 O reflects upstream rainout over the Indian Ocean and may be influenced by solar forcing. [ABSTRACT FROM AUTHOR]

Deregulation of several microRNAs (miRs) can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but shut down in the B-cell lineage, and the gene encoding miR-125b lacked transcriptional activation markers in B cells. To understand the biological importance of the physiological silencing of miR-125b expression in B cells, we drove its expression in the B-cell lineage and found that dysregulated miR-125b expression impaired egress of immature B cells from the bone marrow to peripheral blood. Such impairment appeared to be mediated primarily by inhibited expression of the sphingosine-1- phosphate receptor 1 (S1PR1). Enforced expression of S1PR1 or clustered regularly interspaced short palindromic repeats/Cas9-mediated genome editing of the miR-125b targeting site in the S1PR1 39 untranslated region rescued the miR-125b-mediated defect in B-cell egress. In addition to impaired B-cell egress, miR-125b dysregulation initially reduced pre-B-cell output but later induced pre-B-cell lymphoma/leukemia in mice. Genetic deletion of IRF4 was found in miR-125b-induced B-cell cancer, but its role in oncogenic miR-125b-induced B-cell transformation is still unknown. Here, we further demonstrated an interaction of the effects of miR-125b and IRF4 in cancer induction by showing that miR125b-induced B-cell leukemia was greatly accelerated in IRF4 homozygous mutant mice. Thus, we conclude that physiological silencing of miR-125b is required for normal B-cell development and also acts as a mechanism of cancer suppression. [ABSTRACT FROM AUTHOR]

• A palaeohydrological shift documented in early Pliocene in the North China. • A tectonic-scaled 'tripole-like' rainfall pattern existed in Pliocene over East Asia. • Simulated dynamics of Pacific zonal and meridional SST proposed. Considerable uncertainty remains over the nature and causes(s) of East Asian monsoon evolution since the Late Miocene, a significantly warmer period characterized by substantially weaker meridional and zonal Pacific sea surface temperature (SST) gradients than today and therefore regarded as a potential analog for current and future global warming. However, the extent to which these temperature gradients impacted rainfall patterns across East Asia, and particularly the northern extent of the monsoon domain, remains controversial. Here we present the first hydrological record extending back eight million years (Ma) for North China Plain derived from organic biomarkers preserved in a terrestrial sediment sequence. Our record shows a significant increase in monsoon rainfall during the Early Pliocene (∼4.2-4.5 Ma), coincident with strengthening of Pacific meridional and zonal SST gradients, and the eastern equatorial Pacific cold tongue. This marked intensification of the monsoon rainfall in northern China is also observed in paleoclimate archives from southern Asia, but anti-phased with those from central-eastern China (including southern China), indicating a 'tripole-like' rainfall pattern over East Asia. Through a set of climate model experiments, we show that this redistribution of monsoon rainfall across East Asia during the Early Pliocene (5.33-3.6 Ma) was likely due to an equatorward contraction of the western Pacific warm pool, reduced summer convection in the western subtropical Pacific, and the strengthening of the Hadley and Walker circulations. Our study thus highlights the strong influence of Pacific Ocean temperature gradients on East Asian hydroclimate. [ABSTRACT FROM AUTHOR]

Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response. T-bet is important for Tfh cell production of IFN-γ, but not IL-21, and for a robust GC reaction. STAT4, phosphorylated in Tfh cells upon infection, is required for expression of T-bet and Bcl6 and for IFN-γ and IL-21. These data indicate that T-bet is expressed with Bcl6 in Tfh cells and is required alongside STAT4 to coordinate Tfh cell IL-21 and IFN-γ production and for promotion of the GC response after acute viral challenge., (© 2018 Weinstein et al.)