Systematic identification of factors for provirus silencing in embryonic stem cells.

Embryonic stem cells (ESCs) repress the expression of exogenous proviruses and endogenous retroviruses (ERVs). Here, we systematically dissected the cellular factors involved in provirus repression in embryonic carcinomas (ECs) and ESCs by a genome-wide siRNA screen. Histone chaperones (Chaf1a/b), sumoylation factors (Sumo2/Ube2i/Sae1/Uba2/Senp6), and chromatin modifiers (Trim28/Eset/Atf7ip) are key determinants that establish provirus silencing. RNA-seq analysis uncovered the roles of Chaf1a/b and sumoylation modifiers in the repression of ERVs. ChIP-seq analysis demonstrates direct recruitment of Chaf1a and Sumo2 to ERVs. Chaf1a reinforces transcriptional repression via its interaction with members of the NuRD complex (Kdm1a, Hdac1/2) and Eset, while Sumo2 orchestrates the provirus repressive function of the canonical Zfp809/Trim28/Eset machinery by sumoylation of Trim28. Our study reports a genome-wide atlas of functional nodes that mediate proviral silencing in ESCs and illuminates the comprehensive, interconnected, and multi-layered genetic and epigenetic mechanisms by which ESCs repress retroviruses within the genome.

The impact of age and number of mutations on the size of clonal hematopoiesis.

Clonal hematopoiesis (CH) represents the clonal expansion of hematopoietic stem cells and their progeny driven by somatic mutations. Accurate risk assessment of CH is critical for disease prevention and clinical decision-making. The size of CH has been showed to associate with higher disease risk, yet, factors influencing the size of CH are unknown. In addition, the characteristics of CH in long-lived individuals are not well documented. Here, we report an in-depth analysis of CH in longevous (≥90 y old) and common (60~89 y old) elderly groups. Utilizing targeted deep sequencing, we found that the development of CH is closely related to age and the expression of aging biomarkers. The longevous elderly group exhibited a significantly higher incidence of CH and significantly higher frequency of TET2 and ASXL1 mutations, suggesting that certain CH could be beneficial to prolong life. Intriguingly, the size of CH neither correlates significantly to age, in the range of 60 to 110 y old, nor to the expression of aging biomarkers. Instead, we identified a strong correlation between large CH size and the number of mutations per individual. These findings provide a risk assessment biomarker for CH and also suggest that the evolution of the CH is influenced by factor(s) in addition to age.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

A DNA methylation haplotype block landscape in human tissues and preimplantation embryos reveals regulatory elements defined by comethylation patterns.

DNA methylation and associated regulatory elements play a crucial role in gene expression regulation. Previous studies have focused primarily on the distribution of mean methylation levels. Advances in whole-genome bisulfite sequencing (WGBS) have enabled the characterization of DNA methylation haplotypes (MHAPs), representing CpG sites from the same read fragment on a single chromosome, and the subsequent identification of methylation haplotype blocks (MHBs), in which adjacent CpGs on the same fragment are comethylated. Using our expert-curated WGBS data sets, we report comprehensive landscapes of MHBs in 17 representative normal somatic human tissues and during early human embryonic development. Integrative analysis reveals MHBs as a distinctive type of regulatory element characterized by comethylation patterns rather than mean methylation levels. We show the enrichment of MHBs in open chromatin regions, tissue-specific histone marks, and enhancers, including super-enhancers. Moreover, we find that MHBs tend to localize near tissue-specific genes and show an association with differential gene expression that is independent of mean methylation. Similar findings are observed in the context of human embryonic development, highlighting the dynamic nature of MHBs during early development. Collectively, our comprehensive MHB landscapes provide valuable insights into the tissue specificity and developmental dynamics of DNA methylation.

OpenXGR: a web-server update for genomic summary data interpretation.

How to effectively convert genomic summary data into downstream knowledge discovery represents a major challenge in human genomics research. To address this challenge, we have developed efficient and effective approaches and tools. Extending our previously established software tools, we here introduce OpenXGR (http://www.openxgr.com), a newly designed web server that offers almost real-time enrichment and subnetwork analyses for a user-input list of genes, SNPs or genomic regions. It achieves so through leveraging ontologies, networks, and functional genomic datasets (such as promoter capture Hi-C, e/pQTL and enhancer-gene maps for linking SNPs or genomic regions to candidate genes). Six analysers are provided, each doing specific interpretations tailored to genomic summary data at various levels. Three enrichment analysers are designed to identify ontology terms enriched for input genes, as well as genes linked from input SNPs or genomic regions. Three subnetwork analysers allow users to identify gene subnetworks from input gene-, SNP- or genomic region-level summary data. With a step-by-step user manual, OpenXGR provides a user-friendly and all-in-one platform for interpreting summary data on the human genome, enabling more integrated and effective knowledge discovery.

Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Subsidized gestational diabetes mellitus screening and management program in rural China: a pragmatic multicenter, randomized controlled trial.

BACKGROUND: The increasing prevalence of gestational diabetes mellitus (GDM) is a major challenge, particularly in rural areas of China where control rates are suboptimal. This study aimed to evaluate the effectiveness of a GDM subsidy program in promoting GDM screening and management in these underserved regions. METHODS: This multicenter, randomized controlled trial (RCT) was conducted in obstetric clinics of six rural hospitals located in three provinces in China. Eligible participants were pregnant women in 24-28 weeks' gestation, without overt diabetes, with a singleton pregnancy, access to a telephone, and provided informed consent. Participants were randomly assigned in a 1:1 ratio to either the intervention or control groups using an internet-based, computer-generated randomization system. The intervention group received subsidized care for GDM, which included screening, blood glucose retesting, and lifestyle management, with financial assistance provided to health care providers. In contrast, the control group received usual care. The primary outcomes of this study were the combined maternal and neonatal complications associated with GDM, as defined by the occurrence of at least one pre-defined complication in either the mother or newborn. The secondary outcomes included the GDM screening rate, rates of glucose retesting for pregnant women diagnosed with GDM, dietary patterns, physical activity levels, gestational weight gain, and antenatal visit frequency for exploratory purposes. Primary and secondary outcomes were obtained for all participants with and without GDM. Binary outcomes were analyzed by the generalized linear model with a link of logistic, and odds ratios (OR) with 95% confidence intervals (CIs) were reported. Count outcomes were analyzed by Poisson regression, and incidence rate ratios with 95% CIs were reported. RESULTS: A total of 3294 pregnant women were randomly assigned to either the intervention group (n = 1649) or the control group (n = 1645) between 15 September 2018 and 30 September 2019. The proportion of pregnant women in the intervention group who suffered from combined maternal and/or neonatal complications was lower than in the control group with adjusted OR = 0.86 (0.80 to 0.94, P = 0.001), and a more significant difference was observed in the GDM subgroup (adjusted OR = 0.66, 95% CI 0.47 to 0.95, P = 0.025). No predefined safety or adverse events of ketosis or ketoacidosis associated with GDM management were detected in this study. Both the intervention and control groups had high GDM screening rates (intervention: 97.2% [1602/1649]; control: 94.5% [1555/1645], P < 0.001). Moreover, The intervention group showed a healthier lifestyle, with lower energy intake and more walking minutes (P values < 0.05), and more frequent blood glucose testing (1.5 vs. 0.4 visits; P = 0.001) compared to the control group. CONCLUSION: In rural China, a GDM care program that provided incentives for both pregnant women and healthcare providers resulted in improved maternal and neonatal health outcomes. Public health subsidy programs in China should consider incorporating GDM screening and management to further enhance reproductive health. TRIAL REGISTRATION: China Clinical Trials Registry ChiCTR1800017488. https://www.chictr.org.cn/.

Global vaccine coverage and childhood survival estimates: 1990-2019.

Objective: To quantify the association between reduction in child mortality and routine immunization across 204 countries and territories from 1990 to 2019. Methods: We used child mortality and vaccine coverage data from the Global Burden of Disease Study. We used a modified child survival framework and applied a mixed-effects regression model to estimate the reduction in deaths in children younger than 5 years associated with eight vaccines. Findings: Between 1990 and 2019, the diphtheria-tetanus-pertussis (DTP), measles, rotavirus and Haemophilus influenzae type b vaccines were significantly associated with an estimated 86.9 (95% confidence interval, CI: 57.2 to 132.4) million fewer deaths in children younger than 5 years worldwide. This decrease represented a 24.2% (95% CI: 19.8 to 28.9) reduction in deaths relative to a scenario without vaccines. The DTP and measles vaccines averted 46.7 (95% CI: 30.0 to 72.7) million and 37.9 (95% CI: 25.4 to 56.8) million deaths, respectively. Of the total reduction in child mortality associated with vaccines, 84.2% (95% CI: 83.0 to 85.1) occurred in 73 countries supported by Gavi, the Vaccine Alliance, with an estimated 45.4 (95% CI: 29.8 to 69.2) million fewer deaths from 2000 to 2019. The largest reductions in deaths associated with these four vaccines were in India, China, Ethiopia, Pakistan and Bangladesh (in order of the size of reduction). Conclusion: Vaccines continue to reduce childhood mortality significantly, especially in Gavi-supported countries, emphasizing the need for increased investment in routine immunization programmes.

Stimulated Raman Scattering Microscopy Reveals Bioaccumulation of Small Microplastics in Protozoa from Natural Waters.

Microplastics (MPs) are pollutants of global concern, and bioaccumulation determines their biological effects. Although microorganisms form a large fraction of our ecosystem's biomass and are important in biogeochemical cycling, their accumulation of MPs has never been confirmed in natural waters because current tools for field biological samples can detect only MPs > 10 µm. Here, we show that stimulated Raman scattering microscopy (SRS) can image and quantify the bioaccumulation of small MPs (<10 µm) in protozoa. Our label-free method, which differentiates MPs by their SRS spectra, detects individual and mixtures of different MPs (e.g., polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, polystyrene, and poly(methyl methacrylate)) in protozoa. The ability of SRS to quantify cellular MP accumulation is similar to that of flow cytometry, a fluorescence-based method commonly used to determine cellular MP accumulation. Moreover, we discovered that protozoa in water samples from Yangtze River, Xianlin Wastewater Treatment Plant, Lake Taihu and the Pearl River Estuary accumulated MPs < 10 µm, but the proportion of MP-containing cells was low (∼2-5%). Our findings suggest that small MPs could potentially enter the food chain and transfer to organisms at higher trophic levels, posing environmental and health risks that deserve closer scrutiny.

Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability.

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

PiER: web-based facilities tailored for genetic target prioritisation harnessing human disease genetics, functional genomics and protein interactions.

Integrative prioritisation promotes translational use of disease genetic findings in target discovery. I report 'PiER' (http://www.genetictargets.com/PiER), web-based facilities that support ab initio and real-time genetic target prioritisation through integrative use of human disease genetics, functional genomics and protein interactions. By design, the PiER features two facilities: elementary and combinatory. The elementary facility is designed to perform specific tasks, including three online tools: eV2CG, utilising functional genomics to link disease-associated variants (particularly located at the non-coding genome) to core genes likely responsible for genetic associations in disease; eCG2PG, using knowledge of protein interactions to 'network' core genes and additional peripheral genes, producing a ranked list of core and peripheral genes; and eCrosstalk, exploiting the information of pathway-derived interactions to identify highly-ranked genes mediating crosstalk between molecular pathways. Each of elementary tasks giving results is sequentially piped to the next one. By chaining together elementary tasks, the combinatory facility automates genetics-led and network-based integrative prioritisation for genetic targets at the gene level (cTGene) and at the crosstalk level (cTCrosstalk). Together with a tutorial-like booklet describing instructions on how to use, the PiER facilities meet multi-tasking needs to accelerate computational translational medicine that leverages human disease genetics and genomics for early-stage target discovery and drug repurposing.

Priority index: database of genetic targets in immune-mediated disease.

We describe a comprehensive and unique database 'Priority index' (Pi; http://pi.well.ox.ac.uk) of prioritized genes encoding potential therapeutic targets that encompasses all major immune-mediated diseases. We provide targets at the gene level, each receiving a 5-star rating supported by: genomic evidence arising from disease genome-wide associations and functional immunogenomics, annotation evidence using ontologies restricted to genes with genomic evidence, and network evidence from protein interactions. Target genes often act together in related molecular pathways. The underlying Pi approach is unique in identifying a network of highly rated genes that mediate pathway crosstalk. In the Pi website, disease-centric pages are specially designed to enable the users to browse a complete list of prioritized genes and also a manageable list of nodal genes at the pathway crosstalk level; both switchable by clicks. Moreover, target genes are cross-referenced and supported using additional information, particularly regarding tractability, including druggable pockets viewed in 3D within protein structures. Target genes highly rated across diseases suggest drug repurposing opportunity, while genes in a particular disease reveal disease-specific targeting potential. To facilitate the ease of such utility, cross-disease comparisons involving multiple diseases are also supported. This facility, together with the faceted search, enhances integrative mining of the Pi resource to accelerate early-stage therapeutic target identification and validation leveraging human genetics.

Short-term associations of particulate matter with different aerodynamic diameters with mortality due to mental disorders and dementia in Ningde, China.

Limited evidence is available regarding the impact of ambient inhalable particulate matter (PM) on mental disorder (MD) or dementia-related deaths, particularly PM1, PM1-2.5, and coarse particles (PM2.5-10). Moreover, individual confounders have rarely been considered. In addition, evidence from low-pollution areas is needed but is inadequate. Using death records from the Death Registration System during 2015-2021 in Ningde, a coastal city in southeast China, we combined a conditional quasi-Poisson model with a distributed lag nonlinear model to estimate the nonlinear and lagged associations of PM exposure with MD or dementia-related deaths in Ningde, China, comprehensively controlling for individual time-invariant confounders using a time-stratified case-crossover design. The attributable fraction and number were calculated to quantify the burden of MD or dementia-related deaths that were related to PMs. We found J-shaped relationships between MD or dementia-related deaths and PMs, with different thresholds of 13, 9, 19, 33 and 12 µg/m3 for PM1, PM1-2.5, PM2.5, PM10 and PM2.5-10. An inter-quartile range increase for PM1, PM1-2.5, PM2.5, PM10 and PM2.5-10 above the thresholds led to an increase of 31.8% (95% confidence interval, 14.3-51.9%), 53.7% (22.4-93.1%), 32.6% (15.0-53.0%), 35.1% (17.7-55.0%) and 25.9% (13.0-40.3%) in MD-related deaths at lag 0-3 days, respectively. The associations were significant in the cool season rather than in the warm season and were significantly greater among people aged 75-84 years than in others. The fractions of MD-related deaths attributable to PM1, PM1-2.5, PM2.5, PM10 and PM2.5-10 were 5.55%, 6.49%, 7.68%, 10.66%, and 15.11%, respectively; however, only some of them could be protected by the concentrations recommended by the World Health Organisation or China grade I standard. Smaller associations and similar patterns were observed between PMs and dementia-related death. These findings suggest stricter standards, and provide evidence for the development of relevant policies and measures.

Effects of Cuisine-Based Chinese Heart-Healthy Diet in Lowering Blood Pressure Among Adults in China: Multicenter, Single-Blind, Randomized, Parallel Controlled Feeding Trial.

BACKGROUND: More than one-fifth of the world's population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation. METHODS: A multicenter, patient- and outcome assessor-blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mm Hg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mm Hg reduction in SBP was also calculated. RESULTS: A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mm Hg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was -5.0 (95% CI, -6.5 to -3.5) mm Hg and -2.8 (95% CI, -3.7 to -1.9) mm Hg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were -10.0 (95% CI, -12.1 to -7.9) mm Hg and -3.8 (95% CI, -5.0 to -2.5) mm Hg, respectively. The effect size did not differ among cuisines (P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, -0.1 to 0.2; P=0.558). The incremental cost-effectiveness ratio per 1 mm Hg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups (P=0.259), and none of the adverse events was associated with the intervention. CONCLUSIONS: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03882645.

A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia.

Transcriptional deregulation initiated by oncogenic fusion proteins plays a vital role in leukemia. The prevailing view is that the oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor-α (PML/RARα), generated by the chromosome translocation t(15;17), functions as a transcriptional repressor in acute promyelocytic leukemia (APL). Here, we provide rich evidence of how PML/RARα drives oncogenesis through both repressive and activating functions, particularly the importance of the newly identified activation role for the leukemogenesis of APL. The activating function of PML/RARα is achieved by recruiting both abundant P300 and HDAC1 and by the formation of super-enhancers. All-trans retinoic acid and arsenic trioxide, 2 widely used drugs in APL therapy, exert synergistic effects on controlling super-enhancer-associated PML/RARα-regulated targets in APL cells. We use a series of in vitro and in vivo experiments to demonstrate that PML/RARα-activated target gene GFI1 is necessary for the maintenance of APL cells and that PML/RARα, likely oligomerized, transactivates GFI1 through chromatin conformation at the super-enhancer region. Finally, we profile GFI1 targets and reveal the interplay between GFI1 and PML/RARα on chromatin in coregulating target genes. Our study provides genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development, highlighting the importance of globally dissecting regulatory circuits.

Stereoselective Synthesis of Amphoteric α-Haloalkenyl Boronates by Halogenative Semipinacol Rearrangement of B(MIDA)-Propargylic Alcohols.

The facile synthesis of stereo-defined and transformable functionality-enriched building blocks is of great importance in modern organic chemistry, as it allows the rapid and divergent assembly of complex molecules. Herein a halogen electrophile (N-bromosuccinimide and N-iodosuccinimide) initiated semipinacol rearrangement reaction of B(MIDA)-propargylic alcohols (MIDA=N-methyliminodiacetyl) by aryl migration towards the synthesis of amphoteric α-haloalkenyl boronates in moderate to good yields with excellent stereoselectivities is reported. The value of the products is evidenced by their ability to undergo divergent conversions to polysubstituted alkenes through manipulation of the C-B and C-X (X=Br, I) bonds and the carbonyl group.

Health and Economic Evaluation of Vaccination Against Pertussis in China: A 40-Year Analysis.

OBJECTIVES: This study aimed to evaluate the health and economic impact of diphtheria, tetanus, whole-cell pertussis vaccine (DTwP) and diphtheria-tetanus-acellular pertussis vaccine (DTaP) vaccination on pertussis prevention and control in China during the 40 years from 1978 to 2017. METHODS: We conducted cost-benefit analyses with a decision tree model populated with historical vaccination coverage levels and pertussis incidence and mortality data from before 1978 and during 1978 to 2017. We modeled 40 birth cohorts from birth until death. Costs and benefits were estimated from direct cost and societal perspectives (direct and indirect costs). Costs and benefits were adjusted to 2017 US dollars (USD), and future values were discounted at a 3% annual rate. We calculated net benefit values (net savings) and benefit-cost ratios of pertussis vaccination of children younger than 5 years. We conducted sensitivity analyses by varying key parameters within plausible ranges. RESULTS: Without DTwP and DTaP vaccination, there would be an estimated 115.76 million pertussis cases and 426 650 pertussis deaths in the 40 cohorts. With DTwP/DTaP vaccination, pertussis cases and deaths were decreased by an estimated 92.57% and 97.43%, saving 46 987.81 million USD in direct costs and 82 013.37 million USD from societal perspective. Pertussis vaccination program costs were 2168.76 million USD and 3961.28 million USD from direct cost and societal perspectives. Benefit-cost ratios were 21.67:1 from the direct cost perspective and 20.70:1 from the societal perspective. Sensitivity analyses showed the results to be robust. CONCLUSIONS: Over the lifetime of 40 birth cohorts, China's immunization program is preventing 93% of pertussis cases and 97% of pertussis deaths, resulting in substantial savings to the healthcare system and society.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300.

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

Computation Offloading and Resource Allocation Based on P-DQN in LEO Satellite Edge Networks.

Traditional low earth orbit (LEO) satellite networks are typically independent of terrestrial networks, which develop relatively slowly due to the on-board capacity limitation. By integrating emerging mobile edge computing (MEC) with LEO satellite networks to form the business-oriented "end-edge-cloud" multi-level computing architecture, some computing-sensitive tasks can be offloaded by ground terminals to satellites, thereby satisfying more tasks in the network. How to make computation offloading and resource allocation decisions in LEO satellite edge networks, nevertheless, indeed poses challenges in tracking network dynamics and handling sophisticated actions. For the discrete-continuous hybrid action space and time-varying networks, this work aims to use the parameterized deep Q-network (P-DQN) for the joint computation offloading and resource allocation. First, the characteristics of time-varying channels are modeled, and then both communication and computation models under three different offloading decisions are constructed. Second, the constraints on task offloading decisions, on remaining available computing resources, and on the power control of LEO satellites as well as the cloud server are formulated, followed by the maximization problem of satisfied task number over the long run. Third, using the parameterized action Markov decision process (PAMDP) and P-DQN, the joint computing offloading, resource allocation, and power control are made in real time, to accommodate dynamics in LEO satellite edge networks and dispose of the discrete-continuous hybrid action space. Simulation results show that the proposed P-DQN method could approach the optimal control, and outperforms other reinforcement learning (RL) methods for merely either discrete or continuous action space, in terms of the long-term rate of satisfied tasks.