Spatial atlas of the mouse central nervous system at molecular resolution.

Spatially charting molecular cell types at single-cell resolution across the 3D volume is critical for illustrating the molecular basis of brain anatomy and functions. Single-cell RNA sequencing has profiled molecular cell types in the mouse brain1,2, but cannot capture their spatial organization. Here we used an in situ sequencing method, STARmap PLUS3,4, to profile 1,022 genes in 3D at a voxel size of 194 × 194 × 345 nm3, mapping 1.09 million high-quality cells across the adult mouse brain and spinal cord. We developed computational pipelines to segment, cluster and annotate 230 molecular cell types by single-cell gene expression and 106 molecular tissue regions by spatial niche gene expression. Joint analysis of molecular cell types and molecular tissue regions enabled a systematic molecular spatial cell-type nomenclature and identification of tissue architectures that were undefined in established brain anatomy. To create a transcriptome-wide spatial atlas, we integrated STARmap PLUS measurements with a published single-cell RNA-sequencing atlas1, imputing single-cell expression profiles of 11,844 genes. Finally, we delineated viral tropisms of a brain-wide transgene delivery tool, AAV-PHP.eB5,6. Together, this annotated dataset provides a single-cell resource that integrates the molecular spatial atlas, brain anatomy and the accessibility to genetic manipulation of the mammalian central nervous system.

Spatiotemporally resolved transcriptomics reveals the subcellular RNA kinetic landscape.

Spatiotemporal regulation of the cellular transcriptome is crucial for proper protein expression and cellular function. However, the intricate subcellular dynamics of RNA remain obscured due to the limitations of existing transcriptomics methods. Here, we report TEMPOmap-a method that uncovers subcellular RNA profiles across time and space at the single-cell level. TEMPOmap integrates pulse-chase metabolic labeling with highly multiplexed three-dimensional in situ sequencing to simultaneously profile the age and location of individual RNA molecules. Using TEMPOmap, we constructed the subcellular RNA kinetic landscape in various human cells from transcription and translocation to degradation. Clustering analysis of RNA kinetic parameters across single cells revealed 'kinetic gene clusters' whose expression patterns were shaped by multistep kinetic sculpting. Importantly, these kinetic gene clusters are functionally segregated, suggesting that subcellular RNA kinetics are differentially regulated in a cell-state- and cell-type-dependent manner. Spatiotemporally resolved transcriptomics provides a gateway to uncovering new spatiotemporal gene regulation principles.

Discovery and Characterization of Putative Glycoprotein-Encoding Mycoviruses in the Bunyavirales.

Although segmented negative-sense RNA viruses (SNSRVs) have been frequently discovered in various fungi, most SNSRVs reported only the large segments. In this study, we investigated the diversity of the mycoviruses in the phytopathogenic fungus Fusarium asiaticum using the metatranscriptomic technique. We identified 17 fungal single-stranded RNA (ssRNA) viruses including nine viruses within Mitoviridae, one each in Narnaviridae, Botourmiaviridae, Hypoviridae, Fusariviridae, and Narliviridae, two in Mymonaviridae, and one trisegmented virus temporarily named Fusarium asiaticum mycobunyavirus 1 (FaMBV1). The FaMBV1 genome comprises three RNA segments, large (L), medium (M), and small (S) with 6,468, 2,639, and 1,420 nucleotides, respectively. These L, M, and S segments putatively encode the L protein, glycoprotein, and nucleocapsid, respectively. Phylogenetic analysis based on the L protein showed that FaMBV1 is phylogenetically clustered with Alternaria tenuissima negative-stranded RNA virus 2 (AtNSRV2) and Sclerotinia sclerotiorum negative-stranded RNA virus 5 (SsNSRV5) but distantly related to the members of the family Phenuiviridae. FaMBV1 could be vertically transmitted by asexual spores with lower efficiency (16.7%, 2/42). Comparison between FaMBV1-free and -infected fungal strains revealed that FaMBV1 has little effect on hyphal growth, pathogenicity, and conidium production, and its M segment is dispensable for viral replication and lost during subculture and asexual conidiation. The M and S segments of AtNSRV2 and SsNSRV5 were found using bioinformatics methods, indicating that the two fungal NSRVs harbor trisegmented genomes. Our results provide a new example of the existence and evolution of the segmented negative-sense RNA viruses in fungi. IMPORTANCE Fungal segmented negative-sense RNA viruses (SNSRVs) have been frequently found. Only the large segment encoding RNA-dependent RNA polymerase (RdRp) has been reported in most fungal SNSRVs, except for a few fungal SNSRVs reported to encode nucleocapsids, nonstructural proteins, or movement proteins. Virome analysis of the Fusarium spp. that cause Fusarium head blight discovered a novel virus, Fusarium asiaticum mycobunyavirus 1 (FaMBV1), representing a novel lineage of the family Phenuiviridae. FaMBV1 harbors a trisegmented genome that putatively encodes RdRp, glycoproteins, and nucleocapsids. The putative glycoprotein was first described in fungal SNSRVs and shared homology with glycoprotein of animal phenuivirus but was dispensable for its replication in F. asiaticum. Two other trisegmented fungal SNSRVs that also encode glycoproteins were discovered, implying that three-segment bunyavirus infections may be common in fungi. These findings provide new insights into the ecology and evolution of SNSRVs, particularly those infecting fungi.

N6-methyladenosine levels in peripheral blood RNA: a potential diagnostic biomarker for colorectal cancer.

BACKGROUND: N6-methyladenosine (m6A) is dysregulated in various cancers, including colorectal cancer (CRC). Herein, we assess the diagnostic potential of peripheral blood (PB) m6A levels in CRC. METHODS: We collected PB from healthy controls (HCs) and patients with CRC, analyzed PB RNA m6A levels and the expression of m6A-related demethylase genes FTO and ALKBH5, cocultured CRC cells with PB mononuclear cells (PBMCs), and constructed an MC38 cancer model. RESULTS: PB RNA m6A levels were higher in the CRC than that in HCs. The area under the curve (AUC) of m6A levels (0.886) in the CRC was significantly larger compared with carbohydrate antigen 199 (CA199; 0.666) and carcinoembryonic antigen (CEA; 0.834). The combination of CEA and CA199 with PB RNA m6A led to an increase in the AUC (0.935). Compared with HCs, the expression of FTO and ALKBH5 was decreased in the CRC. After coculturing with CRC cells, the PBMCs RNA m6A were significantly increased, whereas the expression of FTO and ALKBH5 decreased. Furthermore, m6A RNA levels in the PB of MC38 cancer models were upregulated, whereas the expression of FTO and ALKBH5 decreased. CONCLUSIONS: PB RNA m6A levels are a potential diagnostic biomarker for patients with CRC.

Construction of a Dendritic Nanoassembly-Based Fluorescent Biosensor for Electrostatic Interaction-Independent and Label-Free Measurement of Human Poly(ADP-ribose) Polymerase 1 in Lung Tissues.

Poly(ADP-ribose) polymerase 1 (PARP-1) is responsible for catalyzing the creation of poly(ADP-ribose) polymer and involved in DNA replication and repair. Sensitive measurement of PARP-1 is critical for clinical diagnosis. However, the conventional electrostatic attraction-based PAPR-1 assays usually involve laborious procedures, poor sensitivity, and false positives. Herein, we demonstrate the construction of a dendritic nanoassembly-based fluorescent biosensor for electrostatic interaction-independent and label-free measurement of human PARP-1 in lung tumor tissues. When PARP-1 is present, the specific double-stranded DNA (dsDNA)-activated PARP-1 transfers the ADP-ribosyl group from nicotinamide adenine dinucleotide (NAD+)/biotinylated NAD+ to the PARP-1 itself, resulting in the formation of biotinylated dsDNA-PARP-1-PAR polymer bioconjugates that can be captured by magnetic beads. Upon the addition of TdT, APE1, and NH2-modified T-rich probe, the captured dsDNAs with dual 3'-OH termini initiate TdT-activated APE1-mediated hyperbranched amplification to produce abundant dendritic DNA nanoassemblies that can be stained by SYBR Green I to generate a high fluorescence signal. This biosensor is characterized by a template-free, electrostatic interaction-independent, high sensitivity, and label-free assay. It enables rapid (less than 3 h) measurement of PARP-1 with a limit of detection of 4.37 × 10-8 U/µL and accurate measurement of cellular PARP-1 activity with single-cell sensitivity. Moreover, it is capable of screening potential inhibitors and discriminating the PARP-1 level in normal person tissues and lung cancer patient tissues, with great potential in PARP-1-related clinical diagnosis and drug discovery.

Temporal trends in risk of bisphenol A, benzophenone-3 and triclosan exposure among U.S. children and adolescents aged 6-19 years: Findings from the National Health and Nutrition Examination Survey 2005-2016.

BACKGROUND: Phenolic compounds with potential adverse health effects are gradually being replaced. Little is known about the potential health risks of BPA, BP3, and TCS exposure in children and adolescents aged 6-19 years in the United States. OBJECTIVES: To determine trends and rates of change in hazard indices (HI) for three phenolics in U.S. children and adolescents for BPA, BP3, TCS, and to assess changes in gender, race/ethnicity, age, and potential health risks. METHODS: Metabolic biomonitoring data from field-collected urine samples from the National Health and Nutrition Examination Survey (NHANES) were utilized. Daily intake of three phenols (bisphenol A, benzophenone-3, and triclosan) between 2005 and 2016 in children and adolescents were obtained. Cumulative risk indicators, including hazard quotient (HQ), hazard index (HI), and maximum cumulative ratio (MCR), were used for the health risk assessment of the three phenols. RESULTS: During this period, the change in LSGM HI was -2.9% per cycle [95% Cl: (-3.7%, -2.2%)], and the percentage of participants with HI > 0.1 decreased from 15.6% to 10.5%. Children (6-11 years) had higher mean HI values than adolescents (12-19 years), while female had higher LSGM HI values than male. MCR values were generally low and negatively correlated with HI. However, the average value of MCR increased from 1.722 to 2.107 during this period. CONCLUSION: Exposure to phenolics among U.S. children and adolescents has changed in recent decades. However, gaps in data limit the interpretation of trends but legislative activity and advocacy campaigns by nongovernmental organizations may play a role in changing trends. Moreover, there are growing concerns about the potential health risks associated with exposure to multiple phenols in children and adolescents.

Astaxanthin alleviates PM2.5-induced cardiomyocyte injury via inhibiting ferroptosis.

BACKGROUND: Long-term exposure of humans to air pollution is associated with an increasing risk of cardiovascular diseases (CVDs). Astaxanthin (AST), a naturally occurring red carotenoid pigment, was proved to have multiple health benefits. However, whether or not AST also exerts a protective effect on fine particulate matter (PM2.5)-induced cardiomyocyte damage and its underlying mechanisms remain unclear. METHODS: In vitro experiments, the H9C2 cells were subjected to pretreatment with varying concentrations of AST, and then cardiomyocyte injury model induced by PM2.5 was established. The cell viability and the ferroptosis-related proteins expression were measured in different groups. In vivo experiments, the rats were pretreated with different concentrations of AST for 21 days. Subsequently, a rat model of myocardial PM2.5 injury was established by intratracheal instillation every other day for 1 week. The effects of AST on myocardial tissue injury caused by PM2.5 indicating by histological, serum, and protein analyses were examined. RESULTS: AST significantly ameliorated PM2.5-induced myocardial tissue injury, inflammatory cell infiltration, the release of inflammatory factors, and cardiomyocyte H9C2 cell damage. Mechanistically, AST pretreatment increased the expression of SLC7A11, GPX4 and down-regulated the expression of TfR1, FTL and FTH1 in vitro and in vivo. CONCLUSIONS: Our study suggest that ferroptosis plays a significant role in the pathogenesis of cardiomyocyte injury induced by PM2.5. AST may serve as a potential therapeutic agent for mitigating cardiomyocyte injury caused by PM2.5 through the inhibition of ferroptosis.

CRL4Cdt2 ubiquitin ligase regulates Dna2 and Rad16 (XPF) nucleases by targeting Pxd1 for degradation.

Structure-specific endonucleases (SSEs) play key roles in DNA replication, recombination, and repair. SSEs must be tightly regulated to ensure genome stability but their regulatory mechanisms remain incompletely understood. Here, we show that in the fission yeast Schizosaccharomyces pombe, the activities of two SSEs, Dna2 and Rad16 (ortholog of human XPF), are temporally controlled during the cell cycle by the CRL4Cdt2 ubiquitin ligase. CRL4Cdt2 targets Pxd1, an inhibitor of Dna2 and an activator of Rad16, for degradation in S phase. The ubiquitination and degradation of Pxd1 is dependent on CRL4Cdt2, PCNA, and a PCNA-binding degron motif on Pxd1. CRL4Cdt2-mediated Pxd1 degradation prevents Pxd1 from interfering with the normal S-phase functions of Dna2. Moreover, Pxd1 degradation leads to a reduction of Rad16 nuclease activity in S phase, and restrains Rad16-mediated single-strand annealing, a hazardous pathway of repairing double-strand breaks. These results demonstrate a new role of the CRL4Cdt2 ubiquitin ligase in genome stability maintenance and shed new light on how SSE activities are regulated during the cell cycle.

Opposing functions of Fng1 and the Rpd3 HDAC complex in H4 acetylation in Fusarium graminearum.

Histone acetylation, balanced by histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes, affects dynamic transitions of chromatin structure to regulate transcriptional accessibility. However, little is known about the interplay between HAT and HDAC complexes in Fusarium graminearum, a causal agent of Fusarium Head Blight (FHB) that uniquely contains chromosomal regions enriched for house-keeping or infection-related genes. In this study, we identified the ortholog of the human inhibitor of growth (ING1) gene in F. graminearum (FNG1) and found that it specifically interacts with the FgEsa1 HAT of the NuA4 complex. Deletion of FNG1 led to severe growth defects and blocked conidiation, sexual reproduction, DON production, and plant infection. The fng1 mutant was normal in H3 acetylation but significantly reduced in H4 acetylation. A total of 34 spontaneous suppressors of fng1 with faster growth rate were isolated. Most of them were still defective in sexual reproduction and plant infection. Thirty two of them had mutations in orthologs of yeast RPD3, SIN3, and SDS3, three key components of the yeast Rpd3L HDAC complex. Four mutations in these three genes were verified to suppress the defects of fng1 mutant in growth and H4 acetylation. The rest two suppressor strains had a frameshift or nonsense mutation in a glutamine-rich hypothetical protein that may be a novel component of the FgRpd3 HDAC complex in filamentous fungi. FgRpd3, like Fng1, localized in euchromatin. Deletion of FgRPD3 resulted in severe growth defects and elevated H4 acetylation. In contract, the Fgsds3 deletion mutant had only a minor reduction in growth rate but FgSIN3 appeared to be an essential gene. RNA-seq analysis revealed that 48.1% and 54.2% of the genes with altered expression levels in the fng1 mutant were recovered to normal expression levels in two suppressor strains with mutations in FgRPD3 and FgSDS3, respectively. Taken together, our data showed that Fng1 is important for H4 acetylation as a component of the NuA4 complex and functionally related to the FgRpd3 HDAC complex for transcriptional regulation of genes important for growth, conidiation, sexual reproduction, and plant infection in F. graminearum.

Exosomes from bone marrow mesenchymal stem cells decrease chemosensitivity of acute myeloid leukemia cells via delivering miR-10a.

Bone marrow mesenchymal stem cells (BMSCs) are an integral part of the acute myeloid leukemia (AML) bone marrow microenvironment and contribute to AML progression. In this study, we explored the communication between BMSCs and AML cells via exosomes. The AML cells co-cultured with BMSCs-Exos were found to have lower chemosensitivity exposed to cytarabine, suggesting that BMSCs-Exos could protect AML cells from cytarabine. Interestingly, miR-10a was elevated in BMSCs-Exos derived from AML (AML-BMSCs-Exos) compared with that from healthy donor. The expression levels of miR-10a in AML cells was significantly up-regulated after co-culture with BMSCs-Exos. Furthermore, the up-regulated miR-10a was an crucial factor contributing to the chemoresistance of leukemia cells. Down-regulation of miR-10a substantially increase chemosensitivity of AML cells treated with BMSCs-Exos. Chemosensitivity of AML cells was also decreased through down-regulating RPRD1A by miR-10a that ultimately lead to the stimulation of the Wnt/ß-catenin signaling pathway. Collectively, our findings demonstrated that AML-BMSCs could deliver miR-10a to AML cells via exosomes, which could target RPRD1A and activate Wnt/ß-catenin signaling pathway that subsequently decreased chemosensitivity of AML cells.

Clinical assessment of cardiac impairment favored by two-dimensional speckle tracking echocardiology in patients with systemic sclerosis.

BACKGROUND: Cardiac involvement is a major cause of death in SSc, while early detection remains a challenge. OBJECTIVES: The purpose of this study was to investigate the prevalence and clinical implications of cardiac impairment in SSc. METHODS: Ninety-five consecutive SSc patients [55.6 (13.8) years old, 5.3 (8.1) years from diagnosis] were included in the study. Patients with heart diseases onset prior to SSc were excluded. All patients underwent two-dimensional speckle-tracking echocardiology (2D-STE) with measuring left and right ventricular global longitudinal strain (GLS/RGLS). Clinical manifestation, laboratory evaluation (CRP, cTnI, antibodies, etc.) and ECG were collected at the same time. Comparisons between the SSc subgroups (lcSSc and dcSSc) were performed using Student's t-test, Mann-Whitney U or Fisher's exact test. Binary logistic regression was applied to determine the independent effects of variables in cardiac impairment. RESULTS: Early left and right ventricular impairment measured by GLS and RGLS were detected in 22.1% and 24.2% of the SSc patients, respectively. In comparison, only 2.1% showed reduced left ventricular ejection fraction (LVEF). Impaired GLS was mainly observed in the basal and medial segments of anterior, lateral and posterior left ventricle walls, and more profound in dcSSc. Elevated CRP (OR 3.561 95% CI: 1.071, 11.839, P <0.05) was associated with reduced GLS/RGLS. The adoption of GLS/RGLS enhanced the efficacy of routine screening for cardiac impairment that 52.6% of patients showed potential cardiac impairment. CONCLUSIONS: Cardiac impairment is a common manifestation in SSc. Increasing awareness of early cardiac impairment is warranted with elevated CRP and dcSSc.

Triglyceride glucose index exacerbates the risk of future cardiovascular disease due to diabetes: evidence from the China Health and Retirement Longitudinal Survey (CHARLS).

OBJECTIVE: We aimed to investigate the effect of the triglyceride glucose (TyG) index on the association between diabetes and cardiovascular disease (CVD). METHODS: Data from 6,114 individuals were extracted and analyzed from the China Health and Retirement Longitudinal Survey (CHARLS) from 2011 to 2018. Logistic regression analyses were conducted to assess the relationship between diabetes and CVD across the various TyG index groups. The statistical method of subgroup analysis was used to determine the correlation between diabetes and CVD for each TyG index group by sex, history of hypertension and dyslipidemia, smoking, and drinking. RESULTS: Diabetes was positively associated with CVD risk after adjustment in 2011(odds ratio (OR) 1.475, 95% CI 1.243-1.752, P < 0.001). There was a gradient increase in the OR for new-onset CVD in 2018 due to diabetes at baseline across the value of the TyG index based on a fully adjusted model (P for trend < 0.05). The ORs of diabetes at baseline for CVD in 2018 were 1.657 (95% CI 0.928-2.983, P = 0.098), 1.834(95% CI 1.064-3.188, P = 0.037) and 2.234(95% CI 1.349-3.673, P = 0.006) for T1, T2 and T3 of the TyG index respectively. The gradient of increasing risk of CVD still existed among those with hypertension and nondrinkers in the subgroup analysis. CONCLUSION: Elevated TyG index strengthens the correlation between diabetes mellitus and CVD in middle-aged and elderly Chinese adults.

Vascular benefits of vitamin C supplementation against fine particulate air pollution in healthy adults: A double-blind randomised crossover trial.

Evidence on the health benefits of vitamin C supplementation in highly polluted areas has not been evaluated. We aimed to evaluate whether dietary vitamin C supplementation can improve vascular health linked to particulate matter (PM) exposure. A randomised double-blind crossover trial involving 58 health young adults was performed in Shijiazhuang, China in 2018. All subjects were randomly assigned to the vitamin C supplementation group (2000 mg/d) or placebo group for a week alternating with a 2 week washout period. Fifteen circulating biomarkers were measured. Linear mixed-effect model was applied to evaluate the effect of vitamin C supplementation on health outcomes. The average concentrations of PM2.5 and PM10 were 164.91 and 327.05 µg/m3, respectively. Vitamin C supplementation was significantly associated with a 19.47% decrease in interleukin-6 (IL-6), 17.30% decrease in tumour necrosis factor-a (TNF-α), 34.01% decrease in C-reactive protein (CRP), 3.37% decrease in systolic blood pressure (SBP) and 6.03% decrease in pulse pressure (PP). Furthermore, glutathione peroxidase (GSH-Px) was significantly increased by 7.15%. Sex-subgroup analysis showed that vitamin C significantly reduced TNF-α by 27.85% in male participants and significantly increased APOB by 6.28% and GSH-Px by 14.47% only in female participants. This study indicated that vitamin C supplementation may protect vascular vessels against PM exposure among healthy young adults in China.

Effect of proanthocyanidins on blood pressure: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hypertension is a common chronic disease that can lead to serious health problems. Previous studies have not drawn a consistent conclusion about the effect of proanthocyanidins (PCs) on blood pressure (BP). This systematic review and meta-analysis aims to evaluate the effect of PCs supplementation on blood pressure (BP). METHODS: A comprehensive literature search was performed in 6 databases (Pubmed, Scopus, ISI Web of Science, the Cochrane Library, Embase and Google Scholar) to identify the randomized controlled trials (RCTs) that evaluated the BP-lowering effect of PCs. Subgroup and sensitivity analyses were conducted to evaluate the potential heterogeneity. Meta-regression analysis was used to evaluate dose effects of PCs on BP. RESULTS: A total of 6 studies comprising 376 subjects were included in our meta-analysis to estimate the pooled effect size. This meta-analysis suggested that PCs supplementation could significantly reduce systolic blood pressure (SBP) (WMD: -4.598 mmHg; 95 % CI: -8.037, -1.159; I2 = 33.7 %; p = 0.009), diastolic blood pressure (DBP) (WMD: -2.750 mmHg; 95 % CI: -5.087, -0.412; I2 = 0.0 %; p = 0.021) and mean arterial pressure (MAP) (WMD: -3.366 mmHg; 95 % CI: -6.719, -0.041 mmHg; I2 = 0.0 %; p = 0.049), but had no significant effect on pulse pressure (PP) (WMD: -2.131 mmHg; 95 % CI: -6.292, 2.030; I2 = 0.0 %; p = 0.315). When the studies were stratified according to the duration of the study, there was a significant reduction on SBP in the subset of the trials with <12 weeks of duration. On the contrary, there was a significant reduction on DBP in the subset of the trials with ≥12 weeks of duration. The Subgroup analysis by BMI indicated that a significant reduction on SBP for people with a higher BMI (BMI ≥ 25) and a significant reduction on DBP for people with a lower BMI (BMI < 25). Additional subgroup analysis revealed low-dose-PCs (<245 mg/day) could significantly reduce SBP, DBP and MAP. The meta-regression analyses did not indicate the dose effects of PCs on SBP, DBP, PP and MAP. CONCLUSION: Based on the current findings, PCs supplementation may be a useful treatment of hypertensive patients as well as a preventive measure in the prehypertensive and healthy subjects. However, further investigation is needed to confirm these results.

Effect of dietary sodium restriction on blood pressure in type 2 diabetes: A meta-analysis of randomized controlled trials.

AIMS: Although current guidelines recommend reduction of salt intake in patients with diabetes, the benefits of reducing salt intake in people with type 2 diabetes mellitus (T2DM) lack clear evidence. Therefore, we performed a meta-analysis of available randomized controlled trials (RCTs) of sodium restriction and blood pressure (BP) in patients with T2DM. DATA SYNTHESIS: We performed a systematic search of the online databases that evaluated the effect of dietary sodium restriction on BP in patients with T2DM. Sodium intake was expressed by 24 h urinary sodium excretion (UNaV). Q statistics and I2 were used to explore between-study heterogeneity. A random-effects model was used in the presence of significant heterogeneity; otherwise, a fixed-effects model was applied. Eight RCTs with 10 trials (7 cross-over and 3 parallel designs) were included in the meta-analysis. Compared with ordinary sodium intake, dietary sodium restriction significantly decreased UNaV (weighted mean difference, WMD: -38.430 mmol/24 h; 95% CI: -41.665 mmol/24 h to -35.194 mmol/24 h). Sodium restriction significantly lowered systolic BP (WMD: -5.574 mm Hg; 95% CI: -8.314 to -2.834 mm Hg; I2 = 0.0%) and diastolic BP (WMD: -1.675 mm Hg; 95% CI: -3.199 to -0.150 mm Hg; I2 = 0.0%) with low heterogeneity among the studies. No publication bias was found from Begg's and Egger's tests. CONCLUSIONS: Sodium restriction significantly reduces SBP and DBP in patients with T2DM.

Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4(TopBP1).

The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint.

Impact of Prior Ischemic Stroke on Outcomes in Patients With Heart Failure　- A Propensity-Matched Study.

BACKGROUND: Whether ischemic stroke per se, rather than older age or additional comorbidities, accounts for the adverse prognosis of heart failure (HF) is uncertain. The present study examineed the intrinsic association of ischemic stroke with outcomes in a propensity-matched cohort.Methods and Results:Of 1,351 patients hospitalized with HF, 388 (28.7%) had prior ischemic stroke. Using propensity score for prior ischemic stroke, estimated for each patient, a matched cohort of 379 pairs of HF patients with and without prior ischemic stroke, balanced on 32 baseline characteristics was assembled. At 30 days, prior ischemic stroke was associated with significantly higher risks of the combined endpoint of all-cause death or readmission (hazard ratio [HR]: 1.91; 95% confidence interval [CI]: 1.38 to 2.65; P<0.001), all-cause death (HR: 2.08; 95% CI: 1.28 to 3.38; P=0.003), all-cause readmission (HR: 2.67; 95% CI: 1.78 to 4.01; P<0.001), and HF readmission (HR: 2.11; 95% CI: 1.19 to 3.72; P=0.010). Prior ischemic stroke was associated with a significantly higher risk of all 4 outcomes at both 6 months and 1 year. CONCLUSIONS: Prior ischemic stroke was a potent and persistent risk predictor of death and readmission among patients with HF after accounting for clinical characteristics.