First Measurement of the B

We study B^{+}→π^{+}π^{0}π^{0} using 711 fb^{-1} of data collected at the ϒ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We measure an inclusive branching fraction of (19.0±1.5±1.4)×10^{-6} and an inclusive CP asymmetry of (9.2±6.8±0.7)%, where the first uncertainties are statistical and the second are systematic, and a B^{+}→ρ(770)^{+}π^{0} branching fraction of (11.2±1.1±0.9_{-1.6}^{+0.8})×10^{-6}, where the third uncertainty is due to possible interference with B^{+}→ρ(1450)^{+}π^{0}. We present the first observation of a structure around 1 GeV/c^{2} in the π^{0}π^{0} mass spectrum, with a significance of 6.4σ, and measure a branching fraction to be (6.9±0.9±0.6)×10^{-6}. We also report a measurement of local CP asymmetry in this structure.

RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis.

Polycomb repressive complex 1 (PRC1) modifies chromatin through catalysis of histone H2A lysine 119 monoubiquitination (H2AK119ub1). RING1 and RNF2 interchangeably serve as the catalytic subunit within PRC1. Pathogenic missense variants in PRC1 core components reveal functions of these proteins that are obscured in knockout models. While Ring1a knockout models remain healthy, the microcephaly and neuropsychiatric phenotypes associated with a pathogenic RING1 missense variant implicate unappreciated functions. Using an in vitro model of neurodevelopment, we observe that RING1 contributes to the broad placement of H2AK119ub1, and that its targets overlap with those of RNF2. PRC1 complexes harboring hypomorphic RING1 bind target loci but do not catalyze H2AK119ub1, reducing H2AK119ub1 by preventing catalytically active complexes from accessing the locus. This results in delayed DNA damage repair and cell cycle progression in neural progenitor cells (NPCs). Conversely, reduced H2AK119ub1 due to hypomorphic RING1 does not generate differential expression that impacts NPC differentiation. In contrast, hypomorphic RNF2 generates a greater reduction in H2AK119ub1 that results in both delayed DNA repair and widespread transcriptional changes. These findings suggest that the DNA damage response is more sensitive to H2AK119ub1 dosage change than is regulation of gene expression.

Dermatomyositis is associated with an increased risk of cardiovascular and cerebrovascular events: a Taiwanese population-based longitudinal follow-up study.

BACKGROUND: While the chronic inflammation related to autoimmune diseases is known to be associated with an increased cardiovascular risk, much less is known about cerebrovascular risks. OBJECTIVES: The present population-based, age- and sex-matched follow-up study was undertaken to investigate the risks of acute myocardial infarction (AMI) and ischaemic stroke in patients with dermatomyositis (DMS). METHODS: In total 907 patients with DMS were enrolled and compared with a non-DMS control group consisting of 4535 age- and sex-matched, randomly sampled subjects without DMS. The AMI-free and ischaemic stroke-free survival curves were generated using the Kaplan-Meier method. Cox proportional hazard regression was used to estimate the DMS-associated risks of AMI and ischaemic stroke. RESULTS: During the 2-year follow-up period, 14 patients with DMS (1.5%) and 18 patients in the non-DMS control group (0.4%) suffered AMIs. The crude hazard ratio (HR) for suffering an AMI in patients with DMS compared with subjects in the non-DMS group was 3.96 [95% confidence interval (CI) 1.97-7.96, P = 0.0001], while the adjusted HR was 3.37 (95% CI 1.67-6.80, P = 0.0007), after taking into account demographic characteristics and cardiovascular comorbidities. During the same follow-up period, 46 patients (5.1%) and 133 subjects in the control group (2.9%) developed ischaemic strokes. The crude HR for developing an ischaemic stroke in patients with DMS compared with subjects in the non-DMS group was 1.78 (95% CI 1.27-2.49, P = 0.0007), and the adjusted HR was 1.67 (95% CI, 1.19-2.34, P = 0.0028). CONCLUSIONS: These findings suggest that DMS is associated with an increased risk of cardiovascular and cerebrovascular events.

Anti-tumor effect of endostatin in a sleep-apnea mouse model with tumor.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cancer incidence and mortality. The underlying mechanism is unclear. This study aims to evaluate the influence of intermittent hypoxia (IH), a novel hallmark of OSA, on tumor and to access the anti-tumor effect of endostatin on a mouse model with OSA. METHODS: The C57BL/6 J mice were randomly classified into four groups: control (normoxia) (CTL), control plus endostatin (CTL + ED), IH, and IH plus endostatin (IH + ED). Mice in IH and IH + ED groups were subjected to IH 8 h per day in 5 weeks. Lewis lung cancer cells were injected into the flank of each mouse after 1 week of IH exposure. Endostatin was also intraperitoneally injected after tumor volume reached about 200 mm3. The maximum standard uptake values (SUVmax) were detected by micro-positron emission tomography-computed tomography (micro-PET-CT) imaging prior and post-endostatin administration. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were determined for evaluating the anti-tumor effect of endostatin among the normoxia and IH conditions. RESULTS: Mice had higher SUVmax in the IH group than the CTL group (p < 0.01). When compared with mice in the CTL group, those in the IH group had significantly greater MVD values (p < 0.001). The SUVmax can be attenuated by endostatin both in the CTL (p < 0.01) and IH conditions (p < 0.001). When compared with CTL group, mice in the IH group had increased MVD values (p < 0.001) and VEGF expression both at mRNA (p < 0.05) and protein levels (p < 0.001 in western blotting results). Treatment with endostatin attenuated serum and tissue VEGF levels, lowering the MVD values. As compared to normoxia condition, the endostatin-therapeutic effects were more significant under the IH condition (p < 0.05 in western blotting results). CONCLUSIONS: Micro-PET-CT imaging is a promising non-invasive technique to evaluate the tumor metabolic characteristics under IH condition in vivo. The anti-tumor effect of endostatin under IH condition is superior to that of the normoxia condition.

Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy.

OBJECTIVE: To assess the complications in a group of patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. The extraordinarily high incidence of postoperative compensatory hyperhidrosis in our series is stressed and explained. METHODS: The retrospective study included chart reviews and outpatient assessments. Seventy-two patients underwent T2 or T2-T3 endoscopic sympathectomy for primary palmar hyperhidrosis. Patients' hyperhidrosis severity, precipitating factors, postoperative complications, surgical results, and satisfaction were assessed. Severity of palmar hyperhidrosis and compensatory hyperhidrosis was classified by two grading scales. RESULTS: The success rate of sympathectomy was 93%. All patients except one suffered from compensatory sweating, which was the main cause of patients' dissatisfaction postoperatively. Seventeen percent of the patients (12 of 72 patients) experienced new symptoms of gustatory sweating (facial sweating associated with eating). Twenty-one patients experienced other complications, including pneumothorax, Horner's syndrome, nasal obstruction, and intercostal neuralgia. CONCLUSION: Transthoracic endoscopic sympathectomy is an effective and simple modality to treat palmar hyperhidrosis. However, all patients need to be warned of the common complications, particularly compensatory hyperhidrosis, before surgery.

Synthesis and characterization of Pt nanoparticles with different morphologies in mesoporous silica SBA-15 for methanol oxidation reaction.

Mesoporous SBA-15 silica materials functionalized with and without carboxylic acid groups were used to effectively control the morphology of Pt crystals, and the materials thus obtained were applied to methanol oxidation reactions. The Pt particles aggregated to form long spheroids inside the channels in pure SBA-15. When carboxylic acid groups were utilized, the SBA-15(-COOH) material facilitated the formation of higher Pt surface area, smaller Pt nanoparticles and nearly spherical shape due to the strong interaction between Pt(4+) ions and carboxylic acid on SBA-15. The Pt(4+) ions on the SBA-15(-COOH) material can be directly transformed to reduced Pt particles during calcination. The methanol oxidation activity on a Pt surface is strongly dependent on the shape of Pt particles. The near-spherical Pt nanoparticles on the SBA-15(-COOH) exhibited higher catalytic activity during methanol oxidation than Pt catalysts on unmodified SBA-15. The near-spherical Pt particles on the SBA-15(-COOH) contained large numbers of terrace sites on their surfaces, which led to high efficiency during methanol oxidation.

Visualization of repair of double-strand breaks in the bacteriophage T7 genome without normal DNA replication.

An in vitro system based on extracts of Escherichia coli infected with bacteriophage T7 is able to repair double-strand breaks in a T7 genome with efficiencies of 20% or more. To achieve this high repair efficiency it is necessary that the reaction mixtures contain molecules of donor DNA that bracket the double-strand break. Gaps as long as 1,600 nucleotides are repaired almost as efficiently as simple double-strand breaks. DNA synthesis was measured while repair was taking place. It was found that the amount of DNA synthesis associated with repair of a double-strand break was below the level of detection possible with this system. Furthermore, repair efficiencies were the same with or without normal levels of T7 DNA polymerase. However, the repair required the 5'-->3' exonuclease encoded by T7 gene 6. The high efficiency of DNA repair allowed visualization of the repaired product after in vitro repair, thereby assuring that the repair took place in vitro rather than during an in vivo growth step after packaging.

In vitro repair of gaps in bacteriophage T7 DNA.

An in vitro system based upon extracts of Escherichia coli infected with bacteriophage T7 was used to study the mechanism of double-strand break repair. Double-strand breaks were placed in T7 genomes by cutting with a restriction endonuclease which recognizes a unique site in the T7 genome. These molecules were allowed to repair under conditions where the double-strand break could be healed by (i) direct joining of the two partial genomes resulting from the break, (ii) annealing of complementary versions of 17-bp sequences repeated on either side of the break, or (iii) recombination with intact T7 DNA molecules. The data show that while direct joining and single-strand annealing contributed to repair of double-strand breaks, these mechanisms made only minor contributions. The efficiency of repair was greatly enhanced when DNA molecules that bridge the region of the double-strand break (referred to as donor DNA) were provided in the reaction mixtures. Moreover, in the presence of the donor DNA most of the repaired molecules acquired genetic markers from the donor DNA, implying that recombination between the DNA molecules was instrumental in repairing the break. Double-strand break repair in this system is highly efficient, with more than 50% of the broken molecules being repaired within 30 min under some experimental conditions. Gaps of 1,600 nucleotides were repaired nearly as well as simple double-strand breaks. Perfect homology between the DNA sequence near the break site and the donor DNA resulted in minor (twofold) improvement in the efficiency of repair. However, double-strand break repair was still highly efficient when there were inhomogeneities between the ends created by the double-strand break and the T7 genome or between the ends of the donor DNA molecules and the genome. The distance between the double-strand break and the ends of the donor DNA molecule was critical to the repair efficiency. The data argue that ends of DNA molecules formed by double-strand breaks are typically digested by between 150 and 500 nucleotides to form a gap that is subsequently repaired by recombination with other DNA molecules present in the same reaction mixture or infected cell.

Repair of double-strand breaks by incorporation of a molecule of homologous DNA.

An in vitro system based upon extracts of Escherichia coli infected with bacteriophage T7 was used to monitor repair of double-strand breaks in the T7 genome. The efficiency of double-strand break repair was markedly increased by DNA molecules ('donor' DNA) consisting of a 2.1 kb DNA fragment, generated by PCR, that had ends extending approximately 1 kb on either side of the break site. Repair proceeded with greater than 10% efficiency even when T7 DNA replication was inhibited. When the donor DNA molecules were labelled with 32P, repaired genomes incorporated label only near the site of the double-strand break. When repair was carried out with unlabelled donor DNA and [32P]-dCTP provided as precursor for DNA synthesis the small amount of incorporated label was distributed randomly throughout the entire T7 genome. Repair was performed using donor DNA that had adjacent BamHI and PstI sites. When the BamHI site was methylated and the PstI site was left unmethylated, the repaired genomes were sensitive to PstI but not to BamHI endonuclease, showing that the methyl groups at the BamHI recognition site had not been replaced by new DNA synthesis during repair of the double-strand break. These observations are most consistent with a model for double-strand break repair in which the break is widened to a small gap, which is subsequently repaired by physical incorporation of a patch of donor DNA into the gap.

Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation.

Epithelial-mesenchymal transformation in the atrioventricular (AV) cushion of the tubular heart is a critical step in the formation of the valves and membranous septa. Transforming growth factor beta (TGFbeta) ligands are a primary signal of this transformation. To investigate the expression and function of specific Type I TGFbeta receptors during AV cushion transformation, we cloned and characterized the chicken homologues of two mammalian activin receptor-like kinases (ALK), ALK2 and ALK5, and generated specific, polyclonal antibodies against the extracellular binding domains of each. Both the chicken ALK2 (ChALK2) and the chicken ALK5 (ChALK5) cDNAs encode proteins that bind TGFbeta1 in the presence of the Type II TGFbeta receptor. However, as expected, only ChALK5 stimulated the TGFbeta-responsive PAI-1 promoter. These data establish that ChALK2 and ChALK5 are the chicken homologues of the mammalian receptors ALK2 and ALK5. Both ChALK2 and ChALK5 are expressed by AV endocardial cells. AV cushion explants harvested from stage 13-18 embryos were incubated with antisera to ChALK2 or ChALK5. Anti-ChALK2 antisera inhibited mesenchyme formation by 34-50% while neutralizing anti-ChALK5 antisera were without effect. These data demonstrate that ChALK2 can mediate transformation in the AV cushion.