Summary To investigate the regulatory mechanisms of angiogenesis in the development of myelodysplastic syndromes (MDS) and its progression to overt leukaemia (OL), bone marrow samples from control, paired samples from MDS patients before and after transformation to OL (MDS → OL) and de novo acute myeloid leukaemia (AML) were analysed. Immunohistochemical staining showed a significant increase of bone marrow microvascular density (MVD) in MDS and de novo AML compared with controls. Surprisingly, in MDS, MVD significantly decreased upon transformation to OL, which was also significantly lower than the MVD of de novo AML. This evidence was strengthened by the pattern of angiogenic mediator gene expression, confirming the importance of various angiogenic mediators including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumour necrosis factor α (TNFα), hepatocyte growth factor (HGF) and the angiopoietin family of mediators (Ang‐1 and Ang‐2) as well as the receptors for angiogenic mediators, such as VEGF receptor 2 (VEGFR2) and the tyrosine kinase receptor, TIE2. By contrast, the anti‐angiogenic mediator, transforming growth factor‐β (TGFβ) exhibited significantly higher expression in the bone marrow of MDS → OL, indicating the importance of this cytokine as the suppressive factor of angiogenesis in MDS. These findings indicate that the bone marrow microenvironment in MDS → OL and de novo AML differs remarkably, suggesting the different efficacy of anti‐angiogenic therapy between de novo AML and leukaemia secondary to MDS.

In enzymatic saccharification of lignocellulosics, the access of the enzymes to exposed cellulose surfaces is a key initial step in triggering hydrolysis. However, knowledge of the structure-hydrolyzability relationship of the pretreated biomass is still limited. Here we used fluorescent-labeled recombinant carbohydrate-binding modules (CBMs) from Clostridium josui as specific markers for crystalline cellulose (CjCBM3) and non-crystalline cellulose (CjCBM28) to analyze the complex surfaces of wood tissues pretreated with NaOH, NaOH-Na(2)S (kraft pulping), hydrothermolysis, ball-milling, and organosolvolysis. Japanese cedar wood, one of the most recalcitrant softwood species was selected for the analysis. The binding analysis clarified the linear dependency of the exposure of crystalline and non-crystalline cellulose surfaces for enzymatic saccharification yield by the organosolv and kraft delignification processes. Ball-milling for 5-30 min increased saccharification yield up to 77%, but adsorption by the CjCBM-cyan fluorescent proteins (CFPs) was below 5%. Adsorption of CjCBM-CFPs on the hydrothermolysis pulp were less than half of those for organosolvolysis pulp, in coincidence with low saccharification yields. For all the pretreated wood, crystallinity index was not directly correlated with the overall saccharification yield. Fluorescent microscopy revealed that CjCBM3-CFP and CjCBM28-CFP were site-specifically adsorbed on external fibrous structures and ruptured or distorted fiber surfaces. The assay system with CBM-CFPs is a powerful measure to estimate the initiation sites of hydrolysis and saccharification yields from chemically delignified wood pulps.

The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.OBJECTIVE To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial. DESIGN, SETTING, AND PARTICIPANTSAnalysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.INTERVENTION Vericiguat titrated to 10 mg daily vs placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH. RESULTS Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.

Mesoporous silica has been used as a heterogeneous support for catalysts; however, asymmetric induction by the helicity of inorganic mesoporous silica itself has not yet been achieved. P- and M-helical mesoporous silica was found to act as a chiral inorganic trigger for asymmetric autocatalysis to afford (S) and (R)-pyrimidyl alkanol with >99.5% ee, respectively.

Clinical practice recommendations for allied disorders of Hirschprung's disease are given for each CQ, along with an assessment of the current evidence. We hope that the information will be helpful in daily practice and future studies.

Sevoflurane anesthesia attenuates glucose-induced insulin secretion without affecting basic insulin secretion, while propofol anesthesia enhances insulin secretion. Propofol anesthesia exaggerates insulin-resistive conditions, whereas sevoflurane anesthesia dose not impair insulin sensitivity; there may be a possible association of TNF-α with insulin-resistive conditions under propofol anesthesia.

We demonstrated the cumulative incidence rate of secondary neoplasms following retinoblastoma in Japan. The subdistribution hazards ratios of hereditary retinoblastoma and external beam irradiation were high but not significant because of statistical power. The long-term follow-up of retinoblastoma survivors is warranted to understand secondary neoplasm risk.

e We cloned two glycoside hydrolase family 74 genes, the sav_1856 gene and the sav_2574 gene, from Streptomyces avermitilis NBRC14893 and characterized the resultant recombinant proteins. The sav_1856 gene product (SaGH74A) consisted of a catalytic domain and a family 2 carbohydrate-binding module at the C terminus, while the sav_2574 gene product (SaGH74B) consisted of only a catalytic domain. SaGH74A and SaGH74B were expressed successfully and had molecular masses of 92 and 78 kDa, respectively. Both recombinant proteins were xyloglucanases. SaGH74A had optimal activity at 60°C and pH 5.5, while SaGH74B had optimal activity at 55°C and pH 6.0. SaGH74A was stable over a broad pH range (pH 4.5 to 9.0), whereas SaGH74B was stable over a relatively narrow pH range (pH 6.0 to 6.5). Analysis of the hydrolysis products of tamarind xyloglucan and xyloglucan-derived oligosaccharides indicated that SaGH74A was endo-processive, while SaGH74B was a typical endo-enzyme. The C terminus of SaGH74A, which was annotated as a carbohydrate-binding module, bound to ␤-1,4-linked glucan-containing soluble polysaccharides such as hydroxyethyl cellulose, barley glucan, and xyloglucan.