Bacillus thuringiensis strain M019, non-pathogenic to lepidopteran and dipteran insects, produces a parasporal inclusion that consists of three 84-kDa Cry proteins (CPs). CP78A and CP78B, which exhibit 83.5% amino acid identity, were new variants of the previously reported HeLa cell-killing protein (parasporin-1). CP84 was a novel CP showing low-level homology, of 21.9% (56.4% similarity), with the insecticidal Cry2 toxin. In vitro solubilization with dithiothreitol at pH 10.2 and limited hydrolysis with trypsin resulted in the removal of N-terminal portions of the CPs and their activation. The 70-kDa proteins (15- and 55-kDa fragments) from CP78A and CP78B and the 73-kDa protein (14- and 59-kDa fragments) from CP84 exhibited varying degrees of cytocidal activity preferentially toward human hepatocyte cancer HepG2 cells and uterus cervix cancer HeLa cells causing cell swelling or the formation of vacuoles in the cytoplasm. These toxins appeared to attack an identical target on human cells.

BACKGROUND Atrial fibrillation (AF) has a genetic basis, and environmental factors can modify its actual pathogenesis.OBJECTIVE The purpose of this study was to construct a combined risk assessment method including both genetic and clinical factors in the Japanese population.METHODS We screened a cohort of 540 AF patients and 520 non-AF controls for single nucleotide polymorphisms (SNPs) previously associated with AF by genome-wide association studies. The most strongly associated SNPs after propensity score analysis were then used to calculate a weighted genetic risk score (WGRS). We also enrolled 1018 non-AF Japanese subjects as a validation cohort and monitored AF emergence over several years. Finally, we constructed a logistic model for AF prediction combining WGRS and clinical risk factors. RESULTSWe identified 5 SNPs (in PRRX1, ZFHX3, PITX2, HAND2, and NEURL1) associated with AF after Bonferroni correction. There was a 4.92-fold difference in AF risk between the highest and lowest WGRS calculated using these 5 SNPs (P 5 2.32 ! 10 210 ). Receiver operating characteristic analysis of WGRS yielded an area under the curve (AUC) of 0.73 for the screening cohort and 0.72 for the validation cohort. The predictive logistic model constructed using a combination of WGRS and AF clinical risk factors (age, body mass index, sex, and hypertension) demonstrated better discrimination of AF than WGRS alone (AUC 5 0.84; sensitivity 75.4%; specificity 80.2%).CONCLUSION This novel predictive model of combined AF-associated SNPs and known clinical risk factors can accurately stratify AF risk in the Japanese population.

Background Atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA) still remains a serious issue. Ca 2+ handling has a considerable effect on AF recurrence. The histidine-rich calcium-binding protein ( HRC ) genetic single nucleotide polymorphism (SNP), rs3745297 (T>G, Ser96Ala), is known to cause a sarcoplasmic reticulum Ca 2+ leak. We investigated the association between HRC Ser96Ala and AF recurrence after RFCA in paroxysmal AF (PAF) patients. Methods and results We enrolled PAF patients who underwent RFCA ( N = 334 for screening and N = 245 for replication) and were genotyped for HRC SNP (rs3745297). The patient age was younger and rate of diabetes and hypertension lower in the PAF patients with Ser96Ala than in those without (TT/TG/GG, 179/120/35; 64±10/60±12/59±13 y, P = 0.001; 18.5/ 9.2/8.6%, P = 0.04 and 66.1/50.0/37.1%, P = 0.001, respectively). During a mean 19 month follow-up, 57 (17.1%) patients suffered from AF recurrences. The rate of an Ser96Ala was significantly higher in patients with AF recurrence than in those without in the screening set (allele frequency model: odds ratio [OR], 1.80; P = 0.006). We also confirmed this significant association in the replication set (OR 1.74; P = 0.03) and combination ( P = 0.0008). A multivariate analysis revealed that the AF duration, sinus node dysfunction, and HRC Ser96Ala were independent predictors of an AF recurrence (hazard ratio [HR], 1.04, P = 0.037; HR 2.42, P = 0.018; and HR 2.66, P = 0.007, respectively). Conclusion HRC SNP Ser96Ala is important as a new genetic marker of AF recurrence after RFCA.

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Background Urinary liver-type fatty acid-binding protein (L-FABP) has been known as a potential biomarker for acute kidney injury. It has also been suggested to have an effective predictive value for cardiovascular mortality in patients with diabetes or critically ill condition. Therefore, this study aimed to examine the ability of urinary L-FABP in predicting mid-term cardiovascular morbidity and mortality in patients with hypertension. Methods Urinary L-FABP levels in stable outpatients without diabetes who were treated with antihypertensive drugs were measured, and a 5-year follow-up was planned. The primary end-point was a combination of acute heart failure requiring hospitalization, myocardial infarction, stroke, and cardiovascular death. The secondary end-point was kidney disease progression defined as a relative decline in the estimated glomerular filtration rate of ≥30% from the baseline. Results A total of 197 patients were recruited. Primary and secondary end-points occurred in 24 (12.2%) and 42 (21.3%) patients, respectively, during a median follow-up of 5.7 years. Patients with urinary L-FABP levels higher than the upper limit (8.4 µg/g creatinine) were more likely to reach the primary (30.43% vs. 9.77%; P = 0.003) and secondary end-points (56.52% vs. 16.67%; P < 0.001) than those with urinary L-FABP levels within the normal limits. Urinary L-FABP level was independently associated with both primary (hazard ratio (HR) 1.21; P = 0.03) and secondary end-points (HR 1.19; P = 0.02). Conclusions This study demonstrated that increased urinary L-FABP levels may predict adverse cardiovascular events and renal dysfunction progression even among stable nondiabetic patients with hypertension.