Multiple genetic variants influence the risk for development of primary biliary cirrhosis (PBC). To explore the cumulative effects of known susceptibility loci on risk, we utilized a weighted genetic risk score (wGRS) to evaluate whether genetic information can predict susceptibility. The wGRS was created using 26 known susceptibility loci and investigated in 1840 UK PBC and 5164 controls. Our data indicate that the wGRS was significantly different between PBC and controls (P=1.61E-142). Moreover, we assessed predictive performance of wGRS on disease status by calculating the area under the receiver operator characteristic curve. The area under curve for the purely genetic model was 0.72 and for gender plus genetic model was 0.82, with confidence limits substantially above random predictions. The risk of PBC using logistic regression was estimated after dividing individuals into quartiles. Individuals in the highest disclosed risk group demonstrated a substantially increased risk for PBC compared with the lowest risk group (odds ratio: 9.3, P=1.91E-084). Finally, we validated our findings in an analysis of an Italian PBC cohort. Our data suggested that the wGRS, utilizing genetic variants, was significantly associated with increased risk for PBC with consistent discriminant ability. Our study is a first step toward risk prediction for PBC.

Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR(+) ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR(+) B-ALL.

Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR(+) ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR(+) B-ALL.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

We have searched for proton decay via p→e+π0 and p→μ+π0 modes with the enlarged fiducial volume data of Super-Kamiokande from April 1996 to May 2018, which corresponds to 450 kton·years exposure. We have accumulated about 25% more livetime and enlarged the fiducial volume of the Super-Kamiokande detector from 22.5 kton to 27.2 kton for this analysis, so that 144 kton·years of data, including 78 kton·years of additional fiducial volume data, has been newly analyzed. No candidates have been found for p→e+π0 and one candidate remains for p→μ+π0 in the conventional 22.5 kton fiducial volume and it is consistent with the atmospheric neutrino background prediction. We set lower limits on the partial lifetime for each of these modes: τ/B(p→e+π0)>2.4×1034 years and τ/B(p→μ+π0)>1.6×1034 years at 90% confidence level.

As a baryon number violating process with ΔB=2, neutron-antineutron oscillation (n→n¯) provides a unique test of baryon number conservation. We have performed a search for n→n¯ oscillation with bound neutrons in Super-Kamiokande, with the full dataset from its first four run periods, representing an exposure of 0.37 Mton-years. The search used a multivariate analysis trained on simulated n→n¯ events and atmospheric neutrino backgrounds and resulted in 11 candidate events with an expected background of 9.3 events. In the absence of statistically significant excess, we derived a lower limit on n¯ appearance lifetime in O16 nuclei of 3.6×1032 years and on the neutron-antineutron oscillation time of τn→n¯>4.7×108 s at 90% C.L.

We present a search for an excess of neutrino interactions due to dark matter in the form of weakly interacting massive particles (WIMPs) annihilating in the Galactic center or halo based on the data set of Super-Kamiokande-I, -II, -III and -IV taken from 1996 to 2016. We model the neutrino flux, energy, and flavor distributions assuming WIMP self-annihilation is dominant to νν¯, μ+μ-, bb¯, or W+W-. The excess is in comparison to atmospheric neutrino interactions which are modeled in detail and fit to data. Limits on the self-annihilation cross section σ are derived for WIMP masses in the range 1 GeV to 10 TeV, reaching as low as 9.6×10-23 cm3 s-1 for 5 GeV WIMPs in bb¯ mode and 1.2×10-24 cm3 s-1 for 1 GeV WIMPs in νν¯ mode. The obtained sensitivity of the Super-Kamiokande detector to WIMP masses below several tens of GeV is the best among similar indirect searches to date.