There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately utilize repeated measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic lab data at approximate 3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling (GBTM) to identify latent clusters of patients who follow distinct trajectories with regards to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of two major outcomes thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with hazard of thrombotic event (p = 0.4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall p = 0.0002). Additionally, we found that neither hematocrit nor platelet count were significantly associated with hazard of thrombosis or disease evolution. Copyright © 2020 American Society of Hematology.OBJECTIVES A common finding in the mind-wandering literature is that older adults (OAs) tend to mind-wander less frequently than young adults (YAs). Here, we sought to determine whether this age-related difference in mind-wandering is attributable to age-related differences in motivation. METHOD YAs and OAs completed an attention task during which they responded to thought probes that assessed rates of mind-wandering, and they provided self-reports of task-based motivation before and after completion of the attention task. RESULTS Age-related differences in mind-wandering are partially explained by differences in motivation, and that motivating young adults via incentive diminishes mind-wandering differences across these groups. DISCUSSION We consider these results in the context of theories on age-related differences in mind wandering, with a specific focus on their relevance to the recently proposed motivational account of such age-related differences. © The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.BACKGROUND The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI5.60-10.19, p = 5 × 10-40; RAD51D RR = 7.60, 95%CI5.61-10.30, p = 5 × 10-39) and BC (RAD51C RR = 1.99, 95%CI1.39-2.85, p = 1.55 × 10-4; RAD51D RR = 1.83, 95%CI1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI6-21%) for RAD51C and 13% (95%CI7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI15-29%) for RAD51C and 20% (95%CI14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models. © The Author(s) 2020. Published by Oxford University Press.The widespread use of Cas12a (formerly Cpf1) nucleases for genome engineering is limited by their requirement for a rather long TTTV protospacer adjacent motif (PAM) sequence.  https://www.selleckchem.com/products/oprozomib-onx-0912.html  Here we have aimed to loosen these PAM constraints and have generated new PAM mutant variants of the four Cas12a orthologs that are active in mammalian and plant cells, by combining the mutations of their corresponding RR and RVR variants with altered PAM specificities. LbCas12a-RVRR showing the highest activity was selected for an in-depth characterization of its PAM preferences in mammalian cells, using a plasmid-based assay. The consensus PAM sequence of LbCas12a-RVRR resembles a TNTN motif, but also includes TACV, TTCV CTCV and CCCV. The D156R mutation in improved LbCas12a (impLbCas12a) was found to further increase the activity of that variant in a PAM-dependent manner. Due to the overlapping but still different PAM preferences of impLbCas12a and the recently reported enAsCas12a variant, they complement each other to provide increased efficiency for genome editing and transcriptome modulating applications. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.BACKGROUND Systemic infiltration of the brain by tumor cells is a hallmark of glioma pathogenesis which may cause disturbances in functional connectivity. We hypothesized that aggressive high-grade tumors cause more damage to functional connectivity than low-grade tumors. METHODS We designed an imaging tool based on resting-state functional MRI to individually quantify abnormality of functional connectivity and tested it in a prospective cohort of patients with newly diagnosed glioma. RESULTS 34 patients (WHO II 13; WHO III 6; WHO IV 15; mean age 48,7 years) were analyzed. Connectivity abnormality could be observed not only in the lesioned brain area but also in the contralateral hemisphere with a close correlation between connectivity abnormality and aggressiveness of the tumor as indicated by WHO grade. IDH 1 mutation status was also associated with abnormal connectivity, with more alterations in IDH 1 wildtype tumors independent of tumor size. Finally, deficits in neuropsychological performance were correlated with connectivity abnormality.