Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003-2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values > 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10-43, 2.66 × 10-15). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level.Cancer is the second leading cause of death in the United States. Although screening facilitates prevention and early detection and is one of the most effective approaches to reducing cancer mortality, participation is low-particularly among underserved populations. In a large, preregistered field experiment (n = 7711), we tested whether deadlines-both with and without monetary incentives tied to them-increase colorectal cancer (CRC) screening. We found that all screening invitations with an imposed deadline increased completion, ranging from 2.5% to 7.3% relative to control (ps  less then  .004). Most importantly, individuals who received a short deadline with no incentive were as likely to complete screening (9.7%) as those whose invitation included a deadline coupled with either a small (9.1%) or large declining financial incentive (12.0%; ps = .57 and .04, respectively). These results suggest that merely imposing deadlines-especially short ones-can significantly increase CRC screening completion, and may also have implications for other forms of cancer screening.HER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. In this study, we developed bispecific antibodies for T-cell retargeting to HER3-expressing tumor cells, utilizing either a single-chain diabody format (scDb) with one binding site for HER3 and one for CD3 on T-cells or a trivalent bispecific scDb-scFv fusion protein exhibiting an additional binding site for HER3. The scDb-scFv showed increased binding to HER3-expressing cancer cell lines compared to the scDb and consequently more effective T-cell activation and T-cell proliferation. Furthermore, the bivalent binding mode of the scDb-scFv for HER3 translated into more potent T-cell mediated cancer cell killing, and allowed to discriminate between moderate and low HER3-expressing target cells. Thus, our study demonstrated the applicability of HER3 for T-cell retargeting with bispecific antibodies, even at moderate expression levels, and the increased potency of an avidity-mediated specificity gain, potentially resulting in a wider safety window of bispecific T-cell engaging antibodies targeting HER3.Quantifying synergistic environmental effects in water contamination is still an open issue. Here, we have analyzed geolocalized data of pollutants recorded in 2018 in surface and groundwater of Lombardy, one of the areas with the highest agricultural production rates, not only in Italy, but also in Europe. Both herbicides and insecticides are present at concentration levels above the legal limit, mainly in surface waters. Geolocalized analysis allows us to identify interesting areas particularly affected by a combination of multiple pesticides.  https://www.selleckchem.com/products/skf96365.html  We thus investigated possible synergistic effects of these compounds on the environment, using the alga C. reinhardtii as a biosensor. Our results show that exposure for 7 days to four compounds, that we found present together at high concentration in surface waters, was able to induce a stress in the algae, as indicated by the presence of palmelloids. Our work results in a pipeline that could easily be exported to monitor other territories in Italy and abroad.With the rapid growth in the global demand, the shrimp industry needs integrated approaches for sustainable production. A high-quality shrimp larva is one of the crucial key requirements to maximize shrimp production. Survival and growth rates during larval development are often criteria to evaluate larval quality, however many aspects of gene regulation during shrimp larval development have not yet been identified. To further our understanding of biological processes in their early life, transcriptomic analysis of larval developmental stages (nauplius, zoea, mysis, and postlarva) were determined in the black tiger shrimp, Penaeus monodon using next-generation RNA sequencing. Gene clustering and gene enrichment analyses revealed that most of the transcripts were mainly related to metabolic processes, cell and growth development, and immune system. Interestingly, Spätzle and Toll receptors were found in nauplius stage, providing evidence that Toll pathway was a baseline immune system established in early larval stages.