In human pancreatic cancer, we successfully segmented patient sections and further fine-mapped normal and neoplastic cell states. Trained on an external single-cell pancreatic tumor references, we further charted the localization of clinical-relevant and tumor-specific immune cell states, an illustrative example of its flexible application spectrum and future potential in digital pathology.Radiation-induced brain injury (RBI) is a serious complication in patients who have received radiotherapy for head and neck tumors. Currently, there is a scarcity of information on early diagnostic and preventive methods of RBI. Accumulating evidence suggests that microRNAs are involved in the regulation of radiation injury, but the molecular biological mechanism of miRNAs in RBI is largely unknown. Therefore, in our study, microRNA sequencing was used to discover differential miRNAs in the hippocampus of RBI-modeled mice, which suggested that miR-741-3p was most significantly upregulated. To clarify the underlying mechanism of miR-741-3p in RBI-modeled mice, an inhibitor of miR-741-3p (antagomiR-741) was delivered into the brain via the nasal passage before irradiation. The delivery of antagomiR-741 significantly reduced miR-741-3p levels in the hippocampus of RBI-modeled mice, and the cognitive dysfunction and neuronal apoptosis induced by radiation were also alleviated at 6 weeks postirradiation. Downregulation of miR-741-3p was found to improve the protrusion and branching status of microglia after irradiation and reduced the number of GFAP-positive astrocytes. Additionally, antagomiR-741 suppressed the radiation-induced production of pro-inflammatory cytokines IL-6 and TNF-α in the hippocampus and S100B in the serum.  https://www.selleckchem.com/products/hydroxychloroquine-sulfate.html  Furthermore, Ddr2, PKCα and St8sia1 were revealed as target genes of miR-741-3p and as potential regulatory targets for RBI. Overall, our study provides identification and functional evaluation of miRNA in RBI and lays the foundation for improving the prevention strategy for RBI based on the delivery of miRNA via the nose-brain pathway.
  Previously, by using proteomic analysis and RNA sequencing in isolated glomeruli, we identified several novel differentially expressed proteins in human and mouse diabetic nephropathy (DN) versus controls, including dishevelled associated activator of morphogenesis 2 (DAAM2). DAAM2 binds the Wnt effector Dvl. We aimed to study possible contributions of DAAM2 to DN.
 
  We assessed DAAM2 by immunostaining in non-cancer regions of human nephrectomy (Nx), DN and normal donor kidney tissues. We also examined DAAM2 in DN mice (db/db eNOS-/-) and Nx mice. DN mice treated with angiotensin-converting enzyme inhibitor (ACEI), dipeptidyl peptidase 4 inhibitor (DPP4I) or vehicle were compared. DAAM2 was knocked down in primary cultured podocytes by small interfering RNA to study its effects on cell function.
 
  In normal human glomeruli, DAAM2 was expressed only on podocytes. DAAM2 expression was increased in both Nx and DN versus normal donors. Podocyte DAAM2 expression was increased in DN and Nx mouse models. Glomerular DAAM2 expression correlated with glomerular size and was decreased significantly by ACEI while DPP4I only numerically reduced DAAM2. In primary cultured podocytes, knockdown of DAAM2 enhanced adhesion, slowed migration, activated Wnt-β-catenin signaling and downregulated mammalian target of rapamycin complex 1 (mTORC1) and Rho activity.
 
  Podocyte DAAM2 is upregulated in both Nx and DN, which could be contributed to by glomerular hypertrophy. We hypothesize that DAAM2 regulates podocyte function through the mTORC1, Wnt/β-catenin and Rho signaling pathways.
 Podocyte DAAM2 is upregulated in both Nx and DN, which could be contributed to by glomerular hypertrophy. We hypothesize that DAAM2 regulates podocyte function through the mTORC1, Wnt/β-catenin and Rho signaling pathways.As part of ongoing efforts to assess lifespan disease mortality and incidence in 63,715 patients from the Canadian Fluoroscopy Cohort Study (CFCS) who were treated for tuberculosis between 1930 and 1969, we developed a new FLUoroscopy X-ray ORgan-specific dosimetry system (FLUXOR) to estimate radiation doses to various organs and tissues. Approximately 45% of patients received medical procedures accompanied by fluoroscopy, including artificial pneumothorax (air in pleural cavity to collapse of lungs), pneumoperitoneum (air in peritoneal cavity), aspiration of fluid from pleural cavity and gastrointestinal series. In addition, patients received chest radiographs for purposes of diagnosis and monitoring of disease status. FLUXOR utilizes age-, sex- and body size-dependent dose coefficients for fluoroscopy and radiography exams, estimated using radiation transport simulations in up-to-date computational hybrid anthropomorphic phantoms. The phantoms include an updated heart model, and were adjusted to match the eth the uncertainty in exposure duration being most often the dominant source. Uncertainty in patient orientation was important for doses to female breast, and, to a lesser degree, for doses to heart wall. The uncertainty in number of exams was an important contributor to uncertainty for ∼30% of patients. The estimated organ doses and their uncertainties will be used for analyses of incidence and mortality of cancer and non-cancer diseases. The CFCS cohort is an important addition to existing radio-epidemiological cohorts, given the moderate-to-high doses received fractionated over several years, the type of irradiation (external irradiation only), radiation type (X rays only), a balanced combination of both genders and inclusion of people of all ages.G-quadruplexes are noncanonical nucleic acid structures formed by stacked guanine tetrads. They are capable of a range of functions and thought to play widespread biological roles. This diversity raises an important question what determines the biochemical specificity of G-quadruplex structures? The answer is particularly important from the perspective of biological regulation because genomes can contain hundreds of thousands of G-quadruplexes with a range of functions. Here we analyze the specificity of each sequence in a 496-member library of variants of a reference G-quadruplex with respect to five functions. Our analysis shows that the sequence requirements of G-quadruplexes with these functions are different from one another, with some mutations altering biochemical specificity by orders of magnitude. Mutations in tetrads have larger effects than mutations in loops, and changes in specificity are correlated with changes in multimeric state. To complement our biochemical data we determined the solution structure of a monomeric G-quadruplex from the library.