Role of cystatin C in amyloid precursor protein-induced proliferation of neural stem/progenitor cells

The amyloid precursor protein (APP) is well studied for its role in Alzheimer disease. However, little is known about its normal function. In this study, we examined the role of APP in neural stem/progenitor cell (NSPC) proliferation. NSPCs derived from APP-overexpressing Tg2576 transgenic mice proliferated more rapidly than NSPCs from the corresponding background strain (C57Bl/6xSJL) wild-type mice. In contrast, NSPCs from APP knock-out (APP-KO) mice had reduced proliferation rates when compared with NSPCs from the corresponding background strain (C57Bl/6). A secreted factor, identified as cystatin C, was found to be responsible for this effect. Levels of cystatin C were higher in the Tg2576 conditioned medium and lower in the APP-KO conditioned medium. Furthermore, immunodepletion of cystatin C from the conditioned medium completely removed the ability of the conditioned medium to increase NSPC proliferation. The results demonstrate that APP expression stimulates NSPC proliferation and that this effect is mediated via an increase in cystatin C secretion

Theoretical prediction of CNT-CF/PP composite tensile properties using various numerical modeling methods

Development of effective models to predict tensile properties of ‘carbon nanotube coated carbon fibre reinforced polypropylene (CNT-CF/PP)’ composites is briefly discussed. The composite taken as the reference is based on the highest growth mechanism of CNTs over carbon fibres. Halpin-Tsai and Combined Voigt-Reuss model has been implemented. Young's modulus for CNT-CF/PP composites has been found 4.5368 GPa and the tensile strength has been estimated 45.367 MPa considering the optimum operating condition of chemical vapor deposition (CVD) technique. Stiffness of the composite is represented through the stress-strain plots; stiffness is proportional to the steepness of the slope. There are slight deviations of results that have been found theoretically over the experimental issues

Understanding the barriers to integrating maternal and mental health at primary health care in Vietnam

The prevalence of common perinatal mental disorders in Vietnam ranges from 16.9% to 39.9%, and substantial treatment gaps have been identified at all levels. This paper explores constraints to the integration of maternal and mental health services at the primary healthcare level and the implications for the health system’s responsiveness to the needs and expectations of pregnant women with mental health conditions in Vietnam. As part of the RESPONSE project, a three-phased realist evaluation study, we present Phase One findings which employed systematic and scoping literature reviews, and qualitative data collection (focus groups and interviews) with key health system actors, in Bac Giang province, Vietnam, to understand the barriers to maternal mental healthcare provision, utilisation, and integration strategies. A four-level framing of the barriers to integrating perinatal mental health services in Vietnam was used in reporting findings, which comprised individual, socio-cultural, organisational, and structural levels. At the socio-cultural and structural levels, these barriers included: cultural beliefs about the holistic notion of physical and mental health, stigma towards mental health, biomedical approach to healthcare services, absence of comprehensive mental health policy, and a lack of mental health workforce. At the organisational level, there was absence of clinical guidelines on the integration of mental health in routine antenatal visits, a shortage of staff, and poor health facilities. Finally, at the provider level, a lack of knowledge and training on mental health was identified. The integration of mental health into routine antenatal visits at the primary care level has the potential help to reduce stigma towards mental health and improve health system responsiveness by providing services closer to the local level, offering prompt attention, better choice of services, and better communication while ensuring privacy and confidentiality of services. This can improve the demand for mental health services and help reduce the delay of care-seeking

Mechanistic target of rapamycin (MTOR) protein expression in the tumor and its microenvironment correlates with more aggressive pathology at cystectomy

Background: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression correlate with chemoresponsiveness in the tumor and its microenvironment at final pathologic staging after neoadjuvant chemotherapy (NAC). Methods: A single-institution retrospective analysis was performed on 62 patients with cT2–4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and postchemotherapy radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding stroma. Protein expression levels were compared between clinical and pathologic stage. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. Results: Baseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage and response to chemotherapy overall. Nonresponders with advanced pathologic stage at cystectomy (ypT2–4/ypTanyN+) had significantly elevated mTOR tumor staining (P = 0.006) and a sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma (NS). Several genes relevant to mTOR activity were found to be up-regulated in the tumors of nonresponders. Remarkably, complete responders at cystectomy (ypT0) had significant decreases in both mTOR and pmTOR protein expression in the peritumoral and normal stroma (P = 0.01–0.03). Conclusions: Our results suggest that mTOR pathway activity is increased in tumor and sustained in its microenvironment in patients with adverse pathologic findings at cystectomy. These findings suggest the relevance of targeting this pathway in bladder cancer

Theoretical study of lepton events in the atmospheric neutrino experiments at SuperK

Super-Kamiokande has reported the results for the lepton events in the atmospheric neutrino experiment. These results have been presented for a 22.5kT water fiducial mass on an exposure of 1489 days, and the events are divided into sub-GeV, multi-GeV and PC events. We present a study of nuclear medium effects in the sub-GeV energy region of atmospheric neutrino events for the quasielastic scattering, incoherent and coherent pion production processes, as they give the most dominant contribution to the lepton events in this energy region. We have used the atmospheric neutrino flux given by Honda et al. These calculations have been done in the local density approximation. We take into account the effect of Pauli blocking, Fermi motion, Coulomb effect, renormalization of weak transition strengths in the nuclear medium in the case of the quasielastic reactions. The inelastic reactions leading to production of leptons along with pions is calculated in a $\Delta$- dominance model by taking into account the renormalization of $\Delta$ properties in the nuclear medium and the final state interaction effects of the outgoing pions with the residual nucleus. We present the results for the lepton events obtained in our model with and without nuclear medium effects, and compare them with the Monte Carlo predictions used in the simulation and the experimentally observed events reported by the Super-Kamiokande collaboration.Comment: 23 pages, 13 figure

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Measurements of the qsq dependence of the D0 to K mu nu and D0 to pi mu nu form factors

Using a large sample of D0 to K mu nu and pi mu nu decays collected by the FOCUS photoproduction experiment at Fermilab, we present new measurements of the q^2 dependence for the f+(q^2) form factor. These measured f+(q^2) form factors are fit to common parameterizations such as the pole dominance form and compared to recent unquenched Lattice QCD calculations. We find m_pole = 1.93+-0.05+-0.03 GeV/c^2 for D0 to K mu nu and m_pole = 1.91+0.30-0.15+-0.07 GeV/c^2 for D0 to pi mu nu and f-^{K}(0)/f+^{K}(0) = -1.7+1.5-1.4+-0.3.Comment: 14 pages, 6 figure

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe