Notes

Most cancers chemistry deciphered by single-cell transcriptomic sequencing.
Glutathione (GSH) is present ubiquitously, and its role as a crucial cellular antioxidant in tissues, including the retina, is well established. GSH's antioxidant function arises from its ability to scavenge reactive oxygen species or to serve as an essential cofactor for GSH S-transferases and peroxidases. This review summarizes the general functions, retinal distribution, disorders linked to GSH deficiency, and the emerging role for mitochondrial GSH (mGSH) in retinal function. Though synthesized only in the cytosol, the presence of GSH in multiple cell organelles suggests the requirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochondrial carrier proteins in RPE and retina, show that these transporters are highly expressed in human retinal pigment epithelium (RPE) cells and retinal layers, and their expression increases with RPE polarity in cultured cells. Depletion of mGSH levels via inhibition of the two transporters resulted in reduced mitochondrial bioenergetic parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity) and increased RPE cell death. These results begin to reveal a critical role for mGSH in maintaining RPE bioenergetics and cell health. Thus, augmentation of mGSH pool under GSH-deficient conditions may be a valuable tool in treating retinal disorders, such as age-related macular degeneration and optic neuropathies, whose pathologies have been associated with mitochondrial dysfunction.Human epidermal growth factor receptor 2 (HER2) positive (+) classical type invasive lobular carcinoma (cILC) of the breast is extremely rare and its clinicopathologic features have not been well characterized. We compared features of HER2(+) and HER2 negative (-) cILCs. A total of 29 cases were identified from the clinical database at our institution from 2011-2019; 9 were HER2(+) cILC tumors and 20 were HER2(-) cILC tumors. Sunitinib The results reveal that HER2(+) cILC group had significantly increased Ki-67 expression and reduced estrogen receptor (ER) expression compared to HER2(-) cILC group (both p less then 0.05). In addition, HER2(+) cILCs tended to be diagnosed at a younger age and more common in the left breast, and appeared to have a higher frequency of nodal or distant metastases. These clinicopathologic features suggest HER2(+) cILC tumors may have more aggressive behavior than their HER2(-) counterpart although both groups of tumors showed similar morphologic features. Future directions of the study (1) To conduct a multi-institutional study with a larger case series of HER2(+) cILC to further characterize its clinicopathologic features; (2) to compare molecular profiles by next generation sequencing (NGS) assay between HER2(+) cILC and HER2(-) cILC cases to better understand tumor biology of this rare subset of HER2(+) breast cancer; and (3) to compare molecular characteristics of HER2(+) cILC and HER2(+) high grade breast cancer in conjunction with status of tumor response to anti-HER2 therapy to provide insight to management of this special type of low grade breast cancer to avoid unnecessary treatment and related toxicity.Recent studies suggested a potential link between vitamin D deficiency and cardiovascular risk factors, including dyslipidemia. This study aimed to investigate the association between serum 25(OH)D levels and atherogenic lipid profiles, specifically, that of small dense low-density lipoprotein-cholesterol (sdLDL-C). From 2009 to 2011, a total of 715 individuals aged 35-65 without evident cardiovascular disease (CVD) were enrolled. Their levels of serum 25(OH)D and lipid profiles were measured. Vitamin D deficiency was found to be more common in females, smokers, alcohol drinkers, individuals at a younger age, and those who do not exercise regularly. The analysis of lipid profiles revealed that high sdLDL-C levels were associated with low serum vitamin D levels and were more common among cigarette smokers; alcohol drinkers; individuals with hypertension; individuals with high BMI; and those with high levels of fasting blood glucose, triglycerides, LDL-C, and VLDL-C. The use of multivariate logistic regression verified a strong negative correlation between low vitamin D status (serum 25(OH)D less then 15 ng/mL) and the three identified biomarkers of atherogenic dyslipidemia high serum levels of sdLDL-C, triglycerides, and VLDL-C. This study provides strong evidence that vitamin D deficiency is associated with atherogenic dyslipidemia, and in particular, high sdLDL-C levels in middle-aged adults without CVD.In this research, reinforced concrete (RC) and strain-hardening cementitious composite (SHCC) columns subjected to lateral loads combined with a constant load were investigated, both by experiments and predictions, with two distributed inelastic finite element models established by the stiffness and flexibility formulations. SHCC applied in the column plastic hinge region could not only enhance the lateral load and displacement capacities of columns but also offer effective advantages in the control of bending and shear cracks induced by multiple microcracks, the prevention of the spalling of cover concrete, and the resistance to buckling of steel bars. With the layered cross-sectional approach using constitutive laws of SHCC considering a proposed model of the post-cracked high-ductile tensile characteristics, as well as concrete and reinforcing steel bars, an inelastic beam-column finite element model was presented with a distributed flexibility formulation. In comparison with experiments concerning the RC and reinforced strain-hardening cementitious composite (R-SHCC) columns, the current flexibility method showed relatively accurate estimations in the lateral load and displacement responses of column systems as well as in localized nonlinear responses of cross-section as estimated in axial strains of longitudinal reinforcing steel bars. In comparison with the stiffness method, the current flexibility method gave more accurate solutions at both element and structural levels, as manifested in the experiments and analysis solutions.Porous organic polymers have been received considerable attention due to their heteroatom-containing structures and high surface areas, which can offer high electrochemical performance in energy applications. The majority of reported Tröger's base-functionalized porous organic polymers have been applied as effective candidates for sensing and gas separation/adsorption, while their use as electrode materials in supercapacitors is rare. Here, a novel covalent microporous organic polymer containing carbazole and Tröger's base CzT-CMOP has been successfully synthesized through the one-pot polycondensation of 9-(4-aminophenyl)-carbazole-3,6-diamine (Cz-3NH2) with dimethoxymethane. The polycondensation reaction's regioselectivity was studied using spectroscopic analyses and electronic structure calculations that confirmed the polycondensation occurred through the second and seventh positions of the carbazole unit rather than the fourth and fifth positions confirmed by first-principles calculations. Our CzT-CMOP exhibited high thermal stability of approximately 463.5 °C and a relatively high Brunauer-Emmett-Teller surface area of 615 m2 g-1 with a nonlocal density functional theory's pore size and volume of 0.48 cm3 g-1 and 1.66 nm, respectively. In addition, the synthesized CzT-CMOP displayed redox activity due to the existence of a redox-active carbazole in the polymer skeleton. CzT-CMOP revealed high electrochemical performance when used as active-electrode material in a three-electrode supercapacitor with an aqueous electrolyte of 6 M KOH, and it showed specific capacitance of 240 F g-1 at a current density of 0.5 A g-1 with excellent stability after 2000 cycles of 97% capacitance retention. Accordingly, such porous organic polymer appears to have a variety of uses in energy-related applications.Fishermen in low resource settings have limited access to health services and may have a range of health literacy-related difficulties that may lead to poor health outcomes. To provide solutions and interventions based on their needs, co-design is considered best practice in such settings. This study aimed to implement a co-design process as a step towards developing health literacy interventions to improve health and equity in the Borollos Lake region of northern Egypt, a low resource setting with a high prevalence of chronic diseases. This study was guided by the Ophelia (Optimising Health Literacy and Access) process, a widely used and flexible co-design process that seeks to create local and fit-for-purpose health literacy solutions through genuine engagement and participation of community members and relevant stakeholders. Following a health literacy survey using the Health Literacy Questionnaire (HLQ), cluster analysis was conducted to identify the diverse health literacy profiles among the fishing communities. Seven health literacy profiles were identified. Vignettes, representing these profiles, were presented and discussed in ideas generation/co-design workshops with fishermen and health workers to develop intervention ideas. Seventeen fishermen, 22 wives of fishermen, and 20 nurses participated in four workshops. Fifteen key strategies across five themes, including 'Enhancing education among fishing communities', 'Provide good quality health services', 'Financial support for health', 'Social support for health', and 'Promote better health-related quality of life among fishermen', were generated. The ideas did not only target the individuals but also required actions from the government, non-government organizations, and fishermen syndicates. By harnessing local wisdom, the Ophelia process has created meaningful engagement with the local communities, leading to a wide range of practical and feasible solutions that match the special needs and environment of a low resource setting.Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, the proteomic data revealed a dose-dependent increment of the number of glycation adducts in both these cell types. HPDE cells showed a higher number of intracellular AGEs compared to cancer cells. At a molecular level, the glycations in the lysine residues of proteins showed a concurrent increase with the concentration of the glyceraldehyde treatment, while the arginine glycations appeared to be less affected by the glyceraldehyde doses. Further pathway analysis of these glycated proteins suggested that the glycated proteins participate in important biological processes that are major hallmarks of cancer initiation and progression, including metabolic processes, immune response, oxidative stress, apoptosis, and S100 protein binding.
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