Burnettdecker3993

P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) modulate the distribution of drugs and toxins across the blood-brain barrier (BBB). Animal studies reported that infection-induced disruption of these transporters in the developing BBB impairs fetal brain protection. However, the impact of infection mimics on P-gp/BCRP function in human brain endothelium is less well understood. We hypothesized that Toll-like receptor ligands mimicking bacterial and viral infection would modify the expression and function of P-gp and BCRP in human brain endothelial cells (BECs). Human cerebral microvascular endothelial cells (hCMEC/D3) were challenged with bacterial [Lipopolysaccharide (LPS)] and viral-mimics [polyinosinicpolycytidylic acid (PolyIC) or single-stranded RNA (ssRNA)], or pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-ɣ. P-gp and BCRP function was assessed after 4 or 24 h, using Calcein-AM and Chlorin-6 assays, respectively. Western blot and qPCR quantified P-gp/ABCB1 and BCRP/ABCG2 expression following treatments. Infection mimics are potent modulators of drug transporters in human BECs in vitro. LPS and PolyIC increased, while ssRNA exposure reduced P-gp activity. In contrast, LPS and PolyIC decreased, while ssRNA increased BCRP activity (P less then .05). There was little correlation between drug transporter function, gene expression and total protein level. Altered plasma membrane BCRP may suggest modified intracellular trafficking induced by infection in human BECs. Bacterial and viral infection mimics modify P-gp and BCRP transport function in human BECs, in vitro. This knowledge may contribute and have important implications for human brain protection and possible altered biodistribution of drugs and xenobiotics in the brain following exposure to TLR agonists.Populus euphratica Oliv. is a tree that is strongly resistant to drought and salt stress, which is primarily distributed in arid and semiarid lands. The leaves of the species exhibit a special feature that causes them to be designated as heterophylly. In this brief review, we primarily discuss the heteromorphic leaf development and anatomical features, such as the differentiation of spongy and palisade tissues, in heteromorphic leaves of the species. Furthermore, we also discuss the different physiological characteristics in heteromorphic leaves related to the ecological adaptation of P. euphratica to drought environments. These traits in P. euphratica may help researchers evaluate its ecological value in arid areas and evaluate its scientific merit in understanding the mechanism of development of heteromorphic leaves in plants.Pathological changes involving TDP-43 protein ('TDP-43 proteinopathy') are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.Roughly half of all postmenopausal women are affected by the genitourinary syndrome of menopause (GSM). Symptoms of GSM, including vaginal irritation and dyspareunia, occur as reduced estrogen (E) production elicits loss of elasticity and other changes in genital tract tissue. While the use of the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) likewise lowers serum E concentrations in reproductive age women and is associated with decreased genital levels of the cell-cell adhesion molecules desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and impaired genital epithelial barrier function, the relevance of these findings to women in menopause is uncertain. Exploring the impact of menopause on genital epithelial integrity herein, we detected significantly lower levels of DSG1 and DSC1 in ectocervical tissue from menopausal and postmenopausal vs premenopausal women. Using ovariectomized (OVX) mice as a menopause model, we comparably saw significantly lower vaginal tissue levels of DSG1 and DSC1 in OVX mice vs. mice in estrus. Compared to estrus-stage mice and E-treated OVX mice, DMPA-treated ovary-intact mice and OVX mice also exhibited significantly reduced genital epithelial barrier function, greater susceptibility to genital herpes simplex virus type 2 infection, and delayed clearance of genital Chlamydia trachomatis infection. Current studies thus identify analogous loss of genital epithelial integrity in OVX mice and menopausal and postmenopausal women. By showing that loss of genital epithelial integrity is associated with increased mouse susceptibility to bacterial and viral pathogens, our findings also prioritize the need to resolve if reduced genital epithelial integrity in postmenopausal women is a significant risk factor for genital infection.

Long-term dietary phosphorus excess influences disturbances in mineral metabolism, but it is unclear how rapidly the mineral metabolism responds to short-term dietary change in dialysis populations.

This was a post hoc analysis of a randomized crossover trial that evaluated the short-term effects of low-phosphorus diets on mineral parameters in hemodialysis patients. Within a 9-day period, we obtained a total of 4 repeated measurements for each participant regarding dietary intake parameters, including calorie, phosphorus, and calcium intake, and markers of mineral metabolism, including phosphate, calcium, intact parathyroid hormone (iPTH), intact fibroblast growth factor 23 (iFGF23), and C-terminal fibroblast growth factor 23 (cFGF23). The correlations between dietary phosphorus intake and serum mineral parameters were assessed by using mixed-effects models.

Thirty-four patients were analyzed. In the fully adjusted model, we found that an increase in dietary phosphorus intake of 100 mg was associated with an increase in serum phosphate of 0.3 mg/dL (95% confidence intervals [CI], 0.2-0.4,

 < .001), a decrease in serum calcium of 0.06 mg/dL (95% CI, -0.11 to -0.01,

 = .01), an increase in iPTH of 5.4% (95% CI, 1.4-9.3,

 = .01), and an increase in iFGF23 of 5.0% (95% CI, 2.0-8.0,

 = .001). Dietary phosphorus intake was not related to cFGF23.

Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.

Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.BackgroundLigneous conjunctivitis (LC) is a rare disease characterized by the development of a wood-like pseudomembrane on the tarsal conjunctiva secondary to type I plasminogen deficiency. Here we reported on a Chinese patient with LC in a consanguineous family and performed a literature review of all reported mutations for this disease. Methods A 13-month-old girl diagnosed with LC and her parents were included in this study. Hematoxylin and eosin staining was used to perform histopathology examination. The plasminogen activity was determined by chromogenic assay. Sanger sequencing was performed to screen the mutation site for the disease. In silico analysis was applied to predict the pathogenesis of the identified mutation. In addition, we reviewed the literatures on PLG mutations of LC. Results Histopathology examination revealed the infiltration of inflammatory cells on membranous lesions. Plasma plasminogen activity was severely decreased in the patient and moderately decreased in her parents (patient plasminogen activity, 2.50%; father plasminogen activity, 41.02%; mother plasminogen activity, 54.07%). Co-segregation analysis indicated that the patient was homozygous for the c.763 G > A (p.Glu255Lys) mutation in plasminogen gene (PLG). Bioinformatics analysis strongly suggested that the mutation was damaging for the disease. The model analysis indicated the mutation might cause abnormal spatial structure and low stability, thus affecting functional activity. A literature review of the LC mutations indicated a strong genetic heterogeneity of the disease. Conclusions LC exhibited strong genetic heterogeneity, and our study identified a novel homozygous missense mutation of plasminogen (c.763 G > A, p.Glu255Lys) in one Chinese patient with LC.Diabetic nephropathy (DN) is a common complication of diabetes. Yishen capsule, composed of Chinese herbs, improves the clinical outcome in DN patients. However, its therapeutic potential and underlying mechanisms require further elucidation. Hence, our study aimed to investigate the underlying mechanisms and therapeutic potential of Yishen capsule in DN. Streptozotocin-induced DN rats were treated with Yishen capsules (1.25 g/kg/day) for 8 weeks. Then, blood glucose and urine protein levels were measured. Hematoxylin and eosin staining and western blot assays were used to examine the histologic changes and gene expression, respectively, in kidney samples. Mouse podocytes were treated with rat serum containing Yishen capsule and transmission electron microscopy was used to examine autophagosome formation. Cell counting kit-8 assay was performed to examine cell proliferation. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to detect changes in gene expression. The localization of SIRT1 was examined in the podocytes using immunocytofluorescence assay. We found that Yishen capsule relieved pathological changes, decreased urine protein, increased SIRT1, LC3-II, and Beclin-1 expression, and reduced acetylated NF-κB p65 expression in vivo. In addition, rat serum containing Yishen capsule showed improved podocyte proliferation, promoted the mRNA and protein levels of LC3-II and Beclin-1, and induced nuclear translocation of SIRT1. PF-3644022 ic50 Furthermore, it increased SIRT1 expression and decreased mRNA level of NF-κB in the serum. SIRT1 inhibitor increased the mRNA level of NF-κB. Our data suggests that Yishen capsule improves DN by promoting podocyte autophagy via the SIRT1/NF-κB pathway.

Manual quality assurance (QA) of radiotherapy contours for clinical trials is time and labor intensive and subject to inter-observer variability. Therefore, we investigated whether deep-learning (DL) can provide an automated solution to salivary gland contour QA.

DL-models were trained to generate contours for parotid (PG) and submandibular glands (SMG). Sørensen-Dice coefficient (SDC) and Hausdorff distance (HD) were used to assess agreement between DL and clinical contours and thresholds were defined to highlight cases as potentially sub-optimal. 3 types of deliberate errors (expansion, contraction and displacement) were gradually applied to a test set, to confirm that SDC and HD were suitable QA metrics. DL-based QA was performed on 62 patients from the EORTC-1219-DAHANCA-29 trial. All highlighted contours were visually inspected.

Increasing the magnitude of all 3 types of errors resulted in progressively severe deterioration/increase in average SDC/HD. 19/124 clinical PG contours were highlighted as potentially sub-optimal, of which 5 (26%) were actually deemed clinically sub-optimal.