Bacteria-Induced Uroplakin Signaling Mediates Bladder Response to Infection

Urinary tract infections are the second most common infectious disease in humans and are predominantly caused by uropathogenic E. coli (UPEC). A majority of UPEC isolates express the type 1 pilus adhesin, FimH, and cell culture and murine studies demonstrate that FimH is involved in invasion and apoptosis of urothelial cells. FimH initiates bladder pathology by binding to the uroplakin receptor complex, but the subsequent events mediating pathogenesis have not been fully characterized. We report a hitherto undiscovered signaling role for the UPIIIa protein, the only major uroplakin with a potential cytoplasmic signaling domain, in bacterial invasion and apoptosis. In response to FimH adhesin binding, the UPIIIa cytoplasmic tail undergoes phosphorylation on a specific threonine residue by casein kinase II, followed by an elevation of intracellular calcium. Pharmacological inhibition of these signaling events abrogates bacterial invasion and urothelial apoptosis in vitro and in vivo. Our studies suggest that bacteria-induced UPIIIa signaling is a critical mediator of bladder responses to insult by uropathogenic E. coli

Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation

Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC

Deformation of Surface Nanobubbles Induced by Substrate Hydrophobicity

Recent experimental measurements have shown that there exists a population of nanobubbles with different curvature radii, whereas both computer simulations and theoretical analysis indicated that the curvature radii of different nanobubbles should be the same at a given supersaturation. To resolve such inconsistency, we perform molecular dynamics simulations on surface nanobubbles that are stabilized by heterogeneous substrates either in the geometrical heterogeneity model (GHM) or in the chemical heterogeneity model (CHM) and propose that the inconsistency could be ascribed to the substrate-induced nanobubble deformation. We find that, as expected from theory and computer simulation, for either the GHM or the CHM, there exists a universal upper limit of contact angle for the nanobubbles, which is determined by the degree of supersaturation alone. By analyzing the evolution of the shape of nanobubbles as a function of substrate hydrophobicity that is controlled here by the liquid-solid interaction, two different origins of nanobubble deformation are identified. For substrates in the GHM, where the contact line is pinned by surface roughness, variation in the liquid-solid interaction changes only the location of the contact line and the measured contact angle; without causing a change in the nanobubble curvature. For substrates in the CHM, however, the liquid-solid interaction exerted by the bottom substrate can deform the vapor-liquid interface, resulting in variations in both the curvature of the vapor-liquid interface and the contact angle

High prevalence of hyperglycaemia and the impact of high household income in transforming Rural China

<p>Abstract</p> <p>Background</p> <p>The prevalence of hyperglycaemia and its association with socioeconomic factors have been well studied in developed countries, however, little is known about them in transforming rural China.</p> <p>Methods</p> <p>A cross-sectional study was carried out in 4 rural communities of Deqing County located in East China in 2006-07, including 4,506 subjects aged 18 to 64 years. Fasting plasma glucose (FPG) was measured. Subjects were considered to have impaired fasting glucose (IFG) if FPG was in the range from 5.6 to 6.9 mmol/L and to have diabetes mellitus (DM) if FG was 7.0 mmol/L or above.</p> <p>Results</p> <p>The crude prevalences of IFG and DM were 5.4% and 2.2%, respectively. The average ratio of IFG/DM was 2.5, and tended to be higher for those under the age of 35 years than older subjects. After adjustment for covariates including age (continuous), sex, BMI (continuous), smoking, alcohol drinking, and regular leisure physical activity, subjects in the high household income group had a significantly higher risk of IFG compared with the medium household income group (OR: 1.74, 95% CI: 1.11-2.72) and no significant difference in IFG was observed between the low and medium household income groups. Education and farmer occupation were not significantly associated with IFG.</p> <p>Conclusions</p> <p>High household income was significantly associated with an increased risk of IFG. A high ratio of IFG/DM suggests a high risk of diabetes in foreseeable future in the Chinese transforming rural communities.</p

Clinical characteristics of the autumn-winter type scrub typhus cases in south of Shandong province, northern China

<p>Abstract</p> <p>Background</p> <p>Before 1986, scrub typhus was only found endemic in southern China. Because human infections typically occur in the summer, it is called "summer type". During the autumn-winter period of 1986, a new type of scrub typhus was identified in Shandong and northern Jiangsu province of northern China. This newly recognized scrub typhus was subsequently reported in many areas of northern China and was then called "autumn-winter type". However, clinical characteristics of associated cases have not been reported.</p> <p>Methods</p> <p>From 1995 to 2006, all suspected scrub typhus cases in five township hospitals of Feixian county, Shandong province were enrolled. Indirect immunofluorescent assay (IFA) was used as confirmatory serodiagnosis test. Polymerase chain reaction (PCR) connected with restriction fragment length polymorphism (RFLP) and sequence analyses were used for genotyping of <it>O. tsutsugamushi </it>DNAs. Clinical symptoms and demography of confirmed cases were analyzed.</p> <p>Results</p> <p>A total of 480 scrub typhus cases were confirmed. The cases occurred every year exclusively between September and December with a peak occurrence in October. The case numbers were relatively higher in 1995, 1996, 1997, and 2000 than in other years. 57.9% of cases were in the group aged 21–50. More cases occurred in male (56%) than in female (44%). The predominant occupational group of the cases was farmers (85.0%). Farm work was reported the primary exposure to infection in 67.7% of cases. Fever, rash, and eschar were observed in 100.0%, 90.4%, and 88.5% of cases, respectively. Eschars formed frequently on or around umbilicus, abdomen areas, and front and back of waist (34.1%) in both genders. Normal results were observed in 88.7% (WBC counts), 84.5% (PLT counts), and 89.7% (RBC counts) of cases, respectively. Observations from the five hospitals were compared and no significant differences were found.</p> <p>Conclusion</p> <p>The autumn-winter type scrub typhus in northern China occurred exclusively from September to December with a peak occurrence in October, which was different from the summer type in southern China. In comparison with the summer type, complications associated with autumn-winter type scrub typhus were less severe, and abnormalities of routine hematological parameters were less obvious.</p

Diabetes and Pre-Diabetes as Determined by Glycated Haemoglobin A1c and Glucose Levels in a Developing Southern Chinese Population

BACKGROUND: The American Diabetes Association and World Health Organization have recently adopted the HbA1c measurement as one method of diagnostic criteria for diabetes. The change in diagnostic criteria has important implications for diabetes treatment and prevention. We therefore investigate diabetes using HbA1c and glucose criteria together, and assess the prevalent trend in a developing southern Chinese population with 85 million residents. METHODS: A stratified multistage random sampling method was applied and a representative sample of 3590 residents 18 years of age or above was obtained in 2010. Each participant received a full medical check-up, including measurement of fasting plasma glucose, 2-hour post-load plasma glucose, and HbA1c. Information on history of diagnosis and treatment of diabetes was collected. The prevalence of diabetes obtained from the present survey was compared with the data from the survey in 2002. RESULTS: The prevalence of diabetes based on both glucose and HbA1c measurements was 21.7% (95% CI: 17.4%-26.1%) in 2010, which suggests that more than 1 in 5 adult residents were suffering from diabetes in this developing population. Only 12.9% (95% CI: 8.3%-17.6%) of diabetic residents were aware of their condition. The prevalence of pre-diabetes was 66.3% (95% CI: 62.7%-69.8%). The prevalence of diabetes and pre-diabetes which met all the three diagnostic thresholds (fast plasma glucose, 2 hour post-load plasma glucose, and HbA1c) was 3.1% and 5.2%, respectively. Diabetes and pre-diabetes as determined by HbA1c measurement had higher vascular risk than those determined by glucose levels. The prevalence of diabetes increased from 2.9% (95% CI: 2.0%-3.7%) in 2002 to 13.8% (95% CI: 10.2%-17.3%) in 2010 based on the same glucose criteria. CONCLUSIONS: Our results show that the diabetes epidemic is accelerating in China. The awareness of diabetes is extremely low. The glucose test and HbA1c measurement should be used together to increase detection of diabetes and pre-diabetes

Less than 5 Netrin-1 molecules initiate attraction but 200 Sema3A molecules are necessary for repulsion

Guidance molecules, such as Sema3A or Netrin-1, induce growth cone (GC) repulsion or attraction. In order to determine the speed of action and efficiency of these guidance cues we developed an experimental procedure to deliver controlled amounts of these molecules. Lipid vesicles encapsulating 10-10 4 molecules of Sema3A or Netrin-1 were manipulated with high spatial and temporal resolution by optical tweezers and their photolysis triggered by laser pulses. Guidance molecules released from the vesicles diffused and reached the GC membrane in a few seconds. Following their arrival, GCs retracted or grew in 20-120 s. By determining the number of guidance molecules trapped inside vesicles and estimating the fraction of guidance molecules reaching the GC, we show that the arrival of less than 5 Netrin-1 molecules on the GC membrane is sufficient to induce growth. In contrast, the arrival of about 200 Sema3A molecules is necessary to induce filopodia repulsion

Co-Inoculation with Rhizobia and AMF Inhibited Soybean Red Crown Rot: From Field Study to Plant Defense-Related Gene Expression Analysis

Background: Soybean red crown rot is a major soil-borne disease all over the world, which severely affects soybean production. Efficient and sustainable methods are strongly desired to control the soil-borne diseases. Principal Findings: We firstly investigated the disease incidence and index of soybean red crown rot under different phosphorus (P) additions in field and found that the natural inoculation of rhizobia and arbuscular mycorrhizal fungi (AMF) could affect soybean red crown rot, particularly without P addition. Further studies in sand culture experiments showed that inoculation with rhizobia or AMF significantly decreased severity and incidence of soybean red crown rot, especially for coinoculation with rhizobia and AMF at low P. The root colony forming unit (CFU) decreased over 50 % when inoculated by rhizobia and/or AMF at low P. However, P addition only enhanced CFU when inoculated with AMF. Furthermore, root exudates of soybean inoculated with rhizobia and/or AMF significantly inhibited pathogen growth and reproduction. Quantitative RT-PCR results indicated that the transcripts of the most tested pathogen defense-related (PR) genes in roots were significantly increased by rhizobium and/or AMF inoculation. Among them, PR2, PR3, PR4 and PR10 reached the highest level with co-inoculation of rhizobium and AMF. Conclusions: Our results indicated that inoculation with rhizobia and AMF could directly inhibit pathogen growth and reproduction, and activate the plant overall defense system through increasing PR gene expressions. Combined wit

An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors

Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-γ hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-γ) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-γ with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication