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ResearcherID
- J-8841-2015 (1)
Background:
The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.
Methods:
Mice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.
Results:
In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.
Conclusions:
Our studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.
Phosphines are important ligands in homogenous catalysis and have been crucial for many advances, such as in cross-coupling, hydrofunctionalization, or hydrogenation reactions. Herein we report the synthesis and application of a novel class of phosphines bearing ylide substituents. These phosphines are easily accessible via different synthetic routes from commercially available starting materials. Owing to the extra donation from the ylide group to the phosphorus center the ligands are unusually electron-rich and can thus function as strong electron donors. The donor capacity surpasses that of commonly used phosphines and carbenes and can easily be tuned by changing the substitution pattern at the ylidic carbon atom. The huge potential of ylide-functionalized phosphines in catalysis is demonstrated by their use in gold catalysis. Excellent performance at low catalyst loadings under mild reaction conditions is thus seen in different types of transformations.
Background
Wilms’ tumor 1-associating protein (WTAP) is a nuclear protein, which is ubiquitously expressed in many tissues. Furthermore, in various types of malignancies WTAP is overexpressed and plays a role as an oncogene. The function of WTAP in diffuse large B-cell lymphoma (DLBCL), however, remains unclear.
Methods
Immunohistochemistry was applied to evaluate the levels of WTAP expression in DLBCL tissues and normal lymphoid tissues. Overexpression and knock-down of WTAP in DLBCL cell lines, verified on mRNA and protein level served to analyze cell proliferation and apoptosis in DLBCL cell lines by flow cytometry. Finally, co-immunoprecipitation (Co-IP), IP, and GST-pull down assessed the interaction of WTAP with Heat shock protein 90 (Hsp90) and B-cell lymphoma 6 (BCL6) as well as determined the extend of its ubiquitinylation.
Results
WTAP protein levels were consistently upregulated in DLBCL tissues. WTAP promoted DLBCL cell proliferation and improved the ability to confront apoptosis, while knockdown of WTAP in DLBCL cell lines allowed a significant higher apoptosis rate after treatment with Etoposide, an anti-tumor drug. The stable expression of WTAP was depended on Hsp90. In line, we demonstrated that WTAP could form a complex with BCL6 via Hsp90 in vivo and in vitro.
Conclusion
WTAP is highly expressed in DLBCL, promoting growth and anti-apoptosis in DLBCL cell lines. WTAP is a client protein of Hsp90 and can appear in a complex with BCL6 and Hsp90 in DLBCL. Down-regulation of WTAP could improve the chemotherapeutic treatments in DLBCL.
Background:
In previous studies, the gram-positive firmicute genus Paenibacillus was found with significant abundances in nests of wild solitary bees. Paenibacillus larvae is well-known for beekeepers as a severe pathogen causing the fatal honey bee disease American foulbrood, and other members of the genus are either secondary invaders of European foulbrood or considered a threat to honey bees. We thus investigated whether Paenibacillus is a common bacterium associated with various wild bees and hence poses a latent threat to honey bees visiting the same flowers.
Results:
We collected 202 samples from 82 individuals or nests of 13 bee species at the same location and screened each for Paenibacillus using high-throughput sequencing-based 16S metabarcoding. We then isolated the identified strain Paenibacillus MBD-MB06 from a solitary bee nest and sequenced its genome. We did find conserved toxin genes and such encoding for chitin-binding proteins, yet none specifically related to foulbrood virulence or chitinases. Phylogenomic analysis revealed a closer relationship to strains of root-associated Paenibacillus rather than strains causing foulbrood or other accompanying diseases. We found anti-microbial evidence within the genome, confirmed by experimental bioassays with strong growth inhibition of selected fungi as well as gram-positive and gram-negative bacteria.
Conclusions:
The isolated wild bee associate Paenibacillus MBD-MB06 is a common, but irregularly occurring part of wild bee microbiomes, present on adult body surfaces and guts and within nests especially in megachilids. It was phylogenetically and functionally distinct from harmful members causing honey bee colony diseases, although it shared few conserved proteins putatively toxic to insects that might indicate ancestral predisposition for the evolution of insect pathogens within the group. By contrast, our strain showed anti-microbial capabilities and the genome further indicates abilities for chitin-binding and biofilm-forming, suggesting it is likely a useful associate to avoid fungal penetration of the bee cuticula and a beneficial inhabitant of nests to repress fungal threats in humid and nutrient-rich environments of wild bee nests.
Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case–control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case–control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.
This thesis considers a model of a scalar partial differential equation in the presence of a singular source term, modeling the interaction between an inviscid fluid represented by the Burgers equation and an arbitrary, finite amount of particles moving inside the fluid, each one acting as a point-wise drag force with a particle related friction constant.
\begin{align*}
\partial_t u + \partial_x (u^2/2) &= \sum_{i \in N(t)} \lambda_i \Big(h_i'(t)-u(t,h_i(t)\Big)\delta(x-h_i(t))
\end{align*}
The model was introduced for the case of a single particle by Lagoutière, Seguin and Takahashi, is a first step towards a better understanding of interaction between fluids and solids on the level of partial differential equations and has the unique property of considering entropy admissible solutions and the interaction with shockwaves.
The model is extended to an arbitrary, finite number of particles and interactions like merging, splitting and crossing of particle paths are considered.
The theory of entropy admissibility is revisited for the cases of interfaces and discontinuous flux conservation laws, existing results are summarized and compared, and adapted for regions of particle interactions. To this goal, the theory of germs introduced by Andreianov, Karlsen and Risebro is extended to this case of non-conservative interface coupling.
Exact solutions for the Riemann Problem of particles drifting apart are computed and analysis on the behavior of entropy solutions across the particle related interfaces is used to determine physically relevant and consistent behavior for merging and splitting of particles. Well-posedness of entropy solutions to the Cauchy problem is proven, using an explicit construction method, L-infinity bounds, an approximation of the particle paths and compactness arguments to obtain existence of entropy solutions. Uniqueness is shown in the class of weak entropy solutions using almost classical Kruzkov-type analysis and the notion of L1-dissipative germs.
Necessary fundamentals of hyperbolic conservation laws, including weak solutions, shocks and rarefaction waves and the Rankine-Hugoniot condition are briefly recapitulated.
Although many genes have been identified using high throughput technologies in endometriosis (ES), only a small number of individual genes have been analyzed functionally. This is due to the complexity of the disease that has different stages and is affected by various genetic and environmental factors. Many genes are upregulated or downregulated at each stage of the disease, thus making it difficult to identify key genes. In addition, little is known about the differences between the different stages of the disease. We assumed that the study of the identified genes in ES at a system-level can help to better understand the molecular mechanism of the disease at different stages of the development. We used publicly available microarray data containing archived endometrial samples from women with minimal/mild endometriosis (MMES), mild/severe endometriosis (MSES) and without endometriosis. Using weighted gene co-expression analysis (WGCNA), functional modules were derived from normal endometrium (NEM) as the reference sample. Subsequently, we tested whether the topology or connectivity pattern of the modules was preserved in MMES and/or MSES. Common and specific hub genes were identified in non-preserved modules. Accordingly, hub genes were detected in the non-preserved modules at each stage. We identified sixteen co-expression modules. Of the 16 modules, nine were non-preserved in both MMES and MSES whereas five were preserved in NEM, MMES, and MSES. Importantly, two non-preserved modules were found in either MMES or MSES, highlighting differences between the two stages of the disease. Analyzing the hub genes in the non-preserved modules showed that they mostly lost or gained their centrality in NEM after developing the disease into MMES and MSES. The same scenario was observed, when the severeness of the disease switched from MMES to MSES. Interestingly, the expression analysis of the new selected gene candidates including CC2D2A, AEBP1, HOXB6, IER3, and STX18 as well as IGF-1, CYP11A1 and MMP-2 could validate such shifts between different stages. The overrepresented gene ontology (GO) terms were enriched in specific modules, such as genetic disposition, estrogen dependence, progesterone resistance and inflammation, which are known as endometriosis hallmarks. Some modules uncovered novel co-expressed gene clusters that were not previously discovered.
The command area of the Rakh branch canal grows wheat, sugarcane, and rice crops in abundance. The canal water, which is trivial for irrigating these crops, is conveyed to the farms through the network of canals and distributaries. For the maintenance of this vast infrastructure; the end users are charged on a seasonal basis. The present water charges are severely criticized for not being adequate to properly manage the entire infrastructure. We use the residual value to determine the value of the irrigation water and then based on the quantity of irrigation water supplied to farm land coupled with the infrastructure maintenance cost, full cost recovery figures are executed for the study area, and policy recommendations are made for the implementation of the full cost recovery system. The approach is unique in the sense that the pricings are based on the actual quantity of water conveyed to the field for irrigating crops. The results of our analysis showed that the canal water is severely under charged in the culturable command area of selected distributaries, thus negating the plan of having a self-sustainable irrigation system.
Purpose: The metabolically most active lesion in 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic \(^{18}\)F-FDG PET.
Methods: Eighteen patients with progressive MTC underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated.
Results: The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3y (vs. low-risk group, OS=5.3y, 8/18, AUC=0.78, P=0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS=3.5y vs. low-risk group, OS=5y, 7/18, AUC=0.83, P=0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P=0.02, OS, n.s.).
Conclusions: The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction.