Cytosolic sphingolipids and lysosome reactivation in neurodegenerative diseases

Glucosylceramide (GlcCer) is one of the simplest glycosphingolipids (GSLs) synthesized at the cytosolic face of cis-Golgi and translocated to the plasma membrane and organelle lumen. The glucocerebrosidases degrade GlcCer in the cytosol and lysosome. GlcCer has been suggested to be an activator of vATPase, leading to proper endolysosomal acidification. Lysosomal storage disorders (LSDs), are caused by the defective activity of lysosomal proteins, including the accumulation of unmetabolized substrates. The accumulation of substrates is thought to initiate a complex pathogenic cascade that is responsible for disease pathology, Chapter1 firstly summarizes the synthesis of glycolipids and their transportation to lysosomes for degradation and recycling back into the Golgi; however, in the case of LSDs, this is defective. Furthermore, it discusses how impaired endolysosomal acidification and lipid imbalance can be linked and common to LSDs. Chapter 2 depicts decreased lysosomal acidification and increased size in Gaucher/Parkinson's and various other LSD patient fibroblasts. Then it studies whether these defects can be corrected by altering cytosolic GlcCer. Chapter 3 shows decreased MCS between the ER/lysosomes, increased MCS between lysosomes/ the mitochondria in NPCD, and investigates if increasing cytosolic GlcCer can correct these defects. Furthermore, it tests a bank of putative cholesterol transport inhibitors in NPCD based on reports of high cholesterol levels contributing to mitochondrial dysfunction. A chemoproteomics approach has found several proteins that bind ceramides and glycolipids. Chapter 4 sought to confirm the interactions between ceramides/glycolipids and their binding proteins using molecular modelling and gene expression analysis.Schlumberger Foundation faculty for the future

Automatic Blood Vessel Extraction of Fundus Images Employing Fuzzy Approach

Diabetic Retinopathy is a retinal vascular disease that is characterized by progressive deterioration of blood vessels in the retina and is distinguished by the appearance of different types of clinical lesions like microaneurysms, hemorrhages, exudates etc. Automated detection of the lesions plays significant role for early diagnosis by enabling medication for the treatment of severe eye diseases preventing visual loss. Extraction of blood vessels can facilitate ophthalmic services by automating computer aided screening of fundus images. This paper presents blood vessel extraction algorithms with ensemble of pre-processing and post-processing steps which enhance the image quality for better analysis of retinal images for automated detection. Extensive performance based evaluation of the proposed approaches is done over four databases on the basis of statistical parameters. Comparison of both blood vessel extraction techniques on different databases reveals that fuzzy based approach gives better results as compared to Kirsch’s based algorithm. The results obtained from this study reveal that 89% average accuracy is offered by the proposed MBVEKA and 98% for proposed BVEFA

Retinal blood vessel localization to expedite PDR diagnosis

Ophthalmologist relies on the retinal fundus image segmentation for accurate diagnosis of Diabetic Retinopathy caused due to prolonged deterioration in retinal blood vessels. Blood vessel and optical disc localization determines the vascular alterations helpful in identifying retinal diseases with accurate identification of pathologies like microaneurysms and exudates. This work comprises evaluation of proposed Optical Disc Segmentation and blood vessel localization techniques followed by a statistical analysis using three fractal dimensions; box count, information and correlation. Fractal dimensions explored are beneficial for Proliferative Diabetic Retinopathy (PDR) diagnosis as its value for vascular structures increases with increasing level of PDR. Two benchmark fundus image databases, DRIVE and STARE were evaluated by utilizing shape and fractal features for performance validation and average accuracies of 96.79% and 95.68% were achieved for extracted blood vessels using proposed approach

Cytosolic Glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease

A new paradigm for Niemann-Pick C disease is presented where lysosomal storage leads to a deficit in cytoplasmic glucosylceramide (GlcCer) where it performs important functions. Previously it had been reported that Gaucher cells have defective endolysosomal pH. GlcCer also accumulates in Niemann-Pick C disease and also shows this defect. Niemann-Pick C cells were found to have reduced cytoplasmic glucosylceramide (GlcCer) transport. Inhibiting cytoplasmic glucocerebrosidase (GBA2), increased GlcCer, decreased endolysosomal pH in normal cells, reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking and increased expression of vATPase a subunit in Niemann-Pick C fibroblasts. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic GlcCer which are reduced in NPC disease. This work consequently suggests GBA2 and vATPase as new therapeutic targets in Niemann-Pick C and related neurodegenerative diseases. The work was in collaboration with colleagues in the Netherlands and Leicester University. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. NPCD fibroblasts and cells treated with U18666A also show disrupted targeting of fluorescent lipid BODIPY-LacCer to high pH vesicles. Inhibiting non-lysosomal glucocerebrosidase (GBA2) reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking in NPCD fibroblasts. GBA2 KO cells also show decreased endolysosomal pH. NPCD fibroblasts also show increased expression of a key subunit of the lysosomal proton pump vATPase on GBA2 inhibition. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic-facing GlcCer, which are reduced in NPC disease

Placenta accreta not previa: a rare case report of placenta accreta in an unscarred uterus

Placenta accreta spectrum disorders are usually associated with direct surgical scar such as caesarean delivery, surgical termination of pregnancy, Dilatation and curettage, Myomectomy, Endometrial resection and Asherman’s syndrome. It can also be associated with non-surgical scar and uterine anomalies. Rarely it can be encountered in unscarred uterus. Mrs X, 35-year female, unbooked patient, G7P2L2A4 with nine months of amenorrhoea reported in emergency of RML Hospital on 30/07/2019 with history of labour pains since 2 days. Patient gave history of four dilatation and curettage for incomplete abortion. On examination patient was found to be severely anaemic (Hb -6 gm). 2 Packed RBC were transfused preoperatively. There was no progress in labour beyond 6 cm for 4 hours. Patient was thus taken for LSCS for NPOL, with blood on flow. Intraoperatively, after delivery of the baby placenta which was fundo-posterior did not separate. In view of parity and morbidly adherent placenta (clinical grade III), subtotal hysterectomy was done. Patient was transfused 4 PRBC, 4 FFP and 2 platelets. Uterus with placenta in situ was sent for histopathology. Patient was in ICU for 2 days and recovered well. Post-operative period was uneventful. Placenta accreta is defined as abnormal trophoblast invasion of whole or a part of placenta into myometrium of uterine wall. Caesarean delivery is associated with increased risk of placenta accrete and the risk increases with each caesarean section, from 0.3% in woman with one previous caesarean delivery to 6.47% for woman with five or more caesarean deliveries. Placenta accreta spectrum disorders occur in 3% of woman diagnosed with placenta previa and no prior caesarean. In the developing world, the obstetrician should be prepared to encounter un diagnosed placenta accrete even in absence of previous LSCS. Curretage following MTP is also a risk factor, so vigourous currettage should be avoided to prevent endometrial damage

A rare case of cervical fibroid presenting as retained placenta with postpartum hemorrhage

Fibroids during pregnancy are often asymptomatic but sometimes may lead to various complications and unusual presentations. We are reporting an unusual case of cervical fibroid during pregnancy that presented as retained placenta with postpartum hemorrhage following a full term normal vaginal delivery

Uterine primitive neuroectodermal tumor with adenosarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Primitive neuroectodermal tumor of the uterus is extremely rare. They occur as either pure primitive neuroectodermal tumors or admixed with neoplasms of mullerian origin.</p> <p>Case presentation</p> <p>A case of uterine primitive neuroectodermal tumor with adenosarcoma in a 50-year-old Asian Indian woman is presented. Histologically, the neoplasm displayed perivascular pseudorosettes and occasional Homer-Wright rosettes. A strong positivity for neuronspecific enolase and synaptophysin was noted, while chromogranin and CD99 were negative. Merging imperceptibly with the neuroectodermal components were the areas of adenosarcoma.</p> <p>Conclusion</p> <p>To the best of our knowledge, this report represents the second case of a uterine primitive neuroectodermal tumor with an admixed adenosarcoma.</p

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI