Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs.

Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders

A comparative study of different reaction models for turbulent methane/hydrogen/air combustion

Reaction modelling of methane/hydrogen combustion has two important aspects. First, such mixtures may be used in future in combustion devices like gas turbines and gas engines in the frame of the demand for efficient energy storage systems, where the amount of hydrogen in natural gas delivering systems may vary according to varying hydrogen production from renewable energies. Second, this can be an important aspect for safety, as such mixtures may occur in disastrous situations and calculations may allow the prediction of safety issues. Modelling of such mixed fuel combustion processes is non-trivial due to the involved preferential diffusion effects, coming from the different diffusivities of methane and hydrogen. In turbulent flame modelling, this topic is of special interest, as also thermo-diffusive instabilities and local influence of the local burning velocity near leading edges of the flame seem to be of importance even for highly turbulent flames. This numerical work deals therefore with a comparative study of five different turbulent combustion models - Bray-Moss-Libby, Linstedt-Vaos (LV), a modified version LV, Turbulent Flamespeed Closure, and Algebraic Flame Surface Wrinkling model - to the situation of turbulent methane/hydrogen/air flames. Validation is done with extensive experimental data obtained by a low swirl burner in the group by Cheng. Besides a basic case with pure methane/air, special emphasis is laid on flames with 40 to 100 % hydrogen content by volume. It is shown that for such methane/hydrogen fuel mixtures common reaction rate models are not sufficient where the fuel effects are included only via a laminar flame speed. Instead, a recently proposed reaction model with the incorporation of an effective Lewis number of the fuel mixture is found to work rather well. This is of both, practical as well as theoretical importance, as for the latter it confirms controversially discussed assumptions of the influence of preferential diffusion

Generalized Kac-Moody Algebras from CHL dyons

We provide evidence for the existence of a family of generalized Kac-Moody(GKM) superalgebras, G_N, whose Weyl-Kac-Borcherds denominator formula gives rise to a genus-two modular form at level N, Delta_{k/2}(Z), for (N,k)=(1,10), (2,6), (3,4), and possibly (5,2). The square of the automorphic form is the modular transform of the generating function of the degeneracy of CHL dyons in asymmetric Z_N-orbifolds of the heterotic string compactified on T^6. The new generalized Kac-Moody superalgebras all arise as different `automorphic corrections' of the same Lie algebra and are closely related to a generalized Kac-Moody superalgebra constructed by Gritsenko and Nikulin. The automorphic forms, Delta_{k/2}(Z), arise as additive lifts of Jacobi forms of (integral) weight k/2 and index 1/2. We note that the orbifolding acts on the imaginary simple roots of the unorbifolded GKM superalgebra, G_1 leaving the real simple roots untouched. We anticipate that these superalgebras will play a role in understanding the `algebra of BPS states' in CHL compactifications.Comment: LaTeX, 35 pages; v2: improved referencing and discussion; typos corrected; v3 [substantial revision] 44 pages, modularity of additive lift proved, product representation of the forms also given; further references adde

ACUTE TOXICITY STUDY AND THERAPEUTIC ACTIVITY OF MODIFIED ARJUNARISHTA ON ISOPROTERENOL-INDUCED MYOCARDIAL INFARCTION IN RATS

Objective: Ayurvedic formulation derived phytomedicine could bring a specific remedy against myocardial infarction (MI) without any side effects. Arjunarishta is a cardio tonic that nourishes and strengthens the myocardial muscle and promotes cardiac function. The preparation of Arjunarishta is modified and it does not involve fermentation. So it is alcohol-free and safe to all age groups. The study of acute toxicity and therapeutic activity of Modified Arjunarishta (MA) in isoproterenol (IPN) induced MI in rats was conducted to bring scientific evidence. Methods: Acute toxicity study: Mice are divided into three groups. Group I-control group; Group II and group III were test groups and they received an oral dose of 1000 mg/kg and 2000 mg/kg of MA, respectively. The experimental mice were observed for behaviour changes and clinical signs. Their body weight was also recorded. At the end of the experiment, blood sample was collected and glucose, liver function test (LFT), renal function test (RFT) and haematology parameters were analysed. Then they also subjected to gross pathological examination of all the major internal organs. Therapeutic study: Rats were divided into six groups. Group 1-normal control; Group 2 (induced)-IPN 85 mg/kg for the first two days; Group 3 (MA low dose)-received IPN as per group 2 followed by MA 200 mg/kg from the 3rd day to the end of the experiment; Group 4 (MA medium dose)-400 mg/kg; Group 5 (MA high dose)-600 mg/kg; Group 6 (Standard)-IPN as per group 2 followed by Arjunarishta 2 ml/kg body weight from the 3rd day to the end of the experiment. The collected serum sample was used for the estimation of myocardium-expressed proinflammatory cytokines. Heart tissue was homogenized for the estimation of calcium and lipid profile. Results: Acute toxicity: There were no signs of toxicity and no significant change in body weight. The value of glucose, RFT, LFT and haematological parameters are remained normal. Histopathological report showed normal architecture. Therapeutic activity: In the heart samples, significantly (p<0.001) increased cholesterol, Triglyceride (TGL), Free Fatty acids (FFA) and calcium in IPN induced groups was noted. They are all significantly (p<0.001) decreased in MA administrated groups of three different groups. In serum sample, a significantly (p<0.001) increased cytokines of Tumor necrosis factor α (TNFα), Interlukins (IL-6, IL-1α and IL-1β) in IPN induced rats was recorded were as they get significantly (p<0.001) decreased in MA administrated groups of three different doses. Conclusion: The results obtained from the acute toxicity experiment concluded that MA was found to be safe for oral administration. The therapeutic experiment results clearly emphasize the beneficial action of MA against IPN induced MI in rats

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

The role of primary cemented total hip arthroplasty in the management of fractures of the neck of femur in the elderly population

Background: Femoral neck fractures are common injuries in the elderly population and are associated with high rates of morbidity and mortality. The aim of surgical intervention in these elderly patients is to restore them to the pre-fracture status as rapidly as possible. The aim of this study was to evaluate the role of total hip arthroplasty as a primary option in the management of these fractures and to compare the results with studies of other authors as available in literature.Methods: 45 patients with femoral neck fractures treated with cemented total hip arthroplasty were studied from January 2011 to January 2013 and were followed up for a minimum period of two years.Results: There were 18 males and 27 females ranging from 60 to 75 years of age. Mean age was 64.6 years. Majority (80%) of the fractures were completely displaced, Garden type 4 fractures followed by type 3 in 20% of cases. The most common mode of injury was a simple slip and fall. Excellent results were seen in 17 patients, good results in 24 patients and fair results in 4 patients. No poor results were seen. Conclusions: Cemented total hip arthroplasty is a very useful procedure for the primary treatment of femoral neck fractures in elderly patients. This procedure markedly improves the functional status of the patients and gives good functional results

Multiplexed identification, quantification and genotyping of infectious agents using a semiconductor biochip

The emergence of pathogens resistant to existing antimicrobial drugs is a growing worldwide health crisis that threatens a return to the pre-antibiotic era. To decrease the overuse of antibiotics, molecular diagnostics systems are needed that can rapidly identify pathogens in a clinical sample and determine the presence of mutations that confer drug resistance at the point of care. We developed a fully integrated, miniaturized semiconductor biochip and closed-tube detection chemistry that performs multiplex nucleic acid amplification and sequence analysis. The approach had a high dynamic range of quantification of microbial load and was able to perform comprehensive mutation analysis on up to 1,000 sequences or strands simultaneously in <2 h. We detected and quantified multiple DNA and RNA respiratory viruses in clinical samples with complete concordance to a commercially available test. We also identified 54 drug-resistance-associated mutations that were present in six genes of Mycobacterium tuberculosis, all of which were confirmed by next-generation sequencing

Botnet-based Distributed Denial of Service (DDoS) Attacks on Web Servers: Classification and Art

Botnets are prevailing mechanisms for the facilitation of the distributed denial of service (DDoS) attacks on computer networks or applications. Currently, Botnet-based DDoS attacks on the application layer are latest and most problematic trends in network security threats. Botnet-based DDoS attacks on the application layer limits resources, curtails revenue, and yields customer dissatisfaction, among others. DDoS attacks are among the most difficult problems to resolve online, especially, when the target is the Web server. In this paper, we present a comprehensive study to show the danger of Botnet-based DDoS attacks on application layer, especially on the Web server and the increased incidents of such attacks that has evidently increased recently. Botnet-based DDoS attacks incidents and revenue losses of famous companies and government websites are also described. This provides better understanding of the problem, current solution space, and future research scope to defend against such attacks efficiently

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry