Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule.

Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis

TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite Toxoplasma gondii

New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. IMPORTANCE We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases

Deciphering reward-based decision-making in schizophrenia: a meta-analysis and behavioral modeling of the Iowa Gambling Task

Background: Patients with schizophrenia (SZP) have been reported to exhibit impairments in reward-based decision-making, but results are heterogeneous with multiple potential confounds such as age, intelligence level, clinical symptoms or medication, making it difficult to evaluate the robustness of these impairments. Methods: We conducted a meta-analysis of studies comparing the performance of SZP and healthy controls (HC) in the Iowa Gambling Task (IGT) as well as comprehensive analyses based on subject-level data (n = 303 SZP, n = 188 HC) to investigate reward-based decision-making in SZP. To quantify differences in the influence of individual deck features (immediate gain, gain frequency, net loss) between SZP and HC, we additionally employed a least-squares model. Results: SZP showed statistically significant suboptimal decisions as indicated by disadvantageous deck choices (d from 0.51 to −0.62) and lower net scores (d from −0.35 to −1.03) in a meta-analysis of k = 29 samples (n = 1127 SZP, n = 1149 HC) and these results were confirmed in a complementary subject-level analysis. Moreover, decision-making in SZP was characterized by a relative overweighting of immediate gain and net losses and an underweighting of gain frequency. Moderator analyses revealed that in part, decision-making in the IGT was moderated by intelligence level, medication and general symptom scores. Conclusion: Our results indicate robust impairments in reward-based decision-making in SZP and suggest that decreased cognitive resources, such as working memory, may contribute to these alterations

Assessment of Impact of Sewage, Industrial Drains and Juke Piles on Krishna River Canal Networks using MATLAB in Vijayawada, Andhra Pradesh, India.

A systematic study was carried out to assess the water quality at downstream of Krishna river canal networks, which are now facing a severe problem of pollution in Vijayawada. Deterioration of Krishna River canal networks was observed because of the disposal of untreated municipal and industrial sewage through various sewers. During the field visit and sample collection, we observed that time and money for labour force and huge investments for chemicals were needed for continuous sampling laboratory work. Literature reviews state that using systems analysis techniques to plan water pollution control is the foundation for water quality management. Here an attempt was made to develop a water quality model for Krishna River canal networks in Vijayawada by applying Quadratic regression using curve fitting in MATLAB. The result showed that the stimulation is well with the analytical observation, and this model can be used to study other parameters, as well as to reduce the time for laboratory analysis

Study of Capacitor & Diode Aging effects on Output Ripple in Voltage Regulators and Prognostic Detection of Failure

Objectives: To design and simulate a buck converter and detector circuit which can prognostically indicate the power supply failure. Failure of Aluminium Electrolytic Capacitor (AEC) is considered as the parameter causing the power supply failure. To analyse variation of output ripple voltage due to possible changes in the Equivalent Series Resistance (ESR) and effective capacitance of the capacitor and design a detector to detect the failure of power supply prognostically.Methods:  A DC-DC buck converter in SMPS topology is designed by assuming an input voltage of 12V with 3 volts possible fluctuations and an output voltage of 3.3 volts is desired. Simulation is carried out to measure the variation in output ripple voltage caused due to aging of electrolytic capacitor using TINA by Texas Instruments. A detector is also designed to compare the ripple voltage and a predefined threshold voltage so as to indicate the possible failure of Switched Mode Power Supply (SMPS) well in advance by monitoring the output ripple increase.Novelty:    Having a fault tolerant power supply is very important in safety critical applications. Here by monitoring the output ripple variation, the degradation of AEC is predicted by calculating the ESR and capacitance variation. This simple yet effective prognostic detection will support in the design of fault tolerant power supplies.Highlight: It is found that, the ripple at the output increases with aging of the electrolytic capacitor, as with time the equivalent capacitance decreases and Equivalent Series Resistance (ESR) of the capacitor increases. The designed detector output is found to prognostically indicate the failure of SMPS

Single Photon Counting UV Solar-Blind Detectors Using Silicon and III-Nitride Materials

Ultraviolet (UV) studies in astronomy, cosmology, planetary studies, biological and medical applications often require precision detection of faint objects and in many cases require photon-counting detection. We present an overview of two approaches for achieving photon counting in the UV. The first approach involves UV enhancement of photon-counting silicon detectors, including electron multiplying charge-coupled devices and avalanche photodiodes. The approach used here employs molecular beam epitaxy for delta doping and superlattice doping for surface passivation and high UV quantum efficiency. Additional UV enhancements include antireflection (AR) and solar-blind UV bandpass coatings prepared by atomic layer deposition. Quantum efficiency (QE) measurements show QE > 50% in the 100–300 nm range for detectors with simple AR coatings, and QE ≅ 80% at ~206 nm has been shown when more complex AR coatings are used. The second approach is based on avalanche photodiodes in III-nitride materials with high QE and intrinsic solar blindness

Investigation on the Flexural Behaviour of Steel Cold Formed Built up Sections

For the past few decades, substantial progress has been made in material properties and construction methodology, which demands in need of development of stronger and lighter members in structural steel applications. The demands of increase in strength and reduction in weight of sections leads to development of structures which are slender and also stability plays a major role in design. The main goal of this study is to develop and investigate the performance of build-up steel I beam sections with corrugated webs. This study focuses on analysis of flexural behaviour and failure modes of plain web, rectangular, trapezoidal web and triangular web in beams by experimental investigations using three point load test and analytical investigations using ANSYS software. From experimental and analytical analysis, triangular corrugated web beam perform better compared to all section. The experimental results obtained are more similar to analytical results obtained by ANSYS software with only slight deviations. The failure modes in both experimental investigation and analytical analysis are similar

Comparison of Salbutamol Administration by Metered- Dose Inhaler and Spacer with Nebuliser in Adults with Acute Asthma

INTRODUCTION: In the modern era, Bronchial asthma is a disease that is becoming a major health issue in many developing countries. Increased urbanisation may have modified the traditionally low incidence of bronchial asthma in the third world. Depressed socioeconomic conditions may supersede exposure to traffic-related pollution as a factor associated with asthma hospitalization. Although the incidence of new cases of asthma has decreased in recent years, the prevalence of asthma morbidity continues to be a significant clinical and public health issue. The measures of morbidity include the need for urgent medical care and high-dose asthma medications due to uncontrolled asthma symptoms. The word asthma means “panting” or “breathing hard”, it is derived from greek word “aazein”. Asthma is more a clinical diagnosis than a laboratory diagnosis. Bronchial asthma and the resulting spasm was first described by Greek physician Hippocrates in 460-357 BC. That obstruction to bronchial airways lead to symptoms of asthma was put forth by Greco-Roman physician Galen in 130-201 BC. The occurrence of symptoms does not simply mean constriction of airways, it indicates an underlying inflammatory process which occurs as a result of hyperresponsiveness of airways triggered by an allergen. This was discovered by asthma researchers in 1960. AIM AND OBJECTIVES: To analyse the efficacy of salbutamol administered by a nebuliser compared to metered- dose inhaler and spacer in adults with acute Asthma. MATERIALS AND METHODS: In-patients of medical ward in GRH who have clinical features suggestive of bronchial asthma above 13 years of age were prospectively enrolled after informed consent. The diagnosis was based on Pulmonary function tests showing decrease in expiratory flow rates : • Reduction in forced expiratory volume over 1 sec (FEV1) and a proportionally smaller reduction in the forced vital capacity (FVC) and decreased FEV1/FVC ratio (generally 20. • Reversibility test as determined by increase in Peak Expiratory Flow Rate (PEFR) more than twenty percent ; and more than twelve percent or 200-mL increase in Forced Expiratory Volume in 1 second115 minutes after an inhaled short-acting Beta2-agonist. Exclusion Criteria: 1. Patients <13 yrs age. 2. Patients with acute respiratory tract infections, COPD and restrictive lung disease. 3. Patients with heart failure, renal failure and hepatic failure Blood samples were collected for estimation of Blood urea, Serum creatinine and Liver function tests. ECG, ECHO, X RAY CHEST PA view were taken. METHODS: Fifty two patients with acute asthma in the medical ward of Government Rajaji Hospital Madurai were enrolled in the study. All the fifty two patients in the study fulfilled the criteria of American Thoracic Society. Patients above the age of thirteen years with Peak Expiratory flow rates, Forced Expiratory Volume in 1 second below fifty percent of predicted value were eligible for the study. All the patients were on regular treatment with bronchodilators and steroids. A total of 52 patients with acute Bronchial asthma who received salbutamol therapy participated in the study. The patients were divided into 2 groups: 26 (50%) patients in the MDI-Spacer group and 26 (50%) patients in the Nebuliser group. The baseline characteristics of over all cohort were expressed in percentage. Age distribution was 17.3% (40yrs) as shown in Table 1.Sex distribution was males (63.4%) and females( 36.6%) as shown in Table 2. Duration of illness was 19.2% (10yrs), 50% (11-20 yrs), 25% (21-30yrs) and 5.8% (>30yrs) as shown in Table 3. Table 4. shows 75% of patients with seasonal variation and 25% with no seasonal variation. Diurnal variation was demonstrated in 76.9% of patients but not in the rest 23.1%, as illustrated in Table 5. As per Table 6, a positive history of allergy is seen in 80.8% and is negative in 19.2%. As shown in Table 7, 59.6% of patients have a positive family history and 40.4% do not. 26.9% of patients had a history of smoking and 73.1% were non smokers (Table 8). The frequency of illness was 38.5% (daily), 21.1% (2/ week) as depicted. CONCLUSION: 1. Base line characters were not comparable in the study. The patients were equally divided into two groups for better comparison. 2. PEFR improvement was significant at 30 mts and at end of treatment with the MDI-Spacer group than the nebulised group. 3. FEV1 improvement was also significant at 30 mts and at end of treatment with the MDI-Spacer group than the nebulised group. 4. FVC improvement was also significant at 30 mts and at end of treatment with the MDI-Spacer group than the nebulised group. 5. For oxygen saturation, the magnitude of improvement was significant at 30 mts in the spacer group, but at the end of treatment the improvements were similar in both the groups. 6. Heart rate and respiratory rate improvement was present in both groups and were similar in both at 30 mts and at the end of treatment. 7. Clinical improvement was achieved even at a lower dosage in the MDI-spacer group compared to nebuliser group. Salbutamol administration by metered dose inhaler and spacer is as efficacious as nebuliser in adults with acute asthma. Now-a-days Metered Dose Inhaler and Spacer is the best alternative to nebuliser in acute asthma

A Study on the Great Saphenous Vein including it’s Surgical and Radiological implications.

Great saphenous vein, the vessel of surgical significance, has been studied in detail by dissection and radiological methods. The formation, length and diameter of Great saphenous vein, its level of termination, drainage pattern, its relation with adjacent important structures in detail have been observed and co-related with the findings of already existing studies. The following conclusions are derived from these parameters. In most of the cases the formation of Great saphenous vein was by the union of medial end of dorsal venous arch with medial marginal vein. The mean total length of the Great saphenous vein is 69.08 cm. The average diameter of Great saphenous vein in thigh is 0.29 cm and that in the leg is 0.38 cm. The sapheno-femoral junction on an average was 2.9 cm from the midpoint of inguinal ligament. In most cases, the sapheno-femoral junction was located 3 to 5 cm from pubic tubercle. The average distance from anterior superior iliac spine to saphenofemoral junction is 10.22 cm. High proportion of cases display the drainage pattern with superficial circumflex iliac vein, superficial epigastric vein and lateral accessory saphenous vein forming a common trunk and terminating at fossa ovalis. In 1/3 of instances, the superficial external pudendal vein drains directly into Great saphenous vein. External pudendal artery passed anterior to termination of Great saphenous vein in significant proportion of cases. Most commonly the Great saphenous vein and the saphenous nerve came close few cm below the knee, after which they were in separable. Average no of perforating veins in the thigh is 1.14. Average no of valves in the Great saphenous vein is 8.2. In 6 foetal specimens, the sapheno femoral junction is found to be on an average 2.78 cm from the anterior superior iliac spine, 0.96 cm from pubic tubercle, 0.68 cm from mid point of inguinal ligament Based on this study, I hereby conclude that Great saphenous vein has complex variations in length, drainage pattern and its relationship with external pudendal artery and saphenous nerve. Surgery for varicose veins and saphenous vein grafting require a thorough knowledge of variations in Great saphenous vein. Hence this study will be of use to surgeons

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts