Transcriptome-based reconstructions from the murine knockout suggest involvement of the urate transporter, URAT1 (slc22a12), in novel metabolic pathways.

URAT1 (slc22a12) was identified as the transporter responsible for renal reabsorption of the medically important compound, uric acid. However, subsequent studies have indicated that other transporters make contributions to this process, and that URAT1 transports other organic anions besides urate (including several in common with the closely related multi-specific renal organic anion transporters, OAT1 (slc22a6) and OAT3 (slc22a8)). These findings raise the possibility that urate transport is not the sole physiological function of URAT1. We previously characterized mice null for the murine ortholog of URAT1 (mURAT1; previously cloned as RST), finding a relatively modest decrement in urate reabsorptive capacity. Nevertheless, there were shifts in the plasma and urinary concentrations of multiple small molecules, suggesting significant metabolic changes in the knockouts. Although these molecules remain unidentified, here we have computationally delineated the biochemical networks consistent with transcriptomic data from the null mice. These analyses suggest alterations in the handling of not only urate but also other putative URAT1 substrates comprising intermediates in nucleotide, carbohydrate, and steroid metabolism. Moreover, the analyses indicate changes in multiple other pathways, including those relating to the metabolism of glycosaminoglycans, methionine, and coenzyme A, possibly reflecting downstream effects of URAT1 loss. Taken together with the available substrate and metabolomic data for the other OATs, our findings suggest that the transport and biochemical functions of URAT1 overlap those of OAT1 and OAT3, and could contribute to our understanding of the relationship between uric acid and the various metabolic disorders to which it has been linked

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism.

Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood

Effect of mifepristone in cervical ripening for induction of labour

Background: Mifepristone is potentially a method of inducing labour in late pregnancy by increasing uterine contractility and by increasing the sensitivity of the uterus to the actions of prostaglandins. Present study was done to portrait the beneficial of mifepristone induction of labour. The objective was to study the effect of mifepristone in induction of labour with the outcome of induction of labour (IOL).Methods: 100 patients (term) were included, after their informed consent. Patients were categorized by BISHOP SCORE at the beginning of induction for comparison of BS, mode of delivery, induction delivery interval (IDI). Women undergoing induction with RU486 (200mg PO) were grouped in one and those with placebo control group into another. Statistical analysis of categorical variables was done.Results: Rate of successful IOL or vaginal delivery was 76% in study group and only 36% in control group. After induction with mifepristone for cervical ripening in study group 76% patient who had cervical score 8 within 24 hours, whereas in control group 2% female’s cervical score was>8. Among the babies, 44% in the control group required baby unit admission as compared to 36% in the study group.Conclusions: In the present study, the women who were induced with mifepristone 200 mg per orally showed drastic improvement in cervical score within 24-48 hours and decreased the cesarean rate in the study group and amount of dose requirement of augmentation of labour with Misoprostol or Oxytocin, lesser NICU admission and maternal complication

Role of preoperative sublingual misoprostol in reducing need of analgesia and anaesthesia for gynaecological procedures in rural hospital

Background: Many of gynaecological procedures require dilatation of cervix which may cause complications like excessive pain, cervical damage, creation of false tract and uterine perforation. Most of these may be done as outpatient procedures, which may reduce anaesthetic complications and decrease hospital stay. Misoprostol is a prostaglandin E1 which is proven to be effective in cervical priming hence reducing the fore mentioned complications.Methods: The study was randomized control trial followed a single bind style for two parallel groups. There were two groups, study group (n=100) and control group (n=100). The patients were recruited from the indoor as well as OPD requiring intrauterine procedure (viz D&C, hysteroscopy, HSG). The women of misoprostol group received, 200 microgram of misoprostol sublingualy and the women of placebo group received l mg folic acid 2 hours prior to the intrauterine procedure. Cervical dilatation, time required for the dilatation, cervical resistance, general experience of the patient, side effects, need of anaesthesia and complications were studied.Results: In present study mean post drug cervical dilatation was 4.08 ± 0.88 in study group which was more than control group 2.08 ± 0.27. It was statistically significant by using student‘t’ test as p value <0.05. It was found that preoperative cervical dilatation was mostly equal in both study group and control group. In the present study it was found that mean time required for cervical dilatation was 36.00 ± 11.19 in study group which was less than in control group 75.50 ± 7.43. It was statistically significant by using ‘t’ test as p value <0.05. Cervical dilatation was required in 25% women in study group and 100% in control group. Anaesthesia was required in 25% women in study group and 100% in control group. Side effects regarding bleeding after post drug cervical dilatation in study group were statistically different as compared to control group. No complications were present in present study.Conclusions: Misoprostol PGE1 is commercially widely available, safe and cost effective drug which can be used as a cervical ripening/priming agent before all the gynaecological procedures in non-pregnant women as it increases the cervical dilatation and decreases the need of analgesia or anaesthesia

A physical mechanism for North Atlantic SST influence on the Indian summer monsoon

A link between the Atlantic Multidecadal Oscillation (AMO) and multidecadal variability of the Indian summer monsoon rainfall is unraveled and a long sought physical mechanism linking Atlantic climate and monsoon has been identified. The AMO produces persistent weakening (strengthening) of the meridional gradient of tropospheric temperature (TT) by setting up negative (positive) TT anomaly over Eurasia during northern late summer/autumn resulting in early (late) withdrawal of the south west monsoon and persistent decrease (increase) of seasonal monsoon rainfall. On inter-annual time scales, strong North Atlantic Oscillation (NAO) or North Annular mode (NAM) influences the monsoon by producing similar TT anomaly over Eurasia. The AMO achieves the interdecadal modulation of the monsoon by modulating the frequency of occurrence of strong NAO/NAM events. This mechanism also provides a basis for explaining the observed teleconnection between North Atlantic temperature and the Asian monsoon in paleoclimatic proxies

Collaboration Between the National Tuberculosis Programme and a Non Governmental Organisation in TB/HIV Care at a District level: Experience from Tanzania.

The increase in tuberculosis and HIV/AIDS patients in many countries in Africa including Tanzania, is outstripping the ability of public health services to cope. This calls for a closer collaboration between tuberculosis programmes and other stakeholders involved in HIV/AIDS care. To determine the feasibility of establishing collaboration between the tuberculosis programme and an NGO in TB/ HIV care at a district level in Tanzania. Quantitative and qualitative study designs involving TB as well as HIV suspects and patients together with health workers, were conducted between December, 2001 and September, 2002. A total of 72 patients and 28 key informants were involved. The collaboration was in the following areas; voluntary counselling and testing for HIV, diagnosis and treatment of TB, referral and follow up of patients and suspects, home based care, psychological support and training. Both the tuberculosis programme and NGO benefited from the collaboration. TB case detection among PLWA increased more than three folds and TB treatment was integrated in home based care of NGO. The main barriers identified in this study were; poor communication, poor referral system and lack of knowledge and skills among health staff. The study has shown that it is possible for a tuberculosis programme and a non governmental organisation to collaborate in TB/HIV care. The study has also identified potential areas of collaboration and barriers that needed to be overcome in order to provide such comprehensive services at a district level

Personalized Whole-Cell Kinetic Models of Metabolism for Discovery in Genomics and Pharmacodynamics

SummaryUnderstanding individual variation is fundamental to personalized medicine. Yet interpreting complex phenotype data, such as multi-compartment metabolomic profiles, in the context of genotype data for an individual is complicated by interactions within and between cells and remains an unresolved challenge. Here, we constructed multi-omic, data-driven, personalized whole-cell kinetic models of erythrocyte metabolism for 24 healthy individuals based on fasting-state plasma and erythrocyte metabolomics and whole-genome genotyping. We show that personalized kinetic rate constants, rather than metabolite levels, better represent the genotype. Additionally, changes in erythrocyte dynamics between individuals occur on timescales of circulation, suggesting detected differences play a role in physiology. Finally, we use the models to identify individuals at risk for a drug side effect (ribavirin-induced anemia) and how genetic variation (inosine triphosphatase deficiency) may protect against this side effect. This study demonstrates the feasibility of personalized kinetic models, and we anticipate their use will accelerate discoveries in characterizing individual metabolic variation

Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity.

Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512-50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J &lt; C57BL/6J)-a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes-heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J &lt; C57BL/6J; p 4.2 x 10-15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders

Model Based Analysis and Test Generation for Flight Software

We describe a framework for model-based analysis and test case generation in the context of a heterogeneous model-based development paradigm that uses and combines Math- Works and UML 2.0 models and the associated code generation tools. This paradigm poses novel challenges to analysis and test case generation that, to the best of our knowledge, have not been addressed before. The framework is based on a common intermediate representation for different modeling formalisms and leverages and extends model checking and symbolic execution tools for model analysis and test case generation, respectively. We discuss the application of our framework to software models for a NASA flight mission