The carboxyl terminal mutational hotspot of the ciliary disease protein RPGRORF15 (retinitis pigmentosa GTPase regulator) is glutamylated in vivo

Mutations inRPGR(ORF15)(retinitis pigmentosa GTPase regulator) are a major cause of inherited retinal degenerative diseases. RPGR(ORF15)(1152 residues) is a ciliary protein involved in regulating the composition and function of photoreceptor cilia. The mutational hotspot in RPGR(ORF15)is an unusual C-terminal domain encoded by exon ORF15, which is rich in polyglutamates and glycine residues (Glu-Gly domain) followed by a short stretch of basic amino acid residues (RPGR(C2)domain; residues 1072-1152). However, the properties of the ORF15-encoded domain and its involvement in the pathogenesis of the disease are unclear. Here we show that RPGR(ORF15)is glutamylated at the C-terminus, as determined by binding to GT335, which recognizes glutamylated substrates. This reactivity is lost in two mouse mutants ofRpgr, which do not express RPGR(ORF15)due to disease-causing mutations in exon ORF15. Our results indicate that RPGR(ORF15)is posttranslationally glutamylated in the Glu-Gly domain and that the GT335 antibody predominantly recognizes RPGR(ORF15)in photoreceptor cilia

Adaptive Estimation of Line-of-sight Rate Measurement from a Radio Frequency Seeker

The line-of-sight (LOS) rate output from a radio frequency (RF) seeker is widely used during the homing phase guidance of a tactical missile: The LOS rate is noisy and needs to be filtered.The application of an adaptive Kalman filter for the L.OS rate state estimation has been studied. This filter requires minimal a priori knowledge about technical parameters of the seeker. It isalso capable of estimating the variable noise statistics

Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition

Cilia regulate several developmental and homeostatic pathways that are critical to survival. Sensory cilia of photoreceptors regulate phototransduction cascade for visual processing. Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are a prominent cause of severe blindness disorders due to degeneration of mature photoreceptors. However, precise function of RPGR is still unclear. Here we studied the involvement of RPGR in ciliary trafficking by analyzing the composition of photoreceptor sensory cilia (PSC) in Rpgr(ko) retina. Using tandem mass spectrometry analysis followed by immunoblotting, we detected few alterations in levels of proteins involved in proteasomal function and vesicular trafficking in Rpgr(ko) PSC, prior to onset of degeneration. We also found alterations in the levels of high molecular weight soluble proteins in Rpgr(ko) PSC. Our data indicate RPGR regulates entry or retention of soluble proteins in photoreceptor cilia but spares the trafficking of key structural and phototransduction-associated proteins. Given a frequent occurrence of RPGR mutations in severe photoreceptor degeneration due to ciliary disorders, our results provide insights into pathways resulting in altered mature cilia function in ciliopathies

Prenylated retinal ciliopathy protein RPGR regulates ciliary localization of Joubert Syndrome-associated protein INPP5E in cooperation with PDE6

Ciliary dysfunction is an underlying cause of severe human disorders (collectively called ciliopathies), such as retinitis pigmentosa (RP), Joubert Syndrome (JBTS), and Bardet-Biedl Syndrome. Ciliary proteins form distinct functional networks for localization to cilia as well as regulation of ciliary function. However, not much is known about the mechanism of ciliary localization and function of RPGR (retinitis pigmentosa GTPase regulator), a ciliary protein frequently associated with RP worldwide. Using tandem mass spectrometry analysis, we show that RPGR interacts with two JBTS-associated proteins: PDE6Π (delta subunit of Phosphodiesterase; a prenyl-binding protein) and INPP5E (inositol polyphosphate-5-phosphatase 5E; a ciliary cargo). Whereas PDE6Π binds in a prenylation-dependent manner to the C-terminus of RPGR, INPP5E associates with the N-terminus of RPGR. Prenylation and interaction of RPGR with PDE6Π are critical for its localization to cilia. We further show that loss of RPGR results in reduced amount of INPP5E in cilia of fibroblasts and in photoreceptor outer segment, a modified sensory cilium. Overall, our results suggest that RPGR, in complex with PDE6D, regulates the trafficking of ciliary cargo INPP5E and implicate reduction in ciliary INPP5E in the pathogenesis of RPGR-ciliopathy

A study of adverse drug reaction profile of tuberculosis patients attending DOTS center at Dr. Bhim Rao Ambedkar memorial hospital, Raipur, Chhattisgarh, India

Background: Tuberculosis is second leading cause of death in the world. The causative organism is Mycobacterium tuberculosis. The objective was to study the adverse reactions of the patients attending the DOTS center and to assess their causality and severity of reported ADRs.Methods: Present study was a prospective observational study carried at the DOTS center of Dr. Bhim Rao Ambedkar Memorial Hospital, Raipur, Chhattisgarh, India between August 2011 to July 2012 (One year). The patients were monitored for adverse drug reactions. The assessment of ADRs were based upon the WHO assessment scale, Naranjo scale, European A.B.O scale.Results: Total number of patients attending DOTS center was 816. The number of males (428) exceeded that of females (388). Majority of patients in this study belonged to 21-30 years (26.96%) next 31-40 years (25.24%) and 41-50 years (16.5%) of age group. Prevalence of ADRs were more in males (57%) than in females 32 (43%). Majority of ADRs reported were moderate 33 (35.22%) followed by 29 (46,77%) were mild, no severe ADRs reported. According to severity of ADRs seen were gastritis 28 (45%) followed by 10 (16% ) rashes , 10 (16,12%) of arthralgia, 3 (4.83%) of hepatitis, 6 (9.7%) of peripheral neuropathy, 2 (3%) onsets of ADRs after starting anti-tubercular drug were 12 (19.35%) in 0-1 week followed by 19 (30%) ADRs showed onset in 1-2 week and 2-3 week, 8 (13%) in 3-4 week 3 (5%) in 4-5 week and 1 (2%) in 5-6 week.Conclusions: The casual link between the ADRs and the suspected anti-tubercular drug by Naranjo scale definitely relationship was established between the anti-tubercular drug and ADRs in 7 (11.25%) patient while 22 (35.45%) probable and 33 (53.22%) ADRs were categorized as possible

Polarity sorting of axonal microtubules: a computational study

We present a computational model to test a “polarity sorting” mechanism for microtubule (MT) organization in developing axons. We simulate the motor-based axonal transport of short MTs to test the hypothesis that immobilized cytoplasmic dynein motors transport short MTs with their plus ends leading, so “mal-oriented” MTs with minus-end-out are transported toward the cell body while “correctly” oriented MTs are transported in the anterograde direction away from the soma. We find that dynein-based transport of short MTs can explain the predominately plus-end-out polarity pattern of axonal MTs but that transient attachments of plus-end-directed motor proteins and nonmotile cross-linker proteins are needed to explain the frequent pauses and occasional reversals observed in live-cell imaging of MT transport. Static cross-linkers increase the likelihood of a stalled “tug-of-war” between retrograde and anterograde forces on the MT, providing an explanation for the frequent pauses of short MTs and the immobility of longer MTs. We predict that inhibition of the proposed static cross-linker will produce disordered transport of short MTs and increased mobility of longer MTs. We also predict that acute inhibition of cytoplasmic dynein will disrupt the polarity sorting of MTs by increasing the likelihood of “incorrect” sorting of MTs by plus-end-directed motors

Rationality verses irrationality in fixed dose combinations: at a tertiary teaching hospital of rural Chhattisgarh, India

Background: Rational drug prescribing can be defined as appropriate drugs prescribed in the right dose, at correct time intervals and for a sufficient duration. Irrational drug use is a common problem in many countries of the world.Methods: A prospective observational study was conducted, total 300 patients attending various outpatient departments of tertiary health care rural hospital in Rajnandgaon district were interviewed and their prescriptions were analysed.Results: Total 350 drugs were prescribed 60 (17.14%) were prescribed by generic name and the rest 290 (82.86%) were prescribed by brand name. Only 18 (5.14%) drugs were not prescribed from hospital formulary. 264 (75.43%) drugs were dispensed from hospital pharmacy. On the basis of rationality score 53% prescriptions were rational, 30% semi rational and 17% irrational.Conclusions: In a rural hospital, where hospital formulary is based on WHO Essential medicine list, hundred percent utilization of hospital pharmacy service doctors and patients would ensure rational prescribing benefits of the patients coming from rural and uneducated background

Application of Non-thermal Plasmas in Medicine and Energy-Food-Water

Non-thermal plasma (NTP) due to their versatile nature have been successfully used in many applications ranging from hydrocarbon destruction to cancer treatment. The NTPs, can deliver high electron temperatures and high densities of radicals at near ambient conditions making it a unique source for applications ranging from treatment of extremely heat sensitive surfaces to complex chemical reactions which are feasible only at low temperatures. This work presents some of the recent understandings on how various NTP reactors can be designed and characterized for various applications. The results obtained from a pin-to-water plasma discharge system, in generating plasma activated water for agricultural applications are discussed. The application of NTPs in hydrocarbon reforming to obtain a tar-free gas from a waste to energy thermo-chemical process is discussed. The results of selective killing of cancer cells using a DBD is presented. Also, application of NTPs in wastewater treatment systems to treat household chemical products are presented

Assessment of knowledge of pharmacotherapeutics amongst medical undergraduates of a tertiary care teaching hospital of Chhattisgarh, India: a questionnaire based study

Background: Knowledge of pharmacology forms the basis of rational pharmacotherapy practice. Teaching the medical students about systematic application of pharmacology in patients’ care forms an essential component. It facilitates the medical students to develop a methodical approach in solving patients’ clinical problems.Methods: A questionnaire-based study was conducted, at Government Medical College Rajnandgaon involving second year MBBS students. Total 100 students participated in the study.Results: Hundred percent of the students responded that pharmacology was presently taught to them, seventy nine percent of them agreed with the fact that pharmacology was preferred to pass the MBBS, eighty eight percent of them responded that in pharmacokinetics was the least preferred topic, ninety seven of them were not aware of the essential drug list. Their suggestions regarding the change in teaching methodology was recorded.Conclusions: This study concludes that efforts are needed to develop a curriculum that encompasses important aspects of clinical pharmacology and therapeutics along with incorporation of the useful suggestions by the undergraduate students