355 research outputs found

    Determination of the breakpoint and molecular diagnosis of a common α-thalassaemia-1 deletion in the Indian population

    Get PDF
    The previously described South African type α-thalassaemia-1 mutation was identified in Indian HbH patients using a polymerase chain reaction (PCR) strategy. A multiplex PCR assay was devised to detect heterozygotes and homozygotes. This α-thalassaemia-1 mutation was found to be the commonest determinant causing HbH disease in this population. In one family this mutation was found in combination with a novel splice donor mutation α2 IVS I-1 (G→A). Characterization of the breakpoint junction sequence revealed, in addition to a 23 kb deletion, that there was an addition of ~160 bp bridging the breakpoints. Similar to other deletions in the α-globin gene cluster, there is an Alu repeat-mediated mechanism for the origin of the deletion

    Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362→Thr (Prothrombin Vellore 1) mutation

    Get PDF
    Prothrombin deficiency is a rare (1:200 000) autosomal recessive disorder caused by diverse mutations in prothrombin gene. We have studied the molecular basis of this disorder in four unrelated Indian patients. The diagnosis was based on prolonged prothrombin (PT) and activated partial thromboplastin times and low factor II coagulant activity (FII: C) measured using a PT based assay. FII: C levels ranged between 4.7% and 17.5%. Mutations were identified in all the four patients. Five different causative mutations including four (80%) missense and an in-frame deletion (20%) were identified. One of them was a novel, Ala362→Thr aminoacid change affecting 'B' chain of α-thrombin. This mutation was present in a compound heterozygous state with a previously reported Arg-1→Gln missense change affecting pro-peptide cleavage site. Ala362→Thr occurred at a codon, evolutionarily conserved in all the 24 different prothrombins or its related serine proteases studied. Molecular modeling of this mutation was found to cause a conformational change around the region involving a catalytic triad residue His363 and a cysteine residue at codon 364. The FII: C level in this patient was 17.5%. Three other previously reported mutations were also detected in the homozygous state: Arg271→Cys in Kringle-2 region, a Glu309?Lys in 'A' chain of α-thrombin and an in-frame deletion of 3 bp (AAG) leading to Del Lys301/302 in 'A' chain of α-thrombin. This is the first report of the molecular basis of prothrombin deficiency in Indian patients and we suggest the eponym 'Prothrombin Vellore 1' for Ala362→Thr mutation

    Six novel mutations including triple heterozygosity for Phe31Ser, 514delT and 516T→G factor X gene mutations are responsible for congenital factor X deficiency in patients of Nepali and Indian origin

    Get PDF
    Factor X (FX) deficiency is a rare (1 : 100000) autosomal recessive disorder caused by heterogeneous mutations in FX gene. We have studied the molecular basis this disease in six Indian and one Nepali patients. Diagnosis was confirmed by measuring the FX coagulant activity (FX: C) using a PT based assay. Six of them had a FX: C of < 1% and one patient had 24% coagulant activity. Mutations were identified in all the seven patients. These included eight (88.8%) missense and one frame-shift (11.2%) mutations of which six were novel. Three of the novel mutations, a Phe31Ser affecting 'Gla' domain and 514delT and 516T?G mutations affecting Cys132 in 'connecting region' were identified in a triple compound heterozygous state in a Nepali patient presenting with a severe phenotype. Two other novel mutations, Gly133Arg, may affect the disulphide bridge between Cys132-Cys302 in the connecting region while Gly223Arg may perturb the catalytic triad (His236, Asp282 and Ser379). The other novel mutation, Ser354Arg, involves the replacement of a small-buried residue by a large basic aminoacid and is likely to have steric or electrostatic effects in the pocket involving Lys351-Arg347-Lys414 that contributes to the core epitope of FXa for binding to FVa. Three previously reported mutations, Thr318Met; Gly323Ser; Gly366Ser were also identified. This is the first report of the molecular basis of FX deficiency in patients from the Indian subcontinent

    Erosion of Trust in the Medical Profession in India : Time for Doctors to Act

    Get PDF
    In India, over the last decade, a series of stewardship failures in the health system, particularly in the medical profession, have led to a massive erosion of trust in these institutions. In many low- and middle-income countries (LMICs), the situation is similar and has reached crisis proportions; this crisis requires urgent attention. This paper draws on the insights from the recent developments in India, to argue that a purely control-based regulatory response to this crisis in the medical profession, as is being currently envisaged by the Parliament and the Supreme Court of India, runs the risk of undermining the trusting interpersonal relations between doctors and their patients. A more balanced approach which takes into account the differences between system and interpersonal forms of trust and distrust is warranted. Such an approach should on one hand strongly regulate the institutions mandated with the stewardship and qualities of care functions, and simultaneously on the other hand, initiate measures to nurture the trusting interpersonal relations between doctors and patients. The paper concludes by calling for doctors, and those mandated with the stewardship of the profession, to individually and collectively, critically self-reflect upon the state of their profession, its priorities and its future direction

    Genetically encoded intrabody sensors report the interaction and trafficking of β-arrestin 1 upon activation of G protein-coupled receptors

    Get PDF
    Agonist stimulation of G protein-coupled receptors (GPCRs) typically leads to phosphorylation of GPCRs and binding to multifunctional proteins called β-arrestins (βarrs). The GPCR-βarr interaction critically contributes to GPCR desensitization, endocytosis, and downstream signaling, and GPCR-βarr complex formation can be used as a generic readout of GPCR and βarr activation. Although several methods are currently available to monitor GPCR-βarr interactions, additional sensors to visualize them may expand the toolbox and complement existing methods. We have previously described antibody fragments (FABs) that recognize activated βarr1 upon its interaction with the vasopressin V2 receptor C-terminal phosphopeptide (V2Rpp). Here, we demonstrate that these FABs efficiently report the formation of a GPCR-βarr1 complex for a broad set of chimeric GPCRs harboring the V2R C terminus. We adapted these FABs to an intrabody format by converting them to single-chain variable fragments (ScFvs) and used them to monitor the localization and trafficking of βarr1 in live cells. We observed that upon agonist simulation of cells expressing chimeric GPCRs, these intrabodies first translocate to the cell surface, followed by trafficking into intracellular vesicles. The translocation pattern of intrabodies mirrored that of βarr1, and the intrabodies co-localized with βarr1 at the cell surface and in intracellular vesicles. Interestingly, we discovered that intrabody sensors can also report βarr1 recruitment and trafficking for several unmodified GPCRs. Our characterization of intrabody sensors for βarr1 recruitment and trafficking expands currently available approaches to visualize GPCR-βarr1 binding, which may help decipher additional aspects of GPCR signaling and regulation

    Методическая работа в дошкольной образовательной организации как условие повышения информационно-коммуникационной компетентности педагогов

    Get PDF
    Тема работы актуальна. В ВКР представлены условия, способствующие развитию компонентов ИКК педагогов. Работа имеет практическую значимост

    Stripe Helical Magnetism and Two Regimes of Anomalous Hall Effect in NdAlGe

    Full text link
    We report the magnetic and electronic transport properties of the inversion and time-reversal symmetry breaking Weyl semimetal NdAlGe. This material is analogous to NdAlSi, whose helical magnetism presents a rare example of a Weyl-mediated collective phenomenon, but with a larger spin-orbit coupling. Our neutron diffraction experiments revealed that NdAlGe, similar to NdAlSi, supports an incommensurate Ising spin density wave (Tinc=6.8T_{\text{inc}}=6.8 K) with a small helical spin canting of 3^\circ and a long-wavelength of \sim 35 nm, which transitions to a commensurate ferrimagnetic state below Tcom=5.1T_{\text{com}}=5.1 K. Using small-angle neutron scattering, we showed that the zero-field cooled ferrimagnetic domains form stripes in real space with characteristic length scales of 18 nm and 72 nm parallel and perpendicular to the [110] direction, respectively. Interestingly, for the transport properties, NdAlSi does not exhibit an anomalous Hall effect (AHE) that is commonly observed in magnetic Weyl semimetals. In contrast to NdAlSi, we identify two different AHE regimes in NdAlGe that are respectively governed by intrinsic Berry curvature and extrinsic disorders/spin fluctuations. Our study suggests that Weyl-mediated magnetism prevails in this group of noncentrosymmetric magnetic Weyl semimetals NdAlXX, but transport properties including AHE are affected by material-specific extrinsic effects such as disorders, despite the presence of prominent Berry curvature.Comment: Preprint, 16 pages, 6 main figures, 6 supplementary figure

    Strategic maintenance technique selection using combined quality function deployment, the analytic hierarchy process and the benefit of doubt approach

    Get PDF
    The business performance of manufacturing organizations depends on the reliability and productivity of equipment, machineries and entire manufacturing system. Therefore, the main role of maintenance and production managers is to keep manufacturing system always up by adopting most appropriate maintenance methods. There are alternative maintenance techniques for each machine, the selection of which depend on multiple factors. The contemporary approaches to maintenance technique selection emphasize on operational needs and economic factors only. As the reliability of production systems is the strategic intent of manufacturing organizations, maintenance technique selection must consider strategic factors of the concerned organization along with operational and economic criteria. The main aim of this research is to develop a method for selecting the most appropriate maintenance technique for manufacturing industry with the consideration of strategic, planning and operational criteria through involvement of relevant stakeholders. The proposed method combines quality function deployment (QFD), the analytic hierarchy process (AHP) and the benefit of doubt (BoD) approach. QFD links strategic intents of the organizations with the planning and operational needs, the AHP helps in prioritizing the criteria for selection and ranking the alternative maintenance techniques, and the BoD approach facilitates analysing robustness of the method through sensitivity analysis through setting the realistic limits for decision making. The proposed method has been applied to maintenance technique selection problems of three productive systems of a gear manufacturing organization in India to demonstrate its effectiveness

    Into Thick(er) Air? Oxygen Availability at Humans’ Physiological Frontier on Mount Everest

    Get PDF
    Global audiences are captivated by climbers pushing themselves to the limits in the hypoxic environment of Mount Everest. However, air pressure sets oxygen abundance, meaning it varies with the weather and climate warming. This presents safety issues for mountaineers, but also an opportunity for public engagement around climate change. Here we blend new observations from Everest with ERA5 reanalysis (1979- 2019) and climate model results to address both perspectives. We find that plausible warming could generate subtle but physiologically relevant changes in summit oxygen availability, including an almost 5% increase in annual minimum VO 2 max for 2°C warming since pre-industrial. In the current climate we find evidence of swings in pressure sufficient to change Everest’s apparent elevation by almost 750 m. Winter pressures can also plunge lower than previously reported, highlighting the importance of air pressure forecasts for the safety of those trying to push the physiological frontier on Mt. Everest
    corecore