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Wilson disease (WD), a copper metabolism disorder caused by mutations in ATP7B, manifests heterogeneous clinical features. Interestingly, in a fraction of clinically diagnosed WD patients, mutations in ATP7B appears to be missing. In this review we discuss the plausible explanations of this missing heritability and propose a workflow that can identify the hidden mutations. Mutation analyses of WD generally includes targeted sequencing of ATP7B exons, exon-intron boundaries, and rarely, the proximal promoter region. We propose that variants in the distal cis-regulatory elements and/or deep intronic variants that impact splicing might well represent the hidden mutations. Heterozygous del/ins that remain refractory to conventional PCR-sequencing method may also represent such mutations. In this review, we also hypothesize that mutations in the key copper metabolism genes, like, ATOX1, COMMD1, and SLC31A1, could possibly lead to a WD-like phenotype. In fact, WD does present overlapping symptoms with other rare genetic disorders; hence, the possibility of a misdiagnosis and thus adding to missing heritability cannot be excluded. In this regard, it seems that whole-genome analysis will provide a comprehensive and rapid molecular diagnosis of WD. However, considering the associated cost for such a strategy, we propose an alternative customized screening schema of WD which include targeted sequencing of ATP7B locus as well as other key copper metabolism genes. Success of such a schema has been tested in a pilot study.

Tyrosinase is the key enzyme (TYR) regulating melanin biosynthesis pathway and different TYR mutants had been shown to be retained within the Endoplasmic Reticulum (ER) in varying degrees, instead of being localized in the melanosome. Interestingly, a direct correlation could be ascertained between the enzyme activities of the mutants and their respective degrees of ER retentions (Moumita Chaki et al., 2011; Mondal, Sengupta, & Ray, 2016); but the molecular bases of such variations in retentions has largely been unknown. In the current study, for the very first time, we tried to check if structural constraints like – (i) position of an amino acid within TYR, whether buried or surface exposed (which is reflected by Accessible Surface Area value), (ii) change in nature of amino acid, (iii) changes in overall electrostatic potential (iv) changes in hydrogen bonding (v) steric hindrance (vi) change in overall stability due to non-synonymous amino acid substitutions have contributing effects upon differential retentions of the mutants within ER. To achieve our aim, we did homology models of 45 TYR variants that have previously been functionally characterized by Mondal, Sengupta, & Ray, 2016, with respect to their degrees of ER retentions, as well as their individual levels of enzyme activities. To our surprise, we did not get any correlations whatsoever between differential functional characteristics of mutant TYRs with differential structural attributes. This indicates towards the role of some hitherto unexplored mechanism of processing of mutant protein variants that contribute toward their differential functional outcomes.

This investigation focuses on a simulation-based power-loss optimization scheme, which is applied to laboratory developed general-purpose inverter-stack circuit, fabricated using high-voltage SiC-MOSFET. The optimization mainly addresses the external elements under fixed output current. It is found, that an increase in switching frequency causes increased loss, which is however less than that calculated by following the conventionally predicted linear dependence on the frequency. The switching loss is also strongly varying, in accordance with the output current variation, which is determined by the circuit requirements. Here, it is demonstrated, that circuit simulation with an accurate compact model can be successfully applied to realize significant improvements, leading to lower power loss under the requested operating condition. It is also found that the SiC-MOSFET can maintain the efficiency of nearly 98% even for high-frequency operations.

Neural tube defects (NTDs) are significant congenital deformities of the central nervous system among which spina bifida is the most common form that occurs due to defect in the neurulation process of embryogenesis. NTDs are among the most common type of birth defects occurring at a range of 0.5–10 in every 1000 live births worldwide and are thought to have multifactorial etiology, including multigenetic and epigenetic notions. Epigenetic regulations control differential gene expression in normal and disease phenotypes. DNA methylation is a significant epigenetic process, guided by DNMT1, one of the most important maintenance methylating agents. However, the relationship between DNMT1 and NTDs had always been inconclusive and poorly understood. In the present study, by utilizing in silico methodologies we tried to figure out potent single nucleotide variants (SNVs) that could play roles in generating functional differences in DNMT1 expression and we also tried to check (by in vitro method) if there is any connection between DNMT1 expression and spina bifida condition. A number of coding and non-coding (both intragenic and intergenic) SNVs of DNMT1 were found (using the in silico methods) that have potentials to alter its expression. From the in vitro experimentations, differential DNMT1 RNA expressions were found between spina bifida affected newborns and their respective mothers when compared with controls. It is the first report of NTD from Eastern India precisely showing inverse correlation between DNMT1 expression and occurrence of NTD. The findings of the present study could be further considered for early prognosis and future experimental designs.

Objectives Mitochondrial dysfunction has long been associated with the pathogenesis of lung cancer (LC). Mitochondrial DNA (mtDNA) haplogroups have been reported to modify the risk of LC in a few different populations; however, no study has been done among the Indians. Here, we explore the relationship between mtDNA haplogroups and LC in a representative eastern Indian sample set. Methods Different combinations of six mtDNA SNPs, which define the major Asian mtDNA haplogroups M and N, and their sub-haplogroups D, G, M7, R, and F were genotyped via polymerase chain reaction (PCR) – restriction fragment length polymorphism (RFLP) – sequencing approach in 94 smoker LC patients and 100 healthy smoker controls from an eastern Indian cohort. Results The distribution of 7 mtDNA haplogroups did not show any significant differences between patients and controls (p Conclusions Our study is the first to indicate that the major Asian mtDNA haplogroups have no significant (p<0.05) association with LC in East Indian population.

Background Parkinson's disease (PD) is a multifaceted illness affecting ~ 0.3% of the world population. The genetic complexity of PD has not been, fully elucidated. Several studies suggest that mitochondrial DNA variants are associated with PD. Objective Here, we have explored the possibility of genetic association between mitochondrial haplogroups as well as three independent SNPs with PD in a representative east Indian population. Methods and material The Asian mtDNA haplogroups: M, N, R, B, D, M7, and 3 other SNPs: 4336 T/C, 9055 G/A, 13708 G/A were genotyped in 100 sporadic PD patients and 100 matched controls via conventional PCR-RFLP-sequencing approach. Results The distribution of mtDNA haplogroups, as well as 3 single polymorphisms, did not show any significant differences (P > 0.05) between patients and controls. Conclusion This is the first of its kind of study from India that suggests no association of selected mitochondrial DNA variations with PD.

This paper presents a comparative study between lab-developed attraction-type levitation prototypes of two different objects with different geometries but, importantly, the same mass. Effects of continuous geometry without sharp corners in spherical ball vis-a-vis that of the plate having sharp corners introduce significant changes in the analysis, operation and set-up development arising out of this subtle but characteristic geometric difference, which lead to change in configuration of field lines. This broadly reflects on the design, finite-element analysis, modelling, stability analysis, fabrication and controller design. The challenges and stepwise procedures in design and fabrication for this change from a spherical shape to cuboid shape for the same mass of levitated object have been highlighted in this work. Inductance, force and current vs. air-gap characteristics, etc. have been determined first using the proposed novel and simplified analytical formulation and then using finite-element (FE)-analysis-based software packages. Particularly, specific permeance-based approach originally proposed by Robert Pohl for inductor alternators having double saliency is extended here successfully for analytical formulation that has not been adopted by other researchers. The proposed analytical model can be used to obtain a sufficiently accurate design, starting from nominal ratings, and hence for building the model geometry for the FEM analysis. The FEM analysis cannot be conducted unless one has the model geometric dimensions. The results thus obtained have been verified by actual experiments too. Thereafter, the mathematical models for control of the systems have been derived analytically. There exists a good agreement between predicted and measured results. This implies that the system modelling is precise, which leads to accurate design and implementation of controllers. Analog controllers have been designed, analysed, implemented and practically experimented upon with steady levitated position for both the systems.

This paper proposes a novel, reliable, efficient and cost-effective implementation of partial soft switching in a silicon carbide (SiC)-based variable-frequency phase-modulated resonant transition converter (PMRTC) used in manual metal arc welding (MMAW) applications at a peak power of 1.3 kW. The switching frequency ( $$f_{sw}$$ ) of the converter is increased from 100 kHz at no load to around 150 kHz for a rated power of 1.0 kW. Such an approach is not found in the existing literature. At such frequencies, a significant proportion of the output filter inductance is contributed by the inherent self-inductance of the output “lead cables”. The switching losses in the semiconductor devices are reduced at no-load condition by reduction of the operating frequency. Load regulation is achieved at 150 kHz by implementing phase-shifted PWM technique. Implementation of partial soft switching without using additional components is another significant contribution of this work. The reduced size and weight of the filter inductor in turn reduces the overall size, weight and cost of the system but puts a restriction on the output lead cable length, which is another salient finding of this work. Since at high frequency the transformer model changes, design and finite-element method (FEM)-based simulation of the transformer are also presented in this paper. Loss calculations at 100 and 150 kHz are discussed. The entire converter is fabricated in the laboratory. Experimental and simulated results are found to be in excellent agreement.

Association studies on lung cancer have often yielded conflicting and inconclusive results. We performed a comprehensive meta-analysis to dissect the precise effects of the candidate variants. We searched for association studies on lung cancer from the Indian subcontinent. Cochran’s Q-test assessed heterogeneity. Both overall and histotype-stratified meta-analysis was done using fixed-effect and random-effects models. Smoking status stratified subgroup analysis and effect modification tests were done. An associated variant with significant heterogeneity was genotyped in an eastern Indian population to investigate the contribution of potential confounders followed by a comprehensive meta-analysis across world populations. Significant heterogeneity was observed for the 8 variants. Both fixed-effect and random-effects meta-analysis of 24 variants showed FDR-corrected associations of rs3547/XRCC1 and rs1048943/CYP1A1 with lung cancer along with 5 nominal associations. del1/GSTT1, rs4646903/CYP1A1, and rs10488943/CYP1A1 were associated with adenocarcinoma, squamous cell carcinoma, and both, respectively. rs4646903/CYP1A1 was associated with lung cancer among smokers with significant effect modification by smoking. rs10488943/CYP1A1 was associated with lung adenocarcinoma in the East Indian case-control study. rs1048943/CYP1A1 was associated with lung cancer across world populations. Our work confirms the risk loci for lung cancer and its subtypes in the context of smoking and other aetiological factors, which could aid in personalised treatment.

The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression. However, the precise role of genetic variants, disrupting the molecular interactions is less understood. All cancer-associated missense variants of ROBO1/4 and SLIT2 from COSMIC were screened for their pathogenicity. Homology modelling was done in Modeller 9.17, followed by molecular simulation in GROMACS. Rigid docking was performed for the cognate partners in PatchDock with refinement in HADDOCK server. Post-docking alterations in conformational, stoichiometric, as well as structural parameters, were assessed. The disruptive variants were ranked using a weighted scoring scheme. In silico prioritisation of 825 variants revealed 379 to be potentially pathogenic out of which, about 12% of the variants, i.e. ROBO1 (14), ROBO4 (8), and SLIT2 (23) altered the cognate docking. Six variants of ROBO1 and 5 variants of ROBO4 were identified as "high disruptors" of interactions with SLIT2 wild type. Likewise, 17 and 13 variants of SLIT2 were found to be "high disruptors" of its interaction with ROBO1 and ROBO4, respectively. Our study is the first report on the impact of cancer-associated missense variants on ROBO1/4 and SLIT2 interactions that might be the drivers of lung cancer progression.

Several traits related to positive and negative affect show a high genetic as well as phenotypic correlation with well-being in humans, and are therefore collectively termed as "Well-being spectrum". Genome-Wide Association studies (GWA studies) on "well-being measurement" have led to identification of several genomic variants (Single Nucleotide Variants - SNVs), but very little has been explained with respect to their functionality and mode of alteration of well-being. Utilizing a pool of 1258 GWA studies based SNVs on "well-being measurement", we prioritized the SNVs and tried to annotate well-being related functionality through several bioinformatic tools to predict whether a protein sequence variation affects protein function, as well as experimentally validated datasets available in ENCODE based web-tools namely rSNPBase, RegulomeDB, Haploreg, along with GTEx Portal and STRING based protein interaction networks. Prioritization yielded three key SNVs; rs3781627-A, rs13072536-T and 5877-C potentially regulating three genes, PSMC3, ITIH4 and SERPINC1, respectively. Interestingly, the genes showed well clustered protein-protein interaction (maximum combined confidence score0.4) with other well-being candidate genes, namely TNF and CRP genes suggesting their important role in modulation of well-being. PSMC3 and ITIH4 genes are also involved in driving acute phase responses signifying a probable cross-talk between well-being and psychoneuroimmunological system. To best of our knowledge this study is the first of its kind where the well-being associated GWA studies-SNVs were prioritized and functionally annotated, majorly based on functional data available in public domain, which revealed PSMC3, ITIH4 and SERPINC1 genes as probable candidates in regulation of well-being spectrum.

This paper presents a novel initial rotor position estimation method for a surface-mounted permanent magnet synchronous motor (SPMSM) using its inherent magnetic features. Here, the initial rotor position has been estimated utilising the variation in phase inductances arising out of the unavoidable but very small saliency occurring either out of magnetic saturation of the machine or the magnet shape. Detailed investigations have been carried out to enumerate the actual magnitude of the inductances of the SPMSM with distributed armature winding and the dynamic saturation status with armature current variation. Here, 3-phase balanced voltage of higher frequency (150 Hz) is applied to the motor terminals for a short period of time (for 300 ms) and the corresponding phase currents are indirectly used to determine the rotor position. Innovative signal processing steps have been used to distinguish small differences in the 3-phase currents caused by the small differences in the phase inductances. The position is determined from the relative values of different phase currents using a novel approach. This still leads to two diametrically opposite (electrical phase) solutions for the instantaneous rotor position. To eliminate this ambiguity, two alternative methods (for pole identification) have been proposed. Extensive co-simulations of finite-element method (FEM)-based electromagnetic simulation and system simulation (for logic implementation) have been conducted. The estimation methods have been validated experimentally on a laboratory-developed prototype SPMSM that was designed and fabricated by the authors. The experimental results are found to be in excellent agreement with the FEM-based simulation results. The complete initial position estimation method takes less than 1 s of real time, which is typically less than the pre-charging time of standard commercial inverters.

This paper presents detailed steps and procedures for the design of a 4-pole, 0.75-hp, 1500-r.p.m. surface-mounted permanent magnet brush-less DC (SPM-BLDC) motor. The motor has been fabricated at the works of a local manufacturer. The parameters of the machine have been analytically evaluated and subsequently compared to the experimentally determined values. Its practical performance on load has been experimentally evaluated in the laboratory and verified against analytical predictions too. Low-cost M45 electrical steel laminations, as used for commercial induction motors (IMs), have been used from considerations of cost and availability. This also enables direct comparison of important parameters (e.g. torque density, power density and efficiency) between the fabricated prototype and commercially available fractional-hp 3-phase and 1-phase IMs of similar rating. This study is significant since electrical motor manufacturers need not change their stator stamping production line for BLDC motor vis-a-vis IM in case of mass production. Such an approach is hardly reported in the available technical literature. Analytical methods adopted include both conventional hand calculations and finite-element analysis using commercially available software package(s). Excellent agreements between analytical and experimental values uphold the correctness of the design process, precision of fabrication and accuracy of experimental investigations.

This paper presents an in-depth analysis, performance evaluation and comparative study of two 5-kW, 8-pole, 750-rpm laboratory prototypes of a permanent magnet synchronous motor (PMSM) of identical nominal ratings with surface and interior permanent magnet (PM) rotor structures having same stator and armature winding (fractional slot distributed winding). The key electrical (such as rated voltage, current, power, speed, number of poles, etc.) and mechanical variables (such as overall volume, air-gap length, rotor diameter, shaft dimensions and magnetic material) of the fabricated prototypes have also been kept same to pin-point the direct influence of the two different rotor configurations (surface and interior PMSM) on the parameters, performance and operation of these PMSMs. For the two machines, a detailed comparison of air-gap flux density distribution, THD in induced voltage, torque ripple, losses, efficiency, torque–speed characteristics, field weakening capability, steady-state parameters at different operating conditions, etc. has been conducted. The salient observations from this comparative study have been duly highlighted. This paper also includes an in-depth comparison of volume and cost of PM used in the two types of PMSMs. The short-time performance figures of the said motors have also been presented. The possibility of demagnetisation of PMs, during a sudden fault, has also been investigated for both PMSMs. Challenges of making of both rotors have been discussed. The theoretically determined parameters and analytically evaluated performance figures have been verified through standard FEM packages and then validated experimentally on the prototypes.

This paper presents a comparative study on the design, modelling, electromagnetic analysis based on finite-element software, fabrication and experiment on rectangular flat (148 g) and C-shaped (148 g) levitation prototypes based on steel plates. No mechanical restrainer has been used in the transverse direction for the levitation. This aspect of the work is an improvement over existing work reported in the published literature. The entire set-up has been designed, fabricated, analytically investigated and experimentally evaluated and verified. The finite-element model (FEM) has been derived using standard commercial package(s). The analytical model has been obtained using specific permeance concepts following Robert Pohl’s method. Excellent correlation between the predicted and experimental results is a highlight of the work. The stability against transverse mechanical perturbation has also been investigated. Control system design and implementation is successfully done.

This paper presents a novel and exhaustive investigation involving in-depth analysis, performance evaluation and comparative study of two 0.75 hp, 4-pole, 1500 rpm laboratory prototypes of Brushless DC (BLDC) motors of identical nominal ratings with surface and interior permanent magnet rotor structures having the same stator and winding (integral slot distributed winding). Both the motors were designed and developed in the lab. The major electrical variables (such as rated power, speed, voltage, current, number of poles, etc.) and the stator (such as core material, stator lamination, stack length, winding pattern and wire gauge) of the fabricated prototypes have also been kept identical to pin-point the direct influence of the two different rotor configurations (viz., surface vs interior permanent magnet) on the parameters, performance and operation of these BLDC motors. Additionally, to ensure unbiased basis for appropriate comparison, the overall volumes of magnets/pole in both the motors have also been kept similar. A detailed comparison of different quantities like air-gap flux density distribution, THD in induced voltage, torque ripple, losses and efficiency, torque–speed characteristics with field-weakening capability, steady state parameters at different operating conditions, etc. has been conducted for the said motors and the salient points duly highlighted. The vulnerability of the permanent magnets to demagnetisation based on armature reaction, particularly during a sudden fault, has also been investigated in both the cases. The theoretically determined parameters and analytically evaluated performance figures have been verified through standard FEM packages, and later validated experimentally on the fabricated prototypes. Very good mutual agreement has been observed between predicted and experimental values.