Department of Bioscience & Bioengineering

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IIT Jodhpur

Objective: The loss of function mutations (biallelic) in frataxin (FXN) has primarily been implicated in Friedreich's ataxia (FRDA), an autosomal recessive cerebellar ataxia. The protein product of FXN is a nuclear-encoded mitochondrial protein required for the biogenesis of iron- clusters (Fe-S). FRDA is characterized by neurological and non-neurological features which show variable expression in affected individuals. An inverse relationship has been demonstrated between GAA repeat size and age at onset and explains 50% variability of the age at onset. MtDNA variations and haplogroups could be one of the contributory factors to explain the remaining heterogeneity in FRDA, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of FRDA. Methods: In our study, targeted resequencing of the D-loop and coding region of mitochondrial genes (ND1-6 and ATP) was conducted in 30 genetically confirmed FRDA patients and 62 ethnicity-matched unrelated healthy controls to identify the functionally important mtDNA variations and to trace the mitochondrial lineage of Indian FRDA patients. Cumulative mitochondrial SNP scores were computed for the identified variations in the functional region and haplogroups were determined by Haplogrep. Results: A significantly higher load of overall mitochondrial variations (with a trend toward the coding region) per individual was noted among FRDA cases rather than controls (p-value. <. 0.03). A non-synonymous variation (p. L237M) in ND2 was over-represented among FRDA cases (p-value 0.04). This variation has a reported association with longevity and myocardial infarction. We also observed over-representation of H haplogroup (Caucasian mitochondrial haplogroup) among FRDA patients. We have not observed the influence of mitochondrial variations and haplogroup upon age at onset of FRDA. Conclusions: Overall, our study identifies the functionally important variations and mitochondrial lineage of Indian FRDA cases and, that underscores the importance of studying the role of mitochondrial genome variations in FRDA. © 2015 Elsevier B.V. and Mitochondria Research Society.

World University root node

Mitochondrion

Investigation of mitochondrial DNA variations among Indian Friedreich's ataxia (FRDA) patients

Gene–environment interactions (G × E) have attracted considerable research interest in the past owing to their scientific and public health implications, but powerful statistical methods are required to successfully track down G × E, particularly at a genome-wide level. Previously, a case-only (CO) design has been proposed as a means to identify G × E with greater efficiency than traditional case–control or cohort studies. However, as with genotype–phenotype association studies themselves, hidden population stratification (PS) can impact the validity of G × E studies using a CO design. Since this problem has been subject to little research to date, we used comprehensive simulation to systematically assess the type I error rate, power and effect size bias of CO studies of G × E in the presence of PS. Three types of PS were considered, namely genetic-only (PSG), environment-only (PSE), and joint genetic and environmental stratification (PSGE). Our results reveal that the type I error rate of an unadjusted Wald test, appropriate for the CO design, would be close to its nominal level (0.05 in our study) as long as PS involves only one interaction partner (i.e., either PSG or PSE). In contrast, if the study population is stratified with respect to both G and E (i.e., if there is PSGE), then the type I error rate is seriously inflated and estimates of the underlying G × E interaction are biased. Comparison of CO to a family-based case–parents design confirmed that the latter is more robust against PSGE, as expected. However, case–parent trios may be particularly unsuitable for G × E studies in view of the fact that they require genotype data from parents and that many diseases with an environmental component are likely to be of late onset. An alternative approach to adjusting for PS is principal component analysis (PCA), which has been widely used for this very purpose in past genome-wide association studies (GWAS). However, resolving genetic PS properly by PCA requires genetic data at the population level, the availability of which would conflict with the basic idea of the CO design. Therefore, we explored three modified Wald test statistics, inspired by the genomic control (GC) approach to GWAS, as an alternative means to allow for PSGE. The modified statistics were benchmarked against a stratified Wald test assuming known population affiliation, which should provide maximum power under PS. Our results confirm that GC is capable of successfully and efficiently correcting the PS-induced inflation of the type I error rate in CO studies of G × E. © 2015, Springer-Verlag Berlin Heidelberg.

Human Genetics

Allowing for population stratification in case-only studies of gene–environment interaction, using genomic control

The presence of voltage controlled negative differential resistance was observed in conduction characteristics recorded at room temperature for 300 nm thick spin-coated films of graphene oxide (GO) sandwiched between indium tin oxide (ITO) substrates and top electrodes of sputtered gold (Au) film. The GO crystallites were found from the X-ray diffraction studies to have an average size in the order of 7.24 nm and to be preferentially oriented along (001) plane. Raman spectroscopy suggested that the material consisted of multilayer stacks with the defects being located at the edges with an average distance of 1.04 nm apart. UV visible spectroscopy studies suggested that the band gap of the material was 4.3 eV, corresponding to direct transitions. The two-terminal ITO/GO/Au devices exhibited memristor characteristics with scan-rate dependent hysteresis, threshold voltage and On/Off ratios. A value of &gt;104 was obtained for On/Off ratio at a scan rate of 400 mVs-1 and 4.2 V. © 2015. The Institution of Engineering and Technology.

Fulltext

IET Circuits, Devices and Systems

Graphene oxide thin films for resistive memory switches

The work reports the synthesis and characterization of novel biopolymeric core-shell microparticles for controlled delivery applications. Alginate (shell) microparticles were prepared by encapsulating semi-solid organogel (core) using the ionotropic gelation method. Confocal and phase contrast microscopic studies showed the existence of distinct shell material around the organogel core. The presence of organogel as the core material of the microparticle was confirmed by X-ray diffraction and differential scanning calorimetric analyses. Entrapment of the organogel within the microparticles improved the drug encapsulation efficiency by preventing the leaching of the internal phase. In vitro drug release studies showed sustained release of ciprofloxacin from the organogel containing microparticles. The drug loaded microparticles were found to have significant antimicrobial activity when tested against Escherichia coli. The microparticles were found to be mucoadhesive in nature. Further, the biocompatibility of the microparticles was tested by hemocompatibility and cytocompatibility studies. The preliminary results suggested that the synthesized core-shell type hybrid microparticles hold promise as carrier for controlled delivery applications. © 2014 Elsevier B.V.

Chemical Engineering Journal

Core-shell-type organogel-alginate hybrid microparticles: A controlled delivery vehicle

Over the past decade, researchers have been trying to develop alternative gel based formulations in comparison to the traditional hydrogels and emulgels. In this perspective, bigels were synthesized by mixing gelatin hydrogel and stearic acid based organogel by hot emulsification method. Two types of bigels were synthesized using sesame oil and soy bean oil based stearate organogels. Gelatin based emulgels prepared using sesame oil and soy bean oil were used as the controls. Microscopic studies revealed that the bigels contained aggregates of droplets, whereas, emulgels showed dispersed droplets within the continuum phase. The emulgels showed higher amount of leaching of oils, whereas, the leaching of the internal phase was negligible from the bigels. Presence of organogel matrix within the bigels was confirmed by XRD, FTIR and DSC methods. Bigels showed higher mucoadhesive and mechanical properties compared to emulgels. Cyclic creep-recovery and stress relaxation studies confirmed the viscoelastic nature of the formulations. Four elemental Burger's model was employed to analyze the cyclic creep-recovery data. Cyclic creep-recovery studies suggested that the deformation of the bigels were lower due to the presence of the organogels within its structure. The formulations showed almost 100% recovery after the creep stage and can be explained by the higher elastic nature of the formulations. Stress relaxation study showed that the relaxation time was higher in the emulgels as compared to the bigels. Also, the % relaxation was higher in emulgels suggesting its fluid dominant nature. The in vitro biocompatibility of the bigels was checked using human epidermal keratinocyte cell line (HaCaT). Both emulgels and bigels were biocompatible in nature. The in vitro drug (ciprofloxacin) release behavior indicated non-Fickian diffusion of the drug from the matrices. The drug release showed good antimicrobial effect against Escherichia coli. Based on the results, it was concluded that the developed bigels may have huge potential to be used as alternatives to emulgels. © 2014 Elsevier Ltd.

Journal of the Mechanical Behavior of Biomedical Materials

Stearate organogel-gelatin hydrogel based bigels: Physicochemical, thermal, mechanical characterizations and in vitro drug delivery applications

The nucleus is one of the most important cellular organelles and molecular anticancer drugs, such as cisplatin and doxorubicin, that target DNA inside the nucleus, are proving to be more effective at killing cancer cells than those targeting at cytoplasm. Nucleus-targeting nanomaterials are very rare. It is a grand challenge to design highly efficient nucleus-targeting multifunctional nanomaterials that are able to perform simultaneous bioimaging and therapy for the destruction of cancer cells. Here, unique nucleus-targeting gold nanoclusters (TAT peptide-Au NCs) are designed to perform simultaneous in vitro and in vivo fluorescence imaging, gene delivery, and near-infrared (NIR) light activated photodynamic therapy for effective cancer cell killing. Confocal laser scanning microscopy observations reveal that TAT peptide-Au NCs are distributed throughout the cytoplasm region with a significant fraction entering into the nucleus. The TAT peptide-Au NCs can also act as DNA nanocargoes to achieve very high gene transfection efficiencies (≈81%) in HeLa cells and in zebrafish. Furthermore, TAT peptide-Au NCs are also able to sensitize formation of singlet oxygen (1O2) without the co-presence of organic photosensitizers for the destruction of cancer cells upon NIR light photoexcitation. A unique nucleus-targeting gold nanocluster(TAT peptide-Au NC)-based multifunctional theranostic platform is designed to perform simultaneous in vitro and in vivo cellular fluorescence imaging, gene delivery, and intrinsic near infrared light-activated photodynamic therapy. This is done without the co-presence of organic photosensitizers for the effective cancer cell killing. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Advanced Functional Materials

Nucleus-targeting gold nanoclusters for simultaneous in vivo fluorescence imaging, gene delivery, and NIR-light activated photodynamic therapy

Abstract Background: Laccases have good potential as bioremediating agents and can be used continuously in the immobilized form like many other enzymes. Methods: In the present study, laccase from Cyathus bulleri was immobilized by entrapment in Poly Vinyl Alcohol (PVA) beads cross-linked with either nitrate or boric acid. Immobilized laccase was used for dye decolorization in both batch and continuous mode employing a packed bed column. The products of degradation of dye Acid Red 27 were identified by LC MS/MS analysis. Results: The method led to very effective (90%) laccase immobilization and also imparted significant stability to the enzyme (more than 70% after 5 months of storage at 4°C). In batch decolorization, 90-95% decolorization was achieved of the simulated dye effluent for up to 10-20 cycles. Continuous decolorization in a packed bed bioreactor led to nearly 90% decolorization for up to 5 days. The immobilized laccase was also effective in decolorization and degradation of Acid Red 27 in the presence of a mediator. Four products of degradation were identified by LC-MS/MS analysis. Conclusions: The immobilized laccase in PVA-nitrate was concluded to be an effective agent in treatment of textile dye effluents. © 2015 Chhabra et al.; licensee BioMed Central.

Journal of Environmental Health Science and Engineering

Immobilized laccase mediated dye decolorization and transformation pathway of azo dye acid red 27

Recently, there has been growing attention to the role of the tumor microenvironment (TME) in cancer growth, metastasis and emergence of chemotherapy resistance. Stromal and tumor cells make up the TME and interact with each other through a complex cross-talk manner. This interaction is facilitated by a variety of growth factors, cytokines, chemokines and S100 proteins. In this review, we focus on chemokines and their cognate receptors in regulating the tumorigenic process. Chemokines are cytokines that have chemotactic potential. Chemokine receptors are expressed on tumor cells and stromal cells. Chemokines and their cognate receptors modulate tumor growth and metastasis in a paracrine and autocrine manner. They play a major role in the modulation of stromal cell recruitment, angiogenic potential, cancer cell proliferation, survival, adhesion, invasion and metastasis to distant sites. In addition, a new class of calcium binding family S100 proteins has been getting attention as they play significant roles in tumor progression and metastasis by modulating TME. Here, we highlight recent developments regarding the inflammatory chemokine/S100 protein systems in the TME. We also focus on how chemokines/S100 proteins, through their role in the TME, modulate cancer cell ability to grow, proliferate, invade and metastasize to different organs. This review highlights the possibility of using the chemokine/chemokine receptor axis as a promising strategy in cancer therapy, the current difficulties in achieving this goal, and how it could be overcome for successful future therapeutic intervention. © 2015.

Cancer letters

Conditioning solid tumor microenvironment through inflammatory chemokines and S100 family proteins

Over the last two decades, organogels have found tremendous use in the pharmaceutical, food, and cosmetics industries with notable developments as drug delivery matrices and trans and saturated fat replacers in processed foods. The functionality of organogels benefits from their ease of preparation, cost effectiveness, and ability to contain both hydrophilic and lipophilic constituents. This review provides thorough insight into different organogelators, their mechanisms of organogel formation, various characterization techniques and their biocompatibility when administered in vivo. Finally, a special treatise is given on the applications of organogels as controlled drug delivery vehicles for topical, dermal/transdermal, parenteral, oral, and nasal routes. In situ forming organogels and their potential for tailored release of incorporated active ingredients are also discussed. Copyright © Taylor & Francis Group, LLC.

Soft Materials

Organogels as matrices for controlled drug delivery: A review on the current state

In primates, the motor cortex consists of at least seven different areas, which are involved in movement planning, coordination, initiation, and execution. However, for rats, only the primary motor cortex has been well described. A rostrally located second motor area has been proposed, but its extent, organization, and even definitive existence remain uncertain. Only a rostral forelimb area (RFA) has been definitively described, besides few reports of a rostral hindlimb area. We have previously proposed existence of a second whisker area, which we termed the rostral whisker area (RWA), based on its differential response to intracortical microstimulation compared with the caudal whisker area (CWA) in animals under deep anesthesia (Tandon et al. [2008] Eur J Neurosci 27:228). To establish that RWA is distinct from the caudally contiguous CWA, we determined sources of thalamic inputs to the two proposed whisker areas. Sources of inputs to RFA, caudal forelimb area (CFA), and caudal hindlimb region were determined for comparison. The results show that RWA and CWA can be distinguished based on differences in their thalamic inputs. RWA receives major projections from mediodorsal and ventromedial nuclei, whereas the major projections to CWA are from the ventral anterior, ventrolateral, and posterior nuclei. Moreover, the thalamic nuclei that provide major inputs to RWA are the same as for RFA, and the nuclei projecting to CWA are same as for CFA. The results suggest that rats have a second rostrally located motor area with RWA and RFA as its constituents. J. Comp. Neurol. 522:528-545, 2014. © 2013 Wiley Periodicals, Inc.