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Understanding the role of genetic variability in LRRK2 in Indian population
No full textBACKGROUND:
Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations.
OBJECTIVES:
To resolve the role of LRRK2 in the Indian population.
METHODS:
We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene.
RESULTS:
We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity.
CONCLUSIONS:
Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society
Formative evaluation of integrated diabetic care in TB patients in Primary Health Centres: a study in Trivandrum, Kerala
No full textDiabetes self-management practices among married men and women seeking treatment from hospitals in Bhubaneswar, Odisha: An exploratory qualitative study
No full textDegradation of Poly(-caprolactone) and bio-interactions with mouse bone marrow mesenchymal stem cells
No full textBio-inspired scaffolds in bone tissue engineering using multipotential mesenchymal stem cells grow at a
rapidrate foundits successfuluse inorthopedic injury treatment. Poly(-caprolactone)/PCL is widelyused
in medical devices, tissue engineering, and drug delivery systems. Most desirable property of biodegradable
polymer to be employed in medical application is synchronization of degradation with functional
tissue regeneration. Limited studies have incorporated the degradation kinetics and implication of degradation
products of pure unmodified PCL. The present study analyzes shortterm in vitro degradation profile
of PCL films in physiological condition. The study reports weight loss, changes in molecular weight distribution
and morphological variation in PCL thin film over a period of 90-day degradation. When the
degradable material is in contact with host tissue, there exists robust and dynamic microenvironment
controlling the cell functionality. To comprehend the biocompatibility aspects of polymer material, the
study considered mouse bone marrow mesenchymal stem cells (BMSCs) as model system mimicking
in vivo. There was no indication of toxicity revealed with MTT, LDH leakage, direct contact assay and
clonogenic assay. Absence of oxidative stress and apoptosis denotes BMSCs functional integrity sustained
upon exposure to PCL degradation products. Cell cycle analysis and DNA ladder assay confirmed cell survival
and genomic stability. The study revealed that the topography of pure unmodified PCL surface is
suitable for cell adhesion. It was also observed that the viability of differentiated cells (osteoblasts) was
maintained in presence of PCL extract. Furthermore, polymer and its degradation products were proved
to be hemocompatible. These results synergistically suggestthat pure unmodified PCL and its degradation
products are non-toxic at molecular level
TLR-4 expression in corrosion metal debri induced hypoxic milieu around stainless steel fracture plates.
No full textThe release of corrosion debris from metallic implants leading to adverse tissue reactions and pain has
jeopardized the lives of patients. This study attempts to observe if this holds true for widely used cost
efficient stainless steel fracture plates and screws by studying the microenvironment in the peri
prosthetic tissue of the retrieved implants. Fracture plates and nails along with adjacent tissues were
collected in 10% neutral buffered formalin. Cellular response was qualitatively evaluated using HE
staining and debris distribution was semi-quantitatively graded. Elemental composition of metallic
debris was analysed by ESEM-EDAX of the tissue sections. The presence of macrophages, endothelial
cells, TLR-4 and HIF-1αwere quantitated by Immunohistochemistry and histomorphometry.
Analysis of TLR-4 gene expression was carried out by real time PCR and the presence of a hypoxic
milieu was confirmed by PCR Array. This study demonstrates the corrosion debris initiated chronic
inflammatory reaction to stainless steel fracture plates. Nickel and Chromium ions released from
implants induce a hypoxic environment resulting in TLR-4 induction. These results emphasize the
need for identification of potential biomarker that could serve as a deciding factor for removal of
stainless steel fracture plates from patients prior to the onset of inflammation associated reaction and
also suggest the use of better manufacturing techniques and newer bio resorbable implants
Post Surgical Outcome of Long Term Epilepsy Associated Tumors (LEAT): A Retrospective Cohort Study
No full textCyclometalated Ir(III) complex as lysosome targeted photodynamic therapeutic agent for integrated imaging and therapy in cancer cells.
No full textOrganelle targeted photosensitizers (PSs) having
luminescence properties are potential theranostic agents for
simultaneous luminescence imaging and photodynamic therapy.
Herein, we report a water soluble luminescent cyclometalated Ir(III)
complex, Ir-Bp-Ly as lysosome targeted theranostic probe. Ir-Bp-Ly
exhibits exceptional photophysical properties of good triplet state
quantum yield (0.90), singlet oxygen generation quantum yield (0.71
at pH 4) and long lifetime (1.47 µs). Interestingly, Ir-Bp-Ly localized
mostly in the lysosome because of the presence of morpholine units,
suggesting its potential as a lyso-tracker. Ir-Bp-Ly displayed notable
PDT effect in C6 glioma cells, as these PS efficiently generated ROS
owing to the close proximity energy levels between triplet energy
states of Ir-Bp-Ly and molecular oxygen (3O2). The mechanism of
cell death was studied through caspase-3/7 and flow cytometry
analysis that clearly established the apoptotic pathway
