Biology subjects

Konar, S.

Publications and source records attributed to Konar, S..

7 recordsLinked to original sources

bioRxiv2026

Ancient human genomes from Ladakh reveal Tibetan, South Asian, and Central Asian admixture over the last three millennia

The trans-Himalayan region of Ladakh occupies a strategic position at the crossroads of South Asia, the Tibetan Plateau, and Central Asia, with archaeological evidence pointing to long-term cultural exchanges across these regions. However, the human genetic history of Ladakh remains largely unexplored. We generated paleogenomic data from seven individuals recovered from two sites in Western Ladakh - the Old Lady Spider Cave and Hanu - of which six are dated to 531-585 CE and one to the 19th century CE. The older individuals share substantial genetic ancestry with Tibetan groups but also harbor major contributions from two additional sources: one corresponding to the currently-oldest observation of the Ancestral North Indian genetic component that characterizes several present-day populations in North India and Pakistan, and another related to ancient Central Asian groups, with admixture events occurring between [~]2,100-2,500 years ago. In contrast, the later individual falls within a previously described ancient northern Himalayan genetic cline based on [~]1,100-1,300-year-old individuals from Himachal Pradesh, with ancestries related to ancient Tibetan and Steppe-related sources. Stable isotope analysis suggests that these individuals were local to Ladakh in late life and practiced an agro-pastoralist subsistence. Our study establishes that Ladakhs central role in Eurasian economic and socio-cultural networks was shaped by dynamic and sustained gene flow linking high-altitude Himalayan groups with both lowland South Asia and Inner Asia.

genetics↗

bioRxiv2024

Design and synthesis of triazine-based hydrogel for combined targeted doxorubicin delivery and PI3Kinhibition

Melanoma, an aggressive skin cancer originating from melanocytes, presents substantial challenges due to its high metastatic potential and resistance to conventional therapies. Hydrogels, three-dimensional networks of hydrophilic polymers with high water-retention capacities, offer significant promise for controlled drug delivery applications. In this study, we report the synthesis and characterization of hydrogelators based on the triazine molecular scaffold, which self-assemble into fibrous networks conducive to hydrogel formation. Rheological analysis confirmed their hydrogelation properties, while microscopic techniques including FE-SEM and FEG-TEM provided insights into their morphological networks. The drug delivery capability of these hydrogelators was evaluated using doxorubicin, a widely employed anticancer agent, demonstrating enhanced biocompatibility and reduced side effects compared to free doxorubicin. Additionally, the hydrogelators exhibited inhibitory activity against phosphoinositide 3-kinase (PI3K), a key enzyme frequently mutated in cancer, and also involved in melanoma progression. The dual functionality of this delivery system - controlled drug release and PI3K inhibition - highlights the potential of triazine-based hydrogelators as innovative therapeutic platforms for melanoma treatment.

cancer biology↗

bioRxiv2024

The genetic landscape, gene flow and adaptation in Ladakh highlanders of trans-Himalayas

Trans-Himalayan Ladakh has witnessed complex cultural movements and demographic changes since the Neolithic period, which is still continue despite the harsh, inhospitable and cold climate. Although geographically isolated from mainland South Asia, Ladakh has historic trade routes and is well connected and accessible to travelers from Tibet and Central Asia. Despite its rich cultural heritage, a detailed description of the genetic landscape of the Ladakh region is completely lacking, particularly with regard to genome-wide analysis and larger sample sizes. Therefore, in the current study, we genotyped 80 individuals from Kargil and Leh districts of the Union Territory of Ladakh, India. Here, we performed a comprehensive genetic analysis based on allele frequency and haplotype sharing. Our analysis revealed the presence of two distinct genetic lineages in the region with quite distinct genetic composition. The population of Leh Region is more similar to East Asian and Southeast Asian populations. In contrast, the population of the Kargil Region (LDKLA) is more similar to Indo-European populations. Demographic modeling suggests that the Leh group shares a genetic history with Tibetans, while the Kargil group showed great affinities with Kashmiri Muslims, Gujjars and Nepalese Brahmins, and both showed recent admixture. Both groups have experienced a founder event around during 11th to 22nd generations ago, the duration of which coincided with the Mughal invasion. The genome-wide scan for a signal of positive selection revealed genetic signatures of high-altitude adaptation (EPAS1 and ELMO2) in the Leh population, while in the Kargil population the key gene signatures were associated with immunity and female fertility.

genetics↗

bioRxiv2023

Molecular dynamics analyses of CLDN15 pore size and charge selectivity

Claudin-15 (CLDN15) molecules form channels that directly regulate cation and water transport. In the gastrointestinal tract, this transport indirectly impacts nutrient absorption. However, the mechanisms governing ion transport through these channels remain poorly understood. We addressed this question by building on our previous cell culture studies and all atom molecular dynamic simulation model of CLDN15. By mutating D55 to a bulkier glutamic acid (E) or neutral amino acid asparagine (N), our in vitro measurements showed that the D55E mutation decreased charge selectivity and favored small ion permeability, while the D55N mutation led to reduced charge selectivity without markedly altering size selectivity. By establishing a simplified (reduced) CLDN15 molecular dynamics model that excludes non-essential transmembrane regions, we were able to probe how D55 modified cation dehydration, charge interaction, and permeability. These results provide novel insight into organization of the CLDN15 selectivity filter and suggests that D55 plays a dual role in shaping both electrostatic and steric properties of the pore, but its electrostatic role is more prominent in determining CLDN15 cation permeability. This knowledge can be used toward the development of effective strategies to modulate CLDN15 function. The experimental approach established can be further extended to study the function of other claudin channels. Together, these advancements will help us to modulate tight junctions to promote human health. SUMMARYCell culture and molecular dynamics simulations reveal the role of the CLDN15-D55 residue in ion size and charge selectivity. A reduced CLDN15 model offers novel insights into ion conductance, providing a valuable tool for therapeutic modulation of tight junctions.

physiology↗

bioRxiv2023

Palmitic acid reduces viability and increases production of reactive oxygen species and respiration in rat tendon-derived cells

Clinically, there is a positive correlation between BMI and the risk of tendinopathy. However, the underlying mechanisms are not understood. Dyslipidaemia and increased circulating free fatty acids (FFA) are associated with increased BMI. We hypothesised that increased FFA concentrations negatively affect rat tendon-derived cells (rTDCs) through mitochondrial-mediated mechanisms. rTDCs were isolated and treated with oleic acid (OA), stearic acid (SA), and palmitic acid (PA). Cell viability was assessed using AlamarBlue assay, and gene expression using real-time PCR. Cell respiration and reactive oxygen species (ROS) production were measured using high-resolution respirometry and MitoSox staining. PA transport into the mitochondria was blocked by pre-treatment with 50{micro}M etomoxir. Treatment with SA and PA at 10 {micro}g/ml decreased rTDC viability by 40% and 60%, respectively. PA decreased the gene expression of the tendon markers Scx and Tnmd, and increased the expression of Mmp3, Mmp13, and Ptgs2 (encoding Cox-2). FFA treatment increased the expression of Cpt1 and Pdk4, indicating an increase in mitochondrial FFA oxidation. PA, at 10 {micro}g/ml, increased cellular respiration and ROS production. Pre-treatment with etomoxir partially inhibited the effects of PA on cell viability, Mmp3 gene expression, ROS production, and cell respiration, but did not affect PA-induced inhibition of Scx or Tnmd expression. We found that increased saturated FFA concentrations in the microenvironment reduce cell viability and alter ROS production, respiration, and gene expression. Blocking PA transport into mitochondria partially reversed the negative effects of PA. Overall, an increase in saturated FFA concentrations may contribute to poor tendon health.

cell biology↗

bioRxiv2023

Mitochondrial Membranes: Model Lipid Compositions, Material Properties and the Changing Curvature of Cardiolipin

Mammalian and Drosophila Melanogaster model mitochondrial membrane compositions are constructed from experimental lipidomics data. Simplified compositions for inner and outer mitochondrial membranes are provided, including an asymmetric inner mitochondrial membrane. We performed atomistic molecular dynamics simulations of these membranes and computed their material properties. When comparing these properties to those obtained by extrapolation from their constituting lipids, we find good overall agreement. Finally, we analyzed the curvature effect of cardiolipin, considering ion concentration effects, oxidation and pH. We draw the conclusion that cardiolipin negative curvature is most likely due to counterion effects, such as cation adsorption, in particular of H3O+. This oft-neglected effect might account for the puzzling behavior of this lipid. SIGNIFICANCEMitochondrial membranes are of fundamental interest to the pathogenesis of neurodegenerative diseases. The biophysics of mitochondrial membranes can be expected to profoundly influence both the electron transport chain and larger-scale mitochondrial morphology. We provide model mitochondrial membrane compositions and examine their mechanic properties. Reconstructing these properties from their constituent lipids, we facilitate the creation of mesoscopic models. Cardiolipin, as the key mitochondrial lipid is given special attention. We find that its mechanical properties, in particular its curvature, are not constant, but highly dependent on specific ion effects, concentration and oxidation state.

biophysics↗

bioRxiv2019

Elucidating the regulation of glucose tolerance through the interaction between the reaction product and active site pocket residues of a β-glucosidase from Halothermothrix orenii

{beta}-glucosidase catalyzes the hydrolysis of {beta}-1,4 linkage between two glucose molecules in cello-oligosaccharides and is prone to inhibition by the reaction product glucose. Relieving the glucose inhibition of {beta}-glucosidase is a significant challenge. Towards the goal of understanding how glucose interacts with {beta}-glucosidase, we expressed in Escherichia coli, the Hore_15280 gene encoding a {beta}-glucosidase in Halothermothrix orenii. Our results show that the enzyme is glucose tolerant, and its activity stimulated in the presence of up to 0.5 M glucose. NMR analyses show the unexpected interactions between glucose and the {beta}-glucosidase at lower concentrations of glucose that however does not lead to enzyme inhibition. We identified non-conserved residues at the aglycone-binding and the gatekeeper site and show that increased hydrophobicity at the pocket entrance and a reduction in steric hindrances are critical towards enhanced substrate accessibility and significant improvement in activity. Analysis of structures and in combination with molecular dynamics simulations show that glucose increases the accessibility of the substrate by enhancing the structural flexibility of the active site pocket and may explain the stimulation in specific activity up to 0.5 M glucose. Such novel regulation of {beta}-glucosidase activity by its reaction product may offer novel ways of engineering glucose tolerance.

biochemistry↗