Biology subjects

Dagar, S.

Publications and source records attributed to Dagar, S..

8 recordsLinked to original sources

bioRxiv2024

On the epistemic role of hippocampal cells: the case of splitter cells

During the past decades, hippocampal formation has undergone extensive studies, leading researchers to identify a vast collection of cells with functional properties. Several investigations, supported by carefully crafted models, have examined the origin of such cells. The most recent models hypothesize that temporal sequences underlie the observed spatial properties. We aim at investigating whether a random recurrent structure is sufficient to allow such latent sequence to appear. To do so, we simulated an agent with egocentric sensory inputs that must navigate and alternate choices at intersections. We were subsequently able to identify several splitter cells inside the model. Remarkably, when we systematically lesioned the identified splitter cells, the models behavioral performance remained intact: in the vast majority of cases, new splitter cells re-emerged through network reorganization, while in the remaining cases, the task was solved without any detectable splitter cells, demonstrating that splitter cells are not necessary to the task resolution. Position, orientation, and decision representations could also be successfully decoded from the reservoir activity, even after repeated lesioning. Subspace alignment analysis further revealed that this reorganization preserves the task-relevant population geometry while redistributing activity within the null sub-space, with the trajectory-encoding dimension rotating in neuron space across lesions. Together, these findings demonstrate that splitter cell activity is primarily task-driven and does not derive from a specific architecture or learning rule: splitter cells emerge generically across random recurrent networks that successfully solve the task, across a broad and robust range of dynamical parameters, and are not necessary for task performance. Our results therefore challenge the notion of functional necessity for specific neural populations.

neuroscience↗

bioRxiv2022

Nonenzymatic template-directed replication using 2'-3' cyclic nucleotides under wet-dry cycles

RNA World Hypothesis is centred around the idea of a period in the early history of lifes origin, wherein nonenzymatic oligomerization and replication of RNA resulted in functional ribozymes. Previous studies in this endeavour have demonstrated template-directed replication using chemically modified nucleotides and primers. Nonetheless, similar studies that used non-activated nucleotides led to the formation of RNA only with abasic sites. In this study, we report template-directed replication with prebiotically relevant cyclic nucleotides, under dehydration-rehydration (DH-RH) cycles occurring at high temperature (90{degrees}C) and alkaline conditions (pH 8). 2'-3' cyclic nucleoside monophosphates (cNMP) resulted in primer extension, while 3'-5' cNMP failed to do so. Intact extension of up to two nucleotide additions was observed with both canonical hydroxy-terminated (OH-primer) and activated amino-terminated (NH2-primer) primers. We demonstrate primer extension reactions using both purine and pyrimidine 2'-3' cNMPs, with higher product yield observed during cAMP additions. Further, the presence of lipid was observed to significantly enhance the extended product in cCMP reactions. In all, our study provides a proof-of-concept for nonenzymatic replication of RNA, using intrinsically activated prebiotically relevant cyclic nucleotides as monomers.

biochemistry↗

bioRxiv2022

pH-responsive self-assembled compartments as tuneable model protocellular membrane systems

Prebiotically plausible single-chain amphiphiles are enticing as model protocellular compartments to study the emergence of cellular life owing to their self-assembling properties. Here, we investigated the self-assembly behaviour of mono-N-dodecyl phosphate (DDP) and mixed systems of DDP with dodecyl 1-dodecanol (DOH) at varying pH conditions. Membranes composed of DDP showed pH-responsive vesicle formation in a wide range of pH with a low critical bilayer concentration (CBC). Further, the addition of DOH to DDP membrane system enhanced vesicle formation and stability in alkaline pH regimes. We also compared the high-temperature behaviour of DDP and DDP-DOH membranes with conventional fatty acid membranes. Both, DDP and DDP:DOH mixed membranes possess packing that is similar to decanoic acid membrane. However, the micropolarity of these systems are similar to phospholipid membranes. Finally, the pH-dependent modulation of different phospholipid membranes doped with DDP was also demonstrated to engineer tuneable membranes with potential translational implications.

biochemistry↗

bioRxiv2021

Porphyrin in prebiotic catalysis: Ascertaining a route for the emergence of early metalloporphyrins

Metal ions are known to catalyze certain prebiotic reactions. However, the transition from metal ions to extant metalloenzymes remains unclear. Porphyrins are found ubiquitously in the catalytic core of many ancient metalloenzymes. In this study, we evaluated the influence of porphyrin-based organic scaffold, on the catalysis, emergence and putative molecular evolution of prebiotic metalloporphyrins. We studied the effect of porphyrins on the transition metal ion-mediated oxidation of hydroquinone (HQ). We report a change in the catalytic activity of the metal ions in the presence of porphyrin. This was observed to be facilitated by the coordination between metal ions and porphyrins or by formation of non-coordinated complexes. The metal-porphyrin complexes also oxidized NADH, underscoring its versatility at oxidizing more than one substrate. Our study highlights the selective advantage that some of the metal ions would have had in the presence of porphyrin, underscoring their role in shaping the evolution of protometalloenzymes.

biochemistry↗

bioRxiv2021

Transsynaptic N-cadherin adhesion complexes control presynaptic vesicle and bulk endocytosis at physiological temperature

At mammalian glutamatergic synapses, most basic elements of synaptic transmission have been shown to be modulated by specific transsynaptic adhesion complexes. However, although crucial for synapse homeostasis, a physiological regulation of synaptic vesicle endocytosis by adhesion molecules has not been firmly established. The homophilic adhesion protein N-cadherin is localized at the peri-active zone, where the highly temperature dependent endocytosis of vesicles occurs. Here, we demonstrate an important modulatory role of N-cadherin in endocytosis at near physiological temperature by synaptophysin-pHluorin imaging. Different modes of endocytosis including bulk endocytosis were dependent on N-cadherin expression and function. N-cadherin modulation was mediated by actin filaments, because actin polymerization rescued the knockout induced endocytosis defect. Using super-resolution imaging, we found a strong recruitment of N-cadherin to glutamatergic synapses upon massive vesicle release, which might in turn enhance vesicle endocytosis. This provides a novel, adhesion protein mediated mechanism for efficient coupling of exo- and endocytosis.

neuroscience↗

bioRxiv2019

Geochemical influences on nonenzymatic oligomerization of prebiotically relevant cyclic nucleotides

The spontaneous emergence of RNA on the early Earth continues to remain an enigma in the field of origins of life. Few studies have looked at the nonenzymatic oligomerization of cyclic nucleotides under neutral to alkaline conditions, in fully dehydrated state. Herein, we systematically investigated the oligomerization of cyclic nucleotides under prebiotically relevant conditions, where starting reactants were subjected to repeated dehydration-rehydration (DH-RH) regimes, like they would have been on an early Earth. DH-RH conditions, a recurring geological theme, are driven by naturally occurring processes including diurnal cycles and tidal pool activity. These conditions have been shown to facilitate uphill oligomerization reactions in terrestrial geothermal niches, which are hypothesized to be pertinent sites for the emergence of life. 2'-3' and 3'-5' cyclic nucleotides of one purine-based (adenosine) and one pyrimidine-based (cytidine) system were evaluated in this study. Additionally, the effect of amphiphiles was also investigated. Furthermore, to discern the effect of realistic conditions on this process, the reactions were also performed using hot spring water samples from an early Earth analogue environment. Our results showed that the oligomerization of cyclic nucleotides under DH-RH conditions resulted in intact informational oligomers. Amphiphiles increased the stability of, both, the starting monomers and the resultant oligomers. In analogue condition reactions, oligomerization of nucleotides and back-hydrolysis of the resultant oligomers was pronounced. Altogether, this study demonstrates how nonenzymatic oligomerization of cyclic purine and pyrimidine nucleotides, under laboratory-simulated and early Earth analogous conditions, could have resulted in RNA oligomers of a putative RNA World.

biochemistry↗

bioRxiv2019

Compositional heterogeneity of protocellular membranes: Implications for emergence of mixed vesicular systems

Protocells are primitive cellular entities that are thought to have emerged during the dawn of life on Earth. Their membranes are considered to be made up of mixtures of single chain amphiphiles, such as fatty acids and their derivatives, moieties that would have been part of the complex prebiotic chemical landscape. In addition to their composition, the physico-chemical properties of these prebiological membranes would have been significantly affected and regulated by the physical environment that they were present in. In this study, the physico-chemical properties of two different chain length membrane systems were systematically characterized, under pertinent early Earth conditions. The membrane systems were designed to comprise a fatty acid and its alcohol and/or glycerol monoester derivative, to make a range of binary and tertiary vesicle combinations. Their properties were then evaluated as a function of multiple factors including their composition, stability under varying pH, Mg2+ ion concentrations and dilution regimes, and their permeability to small molecules. Our results demonstrate how these environmental constraints would have acted as important prebiotic selection pressures to shape the evolution of prebiological membranes. This study also illustrates how different fatty acid derivatives confer varying degree of stability when combined with their respective fatty acid moiety. Interestingly, when the membrane systems were subjected to multiple selection pressures in a consecutive manner, only the heterogeneous membrane systems survived the race. Our results illustrate that compositionally diverse membrane systems are more stable and robust to multiple selection pressures, thereby making them more suitable for supporting protocellular life.\n\nSignificance statementThe physico-chemical environment would have played an important role in shaping the composition and evolution of primitive membrane systems. This study demonstrates the importance of compositional heterogeneity on the stability of protomembrane systems under pertinent prebiotic selection pressures. Two different fatty acid based systems were mixed with their respective alcohol and/or glycerol monoester derivatives, to generate combinations of binary and tertiary membrane systems. Increasing chain length effected the physical property of the membranes thus affecting their stability. Furthermore, we also demonstrate how the head groups of the derivatives employed in this study (e.g. glycerol monoester and alcohol) contribute differently towards stabilizing the mixed membranes under a given selection condition, by discerning the molecular mechanism underlying this process. Our results illustrate how multiple selection pressures would have preferentially supported the emergence of compositionally heterogeneous membrane systems.

biochemistry↗

bioRxiv2018

Horizontal gene transfer as an indispensible driver for Neocallimastigomycota evolution into a distinct gut-dwelling fungal lineage

Survival and growth of the anaerobic gut fungi (AGF, Neocallimastigomycota) in the herbivorous gut necessitate the possession of multiple abilities absent in other fungal lineages. We hypothesized that horizontal gene transfer (HGT) was instrumental in forging the evolution of AGF into a phylogenetically distinct gut-dwelling fungal lineage. Patterns of HGT were evaluated in the transcriptomes of 27 AGF strains, 22 of which were isolated and sequenced in this study, and 4 AGF genomes broadly covering the breadth of AGF diversity. We identified 283 distinct incidents of HGT in AGF transcriptomes, with subsequent gene duplication resulting in an HGT frequency of 2.1-3.6% in AGF genomes. The majority of HGT events were AGF specific (91.5%) and wide (70.7%), indicating their occurrence at early stages of AGF evolution. The acquired genes allowed AGF to expand their substrate utilization range, provided new venues for electron disposal, augmented their biosynthetic capabilities, and facilitated their adaptation to anaerobiosis. The majority of donors were anaerobic fermentative bacteria prevalent in the herbivorous gut. This work strongly indicates that HGT indispensably forged the evolution of AGF as a distinct fungal phylum and provides a unique example of the role of HGT in shaping the evolution of a high rank taxonomic eukaryotic lineage. ImportanceThe anaerobic gut fungi (AGF) represent a distinct basal phylum lineage (Neocallimastigomycota) commonly encountered in the rumen and alimentary tracts of herbivores. Survival and growth of anaerobic gut fungi in these anaerobic, eutrophic, and prokaryotes dominated habitats necessitates the acquisition of several traits absent in other fungal lineages. This manuscript assesses the role of horizontal gene transfer as a relatively fast mechanism for trait acquisition by the Neocallimastigomycota post sequestration in the herbivorous gut. Analysis of twenty-seven transcriptomes that represent the broad Neocallimastigomycota diversity identified 283 distinct HGT events, with subsequent gene duplication resulting in an HGT frequency of 2.1-3.6% in AGF genomes. These HGT events have allowed AGF to survive in the herbivorous gut by expanding their substrate utilization range, augmenting their biosynthetic pathway, providing new routes for electron disposal by expanding fermentative capacities, and facilitating their adaptation to anaerobiosis. HGT in the AGF is also shown to be mainly a cross-kingdom affair, with the majority of donors belonging to the bacteria. This work represents a unique example of the role of HGT in shaping the evolution of a high rank taxonomic eukaryotic lineage.

microbiology↗