Biology subjects

Singh, R. S.

Publications and source records attributed to Singh, R. S..

6 recordsLinked to original sources

bioRxiv2025

Anomalous Thermoresponsive Phase Behavior in a Minimal Lattice Model Mimicking Proteins

Proteins are known to phase separate and form biomolecular condensates that play key roles in cellular functions. Therefore, there is now a growing interest in understanding rational design principles for protein sequences that exhibit rich stimulus-responsive phase behavior. Here, we have developed a minimal lattice-gas model and employed Monte-Carlo simulations to capture rich thermoresponsive phase behavior -- often observed in computational and experimental studies on disordered proteins. Proteins are modelled as particles with two internal states: a ground state representing the native configuration and a degenerate excited state representing unfolded configurations. The computed phase diagrams reveal an anomalous reentrant phase separation behavior with both upper and lower critical solution temperatures, providing insights into its underlying mechanism. We also explored non-equilibrium effects, such as non-Boltzmann population distribution of native and unfolded states, and enhanced translational diffusion due to non-thermal noise on the phase separation. We find that these factors offer an additional dimension for modulating condensate morphologies. We further extended our model to study phase separation in binary protein mixtures and successfully reproduced complex phase-separated states, including wetted, partially wetted, and segregative phases -- observed in computational studies on binary protein mixtures. This model can be easily extended to mimic proteins with multiple internal (partially folded) states, allowing exploration of conformation heterogeneity effects on condensate morphologies. Our findings offer important insights into designing solvent-mediated effective interactions between proteins for controlled phase separation, relevant for engineering functional condensates.

biophysics↗

bioRxiv2023

Discovery & Evaluation of novel fluorescence molecules for selective recognition of G-quadruplexes structure

Currently, G-quadruplex structure targeting strategies are considered as a promising anticancer approach. In the search of selective and potent G-quadruplex binders, Here we discuss an analysis of a few chroman derivatives ligands: (A) chroman 7-[2-pyrrolo]-pyrrole-[1,2-a]12H pyrrolino[2,3-b]chroman-4-one, and (C) 4-methyl-7-[2-pyrrolo]-pyrrole[1,2-a]12H pyrrolino[2,3-b]chroman-4-one and their respective borondifluoride complexes B and D as a quadruplex targeting compounds which found to stabilize G-quadruplex structure. To investigate the binding characteristics of these molecules with G-quadruplex vs. duplex selectivity, In vitro biophysical studies were performed by steady-state fluorescence, UV-visible titration, fluorescent TO displacement assay, CD thermal melting, circular dichroism spectroscopy, and cellular imaging by employing both telomeric and PRCC G-quadruplex forming sequences. Our investigation shows that these chromam ligands and their complexes are able to selectively bind and stabilize parallel and mixed hybrid topology of G-quadruplex both In vitro and in cellular conditions. A molecular docking study also suggests the binding of these compounds with G-quadruplex conformation. Collectively our study suggests these chroman complexes as a potentially useful fluorescent chemical product for G-quadruplex specific ligands and expands an option for G-quadruplex targeting ligands.

biochemistry↗

bioRxiv2023

Repeat investigation during social preference behavior is suppressed in male mice with prefrontal cortex cacna1c (Cav1.2)-deficiency through the dysregulation of neural dynamics

Impairments in social behavior are observed in a range of neuropsychiatric disorders and several lines of evidence have demonstrated that dysfunction of the prefrontal cortex (PFC) plays a central role in social deficits. We have previously shown that loss of neuropsychiatric risk gene Cacna1c that codes for the Cav1.2 isoform of L-type calcium channels (LTCCs) in the PFC result in impaired sociability as tested using the three-chamber social approach test. In this study we aimed to further characterize the nature of the social deficit associated with a reduction in PFC Cav1.2 channels (Cav1.2PFCKO mice) by testing male mice in a range of social and non-social tests while examining PFC neural activity using in vivo GCaMP6s fiber photometry. We found that during the first investigation of the social and non-social stimulus in the three-chamber test, both Cav1.2PFCKO male mice and Cav1.2PFCGFP controls spent significantly more time with the social stimulus compared to a non-social object. In contrast, during repeat investigations while Cav1.2PFCWT mice continued to spend more time with the social stimulus, Cav1.2PFCKO mice spent equal amount of time with both social and non-social stimuli. Neural activity recordings paralleled social behavior with increase in PFC population activity in Cav1.2PFCWT mice during first and repeat investigations, which was predictive of social preference behavior. In Cav1.2PFCKO mice, there was an increase in PFC activity during first social investigation but not during repeat investigations. These behavioral and neural differences were not observed during a reciprocal social interaction test nor during a forced alternation novelty test. To evaluate a potential deficit in reward-related processes, we tested mice in a three-chamber test wherein the social stimulus was replaced by food. Behavioral testing revealed that both Cav1.2PFCWT and Cav1.2PFCKO mice showed a preference for food over object with significantly greater preference during repeat investigation. Interestingly, there was no increase in PFC activity when Cav1.2PFCWT or Cav1.2PFCKO first investigated the food however activity significantly increased in Cav1.2PFCWT mice during repeat investigations of the food. This was not observed in Cav1.2PFCKO mice. In summary, a reduction in Cav1.2 channels in the PFC suppresses the development of a sustained social preference in mice that is associated with lack of PFC neuronal population activity that may be related to deficits in social reward.

neuroscience↗

bioRxiv2022

Men in menopause? Experimental verification of the mate choice theory of menopause with Drosophila melanogaster

Various hypotheses regarding the origin of menopause have been proposed, and although the kin-selection-based theory appears promising, it involves population genetic processes that are insufficient to compensate for loss of fitness. The grandmother hypothesis and its variation the live long hypothesis are untenable; the former requires "climbing a steep fitness hill", as grandmothers share only 25% of their genes with their grandchildren, compared to 50% with their direct offspring, while the latter proposes a prolongation of the post-menopausal lifespan through selection, which is impossible in a population of non-reproducing females. The mate choice theory explains menopause as the result of asymmetric mating involving younger females and older males that leads to an accumulation of infertility mutations and the evolution of menopause in older females. In this study, we investigated the mate choice theory using an infertility mutation accumulation experiment with Drosophila melanogaster that involved mating between individuals of different age groups. After 70 generations of asymmetric mating, the results showed that younger females who were paired with older males showed declining fertility in old age. The same trend was noted with younger males when mated with older females; the fertility of the males declined in old age. These results support the mate choice theory and indicate that menopause is not a life history trait of females but of the sex of the younger mate. Mate choice theory treats the evolution of menopause and post-menopausal lifespan as independent traits that are driven by the mate choices exercised by older males. Menopause may be an atypical process because the evolutionary mechanism (age-restricted asymmetric mating) involved is rarely observed.

evolutionary biology↗

bioRxiv2020

Genome-Wide High Resolution Expression Map and Functions of Key Cell Fate Determinants Reveal the Dynamics of Crown Root Development in Rice

Shoot borne adventitious/crown roots (AR/CR) shape up the root architecture in grasses. Mechanisms underlying initiation and subsequent outgrowth of CR remain largely unknown. Here, we provide genome-wide modulation in the landscape of transcriptional signatures during distinct developmental stages of CR formation in highly derived grass species, rice. Our studies implicate the role of potential epigenetic modifiers, transcription factors and cell division regulators in priming the initiation of CR primordia followed by progressive activation of conserved transcription regulatory modules to ensure their outgrowth. In depth analysis of spatio-temporal expression patterns of key cell fate determinants and functional analyses of rice WUSCHEL RELATED HOMEOBOX10 (OsWOX10) and PLETHORA (OsPLT1) genes reveal their unprecedented role in controlling root architecture. We further show that OsPLT1 activates local auxin biosynthesis and forms an integral part of ERF3-OsWOX11-OsRR2 regulatory module during CR primordia development. Interestingly, OsPLT genes, when expressed in the transcriptional domain of root-borne lateral root primordia of Arabidopsis plt mutant, rescued their outgrowth demonstrating the conserved role of PLT genes in root primordia outgrowth irrespective of their developmental origin. Together, these findings unveil the molecular framework of cellular reprogramming during trans-differentiation of shoot tissue to root leading to culmination of robust root architecture in grass species which got evolutionary diverged from dicots.

plant biology↗

bioRxiv2020

A long tail of truth and beauty: The developmental basis of complexity, symmetry, and beauty in the evolution of the peacocks tail.

One hundred and fifty years after the publication of Darwins sexual selection theory, the problem of the peacocks train remains unsolved. Darwin assumed that the peacocks long train was maladaptive and was the indirect effect of selection by female mate choice based on the trains beauty. While a relationship between the feathers elaborate features and mating success has been shown, the concept of eyespots as the basis of female choice remains controversial. We examined the anatomical plan underlying feather development using museum specimens and observed a zigzag pattern of feather follicles that determined both the number and the hexagonal arrangement of eyespots on the train as well as, strikingly, the individual eyespots color rings. While the zigzag pattern explains the symmetry, complexity, and structural beauty of the peacocks train, it also precludes individual eyespot variation. The only available variation in eyespot number is expected to be due to annual addition of new rows of 10/11 feathers as a function of age, giving rise to an inherently determined eyespot number. New insights show that eyespot number and feather length are developmentally correlated and an asymptotic function of a males age, that their effects on female choice would be confounded and inseparable, and that male vigor would be a crucial factor affecting male fitness. Females may not always choose males with the largest number of eyespots, as older males may lack vigor. We propose a multimodal model of female choice based on male size, vigor, and beauty where females see eyespot and train size not as separate traits but as one complex trait combining both. The new model may be able to explain conflicting results and why eyespot number alone may not be sufficient to explain female choice. Beauty is truth, truth beauty. Keats

evolutionary biology↗