Biology subjects

Mohanty, B.

Publications and source records attributed to Mohanty, B..

9 recordsLinked to original sources

bioRxiv2026

Spontaneous eye behavior is an objective marker of parkinsonian severity

Eye behavior disruption is reported in Parkinson's disease (PD), but its correlation with disease severity has not been well examined. Here, in a nonhuman primate model of PD, we show that spontaneous eye behavior is impaired in parkinsonism and correlates with clinical rating scores and subthalamic beta oscillatory activity. These findings suggest that spontaneous eye behavior could serve as an objective, non-invasive biomarker of parkinsonian severity.

neuroscience↗

bioRxiv2026

Remodelling of chromatin architecture and super-enhancer landscape in lamin A/C depleted HGSOC

Lamins are nuclear intermediate filament proteins that maintain nuclear architecture through interactions with the chromatin. The A- and B-type lamins tether the genome at the peripheral lamina underlying the inner nuclear membrane in the form of heterochromatic lamina-associated domains (LADs). However, LADs associated with A-type lamins are confined not only to lamina but also to the nuclear core, thereby pointing to their distinct and multifarious roles in chromatin organisation and regulation. Previous studies involving lamin B1 depletion depicted the detachment of LADs from the nuclear periphery, accompanied by alteration of chromatin distribution while preserving the topologically associating domains (TADs) in structurally intact form. In this piece of work, we have shown, for the first time in HGSOC, the effects of lamin A/C knockdown on chromatin organisation, which was characterised by significant detethering of gene-poor chromatin from the periphery along with active (A) to inactive (B) compartment switching. This was associated with a rewiring of oncogenic super-enhancer elements corroborated by the differential gene expression profile. Overall analysis tipped the scale in favour of reduced cellular proliferation upon lamin A/C knockdown. This finding was strengthened by the observed proliferative potential of spheroids ex vivo and tumours in a mouse xenograft model.

cancer biology↗

bioRxiv2026

Parkinsonism disrupts the population-level organization of cortical dynamics

Parkinsons disease (PD) is marked by impairments in voluntary movement, including prolonged movement preparation and execution, yet how parkinsonism alters neural processing to produce these deficits remains unresolved. Prior work examining M1 spiking activity in parkinsonian states has largely characterized firing-rate changes and motor representations at the level of individual neurons, with inconsistent results and limited insight into population-level organization. Here we investigated how parkinsonism reshapes the population-level organization of neural activity in M1 during movement. We simultaneously recorded large populations of neurons from M1 in two nonhuman primates performing reaching tasks before and after induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the parkinsonian state, both preparation and reach durations were significantly prolonged. Population-level analyses revealed that parkinsonism increased the dimensionality of M1 activity during both preparation and movement and reduced the orthogonality between preparatory and movement-related subspaces. Moreover, trial-by-trial variability in reach duration was explained by the alignment of the preparatory and reach subspaces, indicating the functional role of subspace orthogonality. Together, these findings suggest that parkinsonism disrupts the population-level organization of cortical dynamics across computations, providing a population-level framework linking altered cortical dynamics to the movement-related dysfunction observed in PD.

neuroscience↗

bioRxiv2025

Peptide molecular glues select between BET paralogues by exploiting allosteric sites and conformational dynamics

Achieving selective target inhibition is critical for minimising drug side effects. This can be especially challenging when targeting individual members of protein families with high sequence similarity. A well-recognised example is the Bromodomain and Extraterminal domain (BET) family of proteins. Chemical inhibition of the acetyllysine (AcK)-binding bromodomains (BDs) of BET proteins has shown considerable promise in a range of disease models. However, despite over a decade of medicinal chemistry efforts, it has proven challenging to develop BET BD inhibitors that exhibit high selectivity between BET family paralogues. Cyclic peptides are versatile scaffolds for therapeutic development and often exhibit high selectivity and affinity for their targets. To explore their potential as selective BET BD inhibitors, we have used mRNA display to identify cyclic peptide ligands for the N-terminal BD of BRD2 and BRD4. The structurally diverse cyclic peptides enriched from the selections boast superior selectivity and affinity to previously developed inhibitors. Most strikingly, we isolated cyclic peptides with [~]1000-fold higher affinity for their target BD over the paralogous BDs, far surpassing selectivities reported to date. Our biochemical and structural data suggest that paralogue-selective cyclic peptides act as molecular glues, exploiting both subtle sequence differences at locations far from the AcK-binding pocket and differences in conformational dynamics between BET BD paralogues to achieve this unprecedented level of specificity. This work provides a blueprint for the development of new classes of selective BET inhibitors and, more generally, underscores the potential of exploiting protein dynamics in the design of selective ligands.

biochemistry↗

bioRxiv2025

Transcranial Alternating Current Stimulation can disrupt or reestablish neural entrainment in a primate model of Parkinson's disease

Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method which can affect brain oscillations by inducing neuronal entrainment through modulation of spike timings. tACS has high potential for clinical applications in many neurological disorders in which the stimulation can be delivered to modulate oscillatory activity and disrupt pathological brain oscillations. For instance, in Parkinsons Disease (PD), electrophysiological activity in the motor network often exhibits excessive and hyper-synchronized beta oscillations. However, the development of tACS as a therapeutic intervention for pathological oscillations requires the prior establishment of physiologically effective stimulation parameters. We recorded neuronal activity in the motor cortical area of three parkinsonian non-human primates and examined the influence of tACS-induced electric fields on neural firing patterns. We found that weak extracellular electric fields first disrupt beta-band spike timing patterns by changing the preferred spiking phase of neurons but eventually reestablish neural entrainment with altered phase preferences when electric fields are high. Additionally, we show that frequency-matched stimulation, when stimulation frequency corresponds to endogenous oscillatory activity, significantly enhances neural entrainment. Thus, tACS exhibits significant potential for controlling and modulating pathological oscillatory patterns in many neurological disorders such as PD.

neuroscience↗

bioRxiv2024

Impairment of Neuronal Activity in the Dorsolateral Prefrontal Cortex Occurs Early in Parkinsonism

BackgroundParkinsons disease (PD) is often characterized by altered rates and patterns of neuronal activity in the sensorimotor regions of the basal ganglia thalamocortical network. Little is known, however, regarding how neuronal activity in the executive control network of the brain changes in the parkinsonian condition. ObjectiveInvestigate the impact of parkinsonism on neuronal activity in the dorsolateral prefrontal cortex (DLPFC), a key region in executive control, during a go/nogo reaching task. MethodsUsing a within-subject design, single and multi-unit neuronal activity was recorded in the DLPFC of a nonhuman primate before and after the induction of mild parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). ResultsCoincident with development of mild parkinsonian motor signs, there was a marked reduction in the percentage of DLPFC cells with significant task-related firing rate modulation during go and nogo conditions. ConclusionsThese results suggest that DLPFC dysfunction may occur early in parkinsonism and contribute to cognitive impairments and disrupted executive function often observed in PD patients.

neuroscience↗

bioRxiv2022

Classification of electrically-evoked compound action potentials in the parkinsonian subthalamic nucleus of non-human primates

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinsons disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n=3) or non-directional (n=1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6-7.4 ms after a stimulus pulse). Using these ECAP features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinsons disease with DBS therapy.

neuroscience↗

bioRxiv2021

Identification and characterization of two drug-like fragments that bind to the same cryptic binding pocket of Burkholderia pseudomallei DsbA

DiSulfide Bond forming proteins (DSB) play a crucial role in the pathogenicity of many Gram-negative bacteria. Disulfide bond protein A (DsbA) catalyzes the formation of disulfide bonds necessary for the activity and stability of multiple substrate proteins, including many virulence factors. Hence, DsbA is an attractive target for the development of new drugs to combat bacterial infections. Here, we identified two fragments - 1 (bromophenoxy propanamide) and 2 (4-methoxy-N-phenylbenzenesulfonamide), that bind to the DsbA from the pathogenic bacterium Burkholderia pseudomallei, the causative agent of melioidosis. Crystal structures of the oxidized B. pseudomallei DsbA (termed BpsDsbA) co-crystallized with 1 or 2 suggests that both fragments bind to a hydrophobic pocket that is formed by a change in the side chain orientation of tyrosine 110. This conformational change opens a "cryptic" pocket that is not evident in the apo-protein structure. This binding location was supported by 2D-NMR studies which identified a chemical shift perturbation of the tyrosine 110 backbone amide resonance of more than 0.05 ppm upon addition of 2 mM of fragment 1 and over 0.04 ppm upon addition of 1 mM of fragment 2. Although binding was detected by both X-ray crystallography and NMR, the binding affinity (KD) for both fragments was low (above 2 mM), suggesting weak interactions with BpsDsbA. This conclusion is also supported by the modelled crystal structures which ascribe partial occupancy to the ligands in the cryptic binding pocket. Small fragments such as 1 and 2 are not expected to have high binding affinity due to their size and the relatively small surface area that can be involved in intermolecular interactions. However, their simplicity makes them ideal for functionalization and optimization. Identification of the binding sites of 1 and 2 to BpsDsbA could provide a starting point for the development of more potent novel antimicrobial compounds that target DsbA and bacterial virulence. SynopsisDescribes the binding properties of two drug-like fragments to a conformationally dynamic site in the disulfide-bond forming protein A from Burkholderia pseudomallei.

molecular biology↗

bioRxiv2018

ERBB2 and KRAS Alterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

The uncommonness of gallbladder cancer has contributed to the generally poor understanding of the disease, with scant reports restricted to advance-stage tumors. Here, using an integrated analysis of whole exome and phospho-proteome, we show recurrent activating ERBB2 and KRAS somatic mutations are present in 6 and 3 of 44 early-stage rare gallbladder tumors, respectively. In vitro and in vivo cell-based and biochemical assays reveal an essential role of ErbB pathway activation for the survival of gallbladder cells. Interestingly, the genetic and pharmacological dependencies of gallbladder cells are dependent on the KRAS mutant allele status, reminiscent of the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer. In overall, we present the first evidence that the presence of KRAS (G12V), but not KRAS (G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, leading to an early adoption of an approved treatment regimen for gallbladder cancer patients.

cancer biology↗