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Raghuraman, S.

Publications and source records attributed to Raghuraman, S..

5 recordsLinked to original sources

Molecular Characterization of Parabrachial Neurons in Xenopus laevis and Silurana tropicalis: Evolutionary Conservation and Sex-Specific Differences

Clawed frogs communicate acoustically to coordinate reproduction, with males producing species-specific advertisement calls to attract females. In Xenopus laevis, males generate fast trills composed of clicks repeated at 60 Hz, a feature absent in both Silurana tropicalis males and X. laevis females, whose calls consist of slower click rates (30 Hz and 7 Hz, respectively). In male X. laevis, fast trills are generated by premotor neurons in the parabrachial nucleus (PBN), known as Fast Trill Neurons (FTNs). We hypothesized that FTNs are unique in male X. laevis, and either absent or molecularly distinct in clawed frogs that do not produce fast trills. To test this, we used constellation pharmacology to profile receptor expression of neurons via intracellular Ca{superscript 2} responses to pharmacological agents in PBN neurons from male X. laevis, male S. tropicalis, and female X. laevis. Surprisingly, we found putative FTNs in all three groups, including those that do not produce fast trills. Furthermore, a similar proportion of FTNs across groups expressed fast-kinetic voltage-gated potassium channels known to support rapid firing, indicating that the presence of these channels does not correlate with the ability to produce fast trills. Instead, some of these channels were more prevalent in males of both species compared to female X. laevis, suggesting a potential sex-specific, non-vocal function. The discovery of FTNs with similar molecular profiles in non-fast-trilling individuals suggests that these neurons are conserved across species and sexes, and may serve other functions. In male X. laevis, FTNs may have been repurposed for fast trill production during speciation. These findings provide new insight into understanding how neural circuits evolve and diversify across species and sexes. Summary statementPremotor vocal neurons share molecular profiles across clawed frogs, despite differences in calls, revealing unexpected conservation and functional divergence of homologous neurons underlying evolution of vocal behavior.

neuroscience↗

Nicotinic acetylcholine receptor partial antagonist polyamides from tunicates and their predatory sea slugs

In our efforts to discover new drugs to treat pain, we identified molleamines A-E (1-5) as major neuroactive components of the sea slug, Pleurobranchus forskalii and their prey, Didemnum molle tunicates. The chemical structures of molleamines were elucidated by spectroscopy and confirmed by the total synthesis of molleamines A (1) and C (3). Synthetic 3 completely blocked acetylcholine-induced calcium flux in peptidergic nociceptors (PNs) in the somatosensory nervous system. Compound 3 affected neither the 7 nAChR nor the muscarinic acetylcholine receptors in calcium flux assays. In addition to nociceptors, 3 partially blocked the acetylcholine-induced calcium flux in the sympathetic nervous system, including neurons from the superior cervical ganglion. Electrophysiology revealed a block of 3{beta}4 (mouse) and 6/3{beta}4 (rat) nicotinic acetylcholine receptors (nAChRs), with IC50 values of 1.4 and 3.1 {micro}M, respectively. Molleamine C (3) is a partial antagonist, reaching a maximum block of 76-82% of the acetylcholine signal and showing no partial agonist response. Molleamine C (3) may thus provide a lead compound for the development of neuroactive compounds with unique biological properties.

neuroscience↗

The tunicate metabolite 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine targets ion channels of vertebrate sensory neurons

Marine tunicates produce defensive amino-acid derived metabolites, including 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA), but their mechanisms of action are rarely known. Using an assay-guided approach, we found that out of the many different sensory cells in the mouse dorsal root ganglion (DRG), DIMTA selectively affected low-threshold cold thermosensors. Whole-cell electrophysiology experiments using DRG cells, channels expressed in Xenopus oocytes and human cell lines revealed that DIMTA blocks several potassium channels, reducing the magnitude of the afterhyperpolarization and increasing the baseline [Ca2+]i of low-threshold cold thermosensors. When injected into mice, DIMTA increased the threshold of cold sensation by >3 oC. DIMTA may thus serve as a lead in the further design of compounds that inhibit problems in the cold-sensory system, such as cold allodynia and other neuropathic pain conditions.

neuroscience↗

Pressure drives rapid burst-like collective migration from 3D cancer aggregates

Collective migration of cells is a key behaviour observed during morphogenesis, wound healing and cancer cell invasion. Hence, understanding the different aspects of collective migration is at the core of further progress in describing and treating cancer and other pathological defects. The standard dogma in cell migration is that cells exert forces on the environment to move and cell-cell adhesion-based forces provide the coordination for collective migration. Here, we report a new collective migration mechanism that is independent of pulling forces on the extra-cellular matrix (ECM), as it is driven by the pressure difference generated inside model tumours. We observe a striking collective migration phenotype, where a rapid burst-like stream of HeLa cervical cancer cells emerges from the 3D aggregate embedded in matrices with low collagen concentration (0.5 mg ml-1). This invasion-like behaviour is recorded within 8 hours post embedding (hpe), and is characterised by high cell velocity and super-diffusive collective motion. We show that cellular swelling, triggered by the soft matrix, leads to a rise in intrinsic pressure, which eventually drives an invasion-like phenotype of HeLa cancer aggregates. These dynamic observations provide new evidence that pressure-driven effects need to be considered for a complete description of the mechanical forces involved in collective migration and invasion.

biophysics↗

Systematic analysis of cell phenotypes and cellular social networks in tissues using the multiplexed image cytometry analysis toolbox (miCAT)

Single-cell, spatially resolved omics analysis of tissues is poised to transform biomedical research and clinical practice. We have developed an open-source computational histology topography analysis toolbox (histoCAT) to enable the interactive, quantitative, and comprehensive exploration of phenotypes of individual cells, cell-to-cell interactions, microenvironments, and morphological structures within intact tissues. histoCAT will be useful in all areas of tissue-based research. We highlight the unique abilities of histoCAT by analysis of highly multiplexed mass cytometry images of human breast cancer tissues.\n\nTechnological advances in the multi-parametric analysis of single cells have revealed an unprecedented heterogeneity of cellular phenotypes and functional states that are concealed in population-based studies1-3. Each cellular phenotype is defined by the interplay of its internal state and the environment in which ...

systems biology↗