Bibudha Parasar

All Publications

• Lifelong restructuring of 3D genome architecture in cerebellar granule cells. Science (New York, N.Y.) Tan, L., Shi, J., Moghadami, S., Parasar, B., Wright, C. P., Seo, Y., Vallejo, K., Cobos, I., Duncan, L., Chen, R., Deisseroth, K. 2023; 381 (6662): 1112-1119

  Abstract

  The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.

  View details for DOI 10.1126/science.adh3253

  View details for PubMedID 37676945

• BSH-TRAP: Bile salt hydrolase tagging and retrieval with activity-based probes. Methods in enzymology Parasar, B., Chang, P. V. 2022; 664: 85-102

  Abstract

  Bile acids are important molecules that participate in digestion and regulate many host physiological processes, including metabolism and inflammation. Primary bile acids are biosynthesized from cholesterol in the liver, where they are conjugated to glycine and taurine before secretion into the intestines. A small fraction of these molecules remain in the gut, where they are modified by a microbial enzyme, bile salt hydrolase (BSH), which deconjugates the glycine and taurine groups. This deconjugation precedes all subsequent biotransformation in the intestines, including regioselective dehydroxylation and epimerization reactions, to produce numerous secondary bile acids. Thus, BSH is considered the gatekeeper enzyme of secondary bile acid metabolism, and, as a result, it controls the overall bile acid composition in the host. Despite the critical role that BSH plays in bile acid metabolism, there exist few tools to probe its activity in complex biological mixtures. In this chapter, we describe a chemoproteomic approach termed BSH-TRAP (bile salt hydrolase tagging and retrieval with activity-based probes) that enables visualization and identification of BSH activity in bacteria. Here, we describe application of BSH-TRAP to cultured bacterial strains and the gut microbes derived from mice. We envision that BSH-TRAP could be used to profile changes in BSH activity and identify novel BSH enzymes in complex biological samples, such as the gut microbiome.

  View details for DOI 10.1016/bs.mie.2021.12.002

  View details for PubMedID 35331380

• Engineered Th17 Cell Differentiation Using a Photoactivatable Immune Modulator JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Parasar, B., Chang, P. 2020; 142 (42): 18103-18108

  Abstract

  T helper 17 (Th17) cells, an important subset of CD4+ T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells or their dynamic ability to trans-differentiate into other CD4+ T cell subsets remains mostly uncharacterized. Here, we report a synthetic immunology approach using a photoactivatable immune modulator (PIM) to increase Th17 cell differentiation on demand with spatial and temporal precision to help elucidate this important and dynamic process. In this chemical strategy, we developed a latent agonist that upon photochemical activation releases a small-molecule ligand that targets the aryl hydrocarbon receptor (AhR) and ultimately induces Th17 cell differentiation. We used this chemical tool to control AhR activation with spatiotemporal precision within cells and to modulate Th17 cell differentiation on demand using UV light illumination. We envision that this approach will enable an understanding of the dynamic functions and behaviors of Th17 cells in vivo during immune responses and in mouse models of inflammatory disease.

  View details for DOI 10.1021/jacs.0c07485

  View details for Web of Science ID 000580559000034

  View details for PubMedID 32975936

• Integrated Regulation of HuR by Translation Repression and Protein Degradation Determines Pulsatile Expression of p53 Under DNA Damage ISCIENCE Guha, A., Ahuja, D., Das Mandal, S., Parasar, B., Deyasi, K., Roy, D., Sharma, V., Willard, B., Ghosh, A., Ray, P. 2019; 15: 342-+

  Abstract

  Expression of tumor suppressor p53 is regulated at multiple levels, disruption of which often leads to cancer. We have adopted an approach combining computational systems modeling with experimental validation to elucidate the translation regulatory network that controls p53 expression post DNA damage. The RNA-binding protein HuR activates p53 mRNA translation in response to UVC-induced DNA damage in breast carcinoma cells. p53 and HuR levels show pulsatile change post UV irradiation. The computed model fitted with the observed pulse of p53 and HuR only when hypothetical regulators of synthesis and degradation of HuR were incorporated. miR-125b, a UV-responsive microRNA, was found to represses the translation of HuR mRNA. Furthermore, UV irradiation triggered proteasomal degradation of HuR mediated by an E3-ubiquitin ligase tripartite motif-containing 21 (TRIM21). The integrated action of miR-125b and TRIM21 constitutes an intricate control system that regulates pulsatile expression of HuR and p53 and determines cell viability in response to DNA damage.

  View details for DOI 10.1016/j.isci.2019.05.002

  View details for Web of Science ID 000470104600030

  View details for PubMedID 31103853

  View details for PubMedCentralID PMC6548907

• Chemoproteomic Profiling of Gut Microbiota-Associated Bile Salt Hydrolase Activity ACS CENTRAL SCIENCE Parasar, B., Zhou, H., Xiao, X., Shi, Q., Brito, I. L., Chang, P. 2019; 5 (5): 867-873

  Abstract

  The metagenome of the gut microbiome encodes tremendous potential for biosynthesizing and transforming small-molecule metabolites through the activities of enzymes expressed by intestinal bacteria. Accordingly, elucidating this metabolic network is critical for understanding how the gut microbiota contributes to health and disease. Bile acids, which are first biosynthesized in the liver, are modified in the gut by enzymes expressed by commensal bacteria into secondary bile acids, which regulate myriad host processes, including lipid metabolism, glucose metabolism, and immune homeostasis. The gateway reaction of secondary bile acid biosynthesis is mediated by bile salt hydrolases (BSHs), bacterial cysteine hydrolases whose action precedes other bile acid modifications within the gut. To assess how changes in bile acid metabolism mediated by certain intestinal microbiota impact gut physiology and pathobiology, methods are needed to directly examine the activities of BSHs because they are master regulators of intestinal bile acid metabolism. Here, we developed chemoproteomic tools to profile changes in gut microbiome-associated BSH activity. We showed that these probes can label active BSHs in model microorganisms, including relevant gut anaerobes, and in mouse gut microbiomes. Using these tools, we identified altered BSH activities in a murine model of inflammatory bowel disease, in this case, colitis induced by dextran sodium sulfate, leading to changes in bile acid metabolism that could impact host metabolism and immunity. Importantly, our findings reveal that alterations in BSH enzymatic activities within the gut microbiome do not correlate with changes in gene abundance as determined by metagenomic sequencing, highlighting the utility of chemoproteomic approaches for interrogating the metabolic activities of the gut microbiota.

  View details for DOI 10.1021/acscentsci.9b00147

  View details for Web of Science ID 000468624100018

  View details for PubMedID 31139722

  View details for PubMedCentralID PMC6535767

• Chemical optogenetic modulation of inflammation and immunity CHEMICAL SCIENCE Parasar, B., Chang, P. V. 2017; 8 (2): 1450-1453

  Abstract

  The immune system is an essential component of host defense against pathogens and is largely mediated by inflammatory molecules produced by immune cells, such as macrophages. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photocontrolled HDAC inhibitors, which can be selectively delivered to target cells by UV irradiation to minimize off-target effects. We strategically photocaged the active moiety of an HDAC inhibitor and showed that mild UV irradiation leads to the selective release of the inhibitor in a spatiotemporal manner. This methodology was used to decrease the amount of pro-inflammatory mediators produced by a subpopulation of macrophages. Our approach could ultimately be used to control inflammation in vivo as a therapeutic for inflammatory diseases, while minimizing off-target effects to healthy tissues.

  View details for DOI 10.1039/c6sc03702j

  View details for Web of Science ID 000395428300073

  View details for PubMedID 28451285

  View details for PubMedCentralID PMC5390787

• Deconvoluting host-gut microbiota co-metabolism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Chang, P., Parasar, B., Zhao, H., Xiao, X., Shi, Q., Brito, I. 2022; 36 Suppl 1

  Abstract

  The metagenome of the gut microbiome encodes tremendous potential for the biosynthesis and transformation of small-molecule metabolites through the activity of many enzymes expressed by the intestinal bacteria. The metabolic activity of this gut bioreactor provides numerous important functions for the host, including breaking down indigestible components of our diet, biosynthesizing essential vitamins and nutrients, and regulating the development of our immune system. Accordingly, elucidating the metabolic potential of the multitude of potential enzymatic reactions is critical for understanding how the activities of the gut microbiota contribute to human health and physiology. Therefore, there is a critical need for new technologies that can determine the enzymatic activities of the gut microbiome because these activities cannot be directly determined by existing metagenomic approaches used to profile microbial taxonomy by genetic content. Activity-based probes, which are mechanism-based covalent tags for enzyme active sites, represent a powerful chemical approach for directly identifying and profiling enzymatic activities. Here, we have developed activity-based probes for a class of cysteine proteases known as bile salt hydrolases (BSHs), which are master regulators of gut microbial transformation of host-derived, or primary, bile acids into a large and diverse group of secondary bile acids. These important metabolites regulate myriad host biological processes, including lipid metabolism, energy metabolism, and immune homeostasis. In addition, changes in bile acid levels are known to accompany different physiological states. However, the role of BSH activity in these processes remains poorly understood due to the lack of adequate tools to address its function. To address this critical gap in knowledge, we have applied our chemical approach to profile BSH activity in gut microbiomes using healthy and diseased samples.

  View details for DOI 10.1096/fasebj.2022.36.S1.0I178

  View details for PubMedID 35553122

• BSH-TRAP: Bile salt hydrolase tagging and retrieval with activity-based probes CHEMICAL MICROBIOLOGY, PT A Parasar, B., Chang, P. V., Carlson, E. E. 2022; 664: 85-102

  View details for Web of Science ID 000890950200005

• Finding the Sweet Spot for Breast Cancer Detection ACS CENTRAL SCIENCE Parasar, B., Chang, P. V. 2020; 6 (12): 2123-2125

  View details for DOI 10.1021/acscentsci.0c01439

  View details for Web of Science ID 000603399200003

  View details for PubMedID 33376773

  View details for PubMedCentralID PMC7760063

• Microwave assisted cross-coupling reactions using palladium nanoparticles in aqueous media SYNTHETIC COMMUNICATIONS Dhara, K., Parasar, B., Patil, A. J., Dash, J. 2019; 49 (6): 859-868

  View details for DOI 10.1080/00397911.2019.1576203

  View details for Web of Science ID 000461489300009

• Bipyridine Facilitates Regioselective Dimerization of Alkynes in the Absence of Transition Metal CHEMISTRYSELECT Midya, G., Parasar, B., Maiti, S., Dash, J. 2017; 2 (18): 5032-5037

  View details for DOI 10.1002/slct.201701091

  View details for Web of Science ID 000406674900008

• Transcript degradation and noise of small RNA-controlled genes in a switch activated network in Escherichia coli NUCLEIC ACIDS RESEARCH Arbel-Goren, R., Tal, A., Parasar, B., Dym, A., Costantino, N., Munoz-Garcia, J., Court, D. L., Stavans, J. 2016; 44 (14): 6707-6720

  Abstract

  Post-transcriptional regulatory processes may change transcript levels and affect cell-to-cell variability or noise. We study small-RNA downregulation to elucidate its effects on noise in the iron homeostasis network of Escherichia coli In this network, the small-RNA RyhB undergoes stoichiometric degradation with the transcripts of target genes in response to iron stress. Using single-molecule fluorescence in situ hybridization, we measured transcript numbers of the RyhB-regulated genes sodB and fumA in individual cells as a function of iron deprivation. We observed a monotonic increase of noise with iron stress but no evidence of theoretically predicted, enhanced stoichiometric fluctuations in transcript numbers, nor of bistable behavior in transcript distributions. Direct detection of RyhB in individual cells shows that its noise is much smaller than that of these two targets, when RyhB production is significant. A generalized two-state model of bursty transcription that neglects RyhB fluctuations describes quantitatively the dependence of noise and transcript distributions on iron deprivation, enabling extraction of in vivo RyhB-mediated transcript degradation rates. The transcripts' threshold-linear behavior indicates that the effective in vivo interaction strength between RyhB and its two target transcripts is comparable. Strikingly, the bacterial cell response exhibits Fur-dependent, switch-like activation instead of a graded response to iron deprivation.

  View details for DOI 10.1093/nar/gkw273

  View details for Web of Science ID 000382999900020

  View details for PubMedID 27085802

  View details for PubMedCentralID PMC5001584

• Chiral carbon dots derived from guanosine 5 '-monophosphate form supramolecular hydrogels CHEMICAL COMMUNICATIONS Ghosh, A., Parasar, B., Bhattacharyya, T., Dash, J. 2016; 52 (74): 11159-11162

  Abstract

  Guanosine 5'-monophosphate, (5'-GMP), is a self-assembling natural nucleotide that has unique potential to form ordered supramolecular structures. We herein describe an intriguing property of Na2(5'-GMP) to form blue emitting chiral carbon dots (G-dots) that exhibit excitation dependent down-conversion and up-conversion fluorescence signature and self-assemble to form fluorescent hydrogels.

  View details for DOI 10.1039/c6cc05947c

  View details for Web of Science ID 000384202000029

  View details for PubMedID 27560935

• A copper based catalyst for poly-urethane synthesis from discarded motherboard RSC ADVANCES Barman, S., Parasar, B., Kundu, P., Roy, S. 2016; 6 (79): 75749-75756

  View details for DOI 10.1039/c6ra14506j

  View details for Web of Science ID 000381513800091

• MICRO-OPTOMECHANICAL MOVEMENTS (MOMs) WITH SOFT OXOMETALATES (SOMs): CONTROLLED MOTION OF SINGLE SOFT OXOMETALATE PEAPODS USING EXOTIC OPTICAL POTENTIALS JOURNAL OF MOLECULAR AND ENGINEERING MATERIALS Roy, B., Ghosh, N., Panigrahi, P. K., Banerjee, A., Sahasrabudhe, A., Parasar, B., Roy, S. 2014; 2 (1)

  View details for DOI 10.1142/S2251237314400061

  View details for Web of Science ID 000216852600007

• Ligand mediated iron catalyzed dimerization of terminal aryl alkynes: scope and limitations ORGANIC & BIOMOLECULAR CHEMISTRY Midya, G., Parasar, B., Dhara, K., Dash, J. 2014; 12 (11): 1812-1822

  Abstract

  Regioselective dimerization of terminal aryl alkynes to produce conjugated enynes has been achieved using FeCl3 and KO(t)Bu in the presence of either DMEDA or dppe. The reaction proceeds smoothly in toluene at 145 °C for 2 h to give the corresponding head-to-head dimers in good to excellent yields (54 to 99%) with high E-selectivity (67 : 33 to 83 : 17 E/Z). Both strongly electron-donating and electron-withdrawing groups are compatible with this procedure. The bidentate phosphine (dppe) ligand exhibits better catalytic activity than the bidentate amine (DMEDA). The aliphatic acetylene fails to react under this catalytic system which suggests that potassium tertiary butoxide activates the conjugated system of aryl acetylene through cation-pi interaction and pi-pi interaction. A radical inhibitor (galvinoxyl or TEMPO) completely suppresses the reaction. Employing FeCl2 as a catalyst instead of FeCl3, only phenyl acetylene afforded the corresponding head to head dimer in good yield. Mechanistic pathways for both FeCl3 catalyzed dimerization of aryl alkynes and FeCl2 catalyzed dimerization of phenyl acetylene have been proposed.

  View details for DOI 10.1039/c3ob42365d

  View details for Web of Science ID 000332225500018

  View details for PubMedID 24514585

• pH dependent multifunctional and multiply-configurable logic gate systems based on small molecule G-quadruplex DNA recognition CHEMICAL COMMUNICATIONS Bhowmik, S., Das, R., Parasar, B., Dash, J. 2013; 49 (18): 1817-1819

  Abstract

  A variety of logic operations such as XNOR, NOR, AND, NAND, NOT have been designed with pH as an external modulator by choosing thiazole orange (TO) and a c-kit2 promoter quadruplex as two inputs and fluorescence signals of pyridyl bis-indole amide (PBIA) and TO as two outputs.

  View details for DOI 10.1039/c3cc38888c

  View details for Web of Science ID 000314650100010

  View details for PubMedID 23358682

• Reduction of organic azides to amines using reusable Fe3O4 nanoparticles in aqueous medium CATALYSIS SCIENCE & TECHNOLOGY Pagoti, S., Surana, S., Chauhan, A., Parasar, B., Dash, J. 2013; 3 (3): 584-588

  View details for DOI 10.1039/c2cy20776a

  View details for Web of Science ID 000314782000007