bioRxiv Science⌕ Search

Biology subjects

Singh, N. C.

Publications and source records attributed to Singh, N. C..

4 recordsLinked to original sources

Cis-regulatory elements orchestrate phase-specific effector gene expression in Ustilago maydis

Plant pathogenic fungi secrete small proteins, termed effectors, to reprogram host metabolism and suppress immune responses during infection. Although transcriptional waves of effector expression have been described in several pathosystems, the cis-regulatory elements encoding infection-stage specificity remain largely unknown. Here, we investigate the temporal regulation of effector genes in the biotrophic smut fungus Ustilago maydis, a model organism for fungal plant pathogenesis. By integrating transcriptome reanalysis with comparative promoter motif enrichment across biotrophic fungi, we identify distinct promoter motifs associated with defined infection phases. In U. maydis, three candidate cis-regulatory elements correlate with early, proliferative, and late infection stages, respectively. Positional enrichment relative to transcription start sites supports their regulatory relevance. Functional promoter mutagenesis demonstrates that the early-phase motif GTGGG significantly contributes to effector gene expression in planta and is sufficient to drive stage-restricted gene expression in synthetic minimal promoters. Collectively, our findings demonstrate that temporal deployment of the effector repertoire is at least partially encoded at the promoter level. The identified cis-regulatory elements provide a framework for dissecting transcriptional control during biotrophic infection and offer tools for infection-stage-specific gene expression in synthetic biology applications.

microbiology↗

Inflammasomes and DNA Damage Orchestrate Divergent Pyroptotic Fates in Neutrophils

The understanding of pyroptotic cell death and its mechanistic insights in neutrophils remains less explored and ambiguous. This study analyzes neutrophil pyroptotic responses under different conditions and dissects distinct pyroptosis-associated events, including IL-1{beta} release and cell death. We decipher the signalling pathways underlying these responses and distinguish them from other cell death mechanisms. Interestingly, we observe IL-1{beta} release and enhanced survival in neutrophils in response to LPS-primed ATP-treatment, in contrast to a combination of IL-1{beta} release with cell death in macrophages. While LPS-primed nigericin-treated neutrophils exhibit IL-1{beta} release and cell death, characterized by nuclear rounding, cell swelling/ ballooning, plasma membrane pore formation, and subsequent cell rupture, confirming the occurrence of pyroptotic cell death. While nigericin alone triggers cytokine uncoupled pyroptosis. Intriguingly, these phenomena do not induce under other death programs, including apoptosis, NETosis. This provides opportunity to unravel the regulation of these pyroptotic responses in neutrophils. Data observed reveal the role of NLRP3 and context-dependent caspase -1 & 11 in IL-1{beta} secretion. While, DNA damage and caspase-7 & 9 regulate pyroptotic death. Intriguingly, forced DNA damage by ATM kinase inhibitor mitigated inflammasome activation and IL-1{beta} release, while spur death. Furthermore, this study identifies perinuclear actomyosin forces driving nuclear rounding and pyroptotic death. Both murine neutrophils exposed to bacteria and human neutrophils treated with nigericin exhibit these pyroptotic processes, highlighting their broad relevance. This study depicts decision whether to secrete cytokines or undergo pyroptotic cell death emphasizing the regulatory role of DNA damage-cytoskeletal axis beyond inflammasome activation. Moreover, LPS and bacteria induced acute lung injury in mice displays nuclear rounding presenting pyroptotic neutrophils and enhanced NLRP3, Caspase-11 activation, and IL-1{beta} release. Together, this study defines intriguing crosstalk of NLRP3, caspases, DNA damage, and actomyosin forces that orchestrate divergent inflammatory fates, potentially leading to opportunities for targeted strategies for combating inflammation. HIGHLIGHTSO_LINeutrophils undergo pyroptotic cell death with nigericin and bacteria, but not with ATP. C_LIO_LILPS priming is essential for IL-1{beta} secretion, while dispensable for cell swelling/ballooning and death. C_LIO_LINLRP3 and Caspase 1/11 regulate IL-1{beta} secretion, while DNA damage and Caspase-7/9 control pyroptotic cell death. C_LIO_LIPerinuclear actomyosin signalling regulates nuclear rounding during pyroptotic cell death. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/673694v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@102da3forg.highwire.dtl.DTLVardef@46838borg.highwire.dtl.DTLVardef@16648faorg.highwire.dtl.DTLVardef@413bc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis

Rheumatoid arthritis (RA) is characterized by the aggressive migration and invasion of fibroblast-like synoviocytes (FLS) into cartilage and bone, a process that is significantly influenced by mitochondrial calcium uptake. This study highlights the critical role of mitochondrial calcium uniporter (MCU) in regulating FLS migration and mitochondrial dynamics, and its potential as a therapeutic target in RA. Notably, RA-FLS exhibited increased MCU expression and mitochondrial dysfunction compared to controls. Treatment with Ru360, a potent MCU inhibitor significantly reduced RA-FLS migration, calcium influx, and mitochondrial reactive oxygen species (ROS) levels, while restoring mitochondrial morphology and enhancing ATP production. Further analysis of MCU complex expression revealed elevated levels of MCU and other regulatory subunits (EMRE, MICU1, MICU2) in RA-FLS compared to controls, indicating mitochondrial dysfunction in RA. Mechanistically, MCU inhibition altered gene expression related to cytoskeletal dynamics, focal adhesion, and metabolic pathways. In human RA-FLS, MCU inhibition suppressed migration and invasion both in vitro and in vivo. The interaction between MCU and Miro1, essential for mitochondrial transport, was validated, and its disruption impaired FLS migration. Our findings highlight MCU as a promising therapeutic target to inhibit FLS migration and ameliorate RA progression.

immunology↗

Perceived closeness and autistic traits modulate interpersonal vocal communication

Vocal modulation is a critical component of interpersonal communication. It not only serves as a dynamic and flexible tool for self-expression and linguistic information but also plays a key role in social behaviour. Variation in vocal modulation can be driven by individual traits of the individual interlocutors, as well as by factors relating to the dyad, such as the perceived closeness between interlocutors. Accordingly, the current study examines the role of a) individual differences in autism-related traits, and b) perceived closeness between interlocutors on vocal modulation. Since lack of appropriate vocal modulation is often associated with Autism Spectrum Disorders we also focus on autism-related individual traits. The role of these individual and dyad-level factors on vocal modulation is tested for cultural generalizability by conducting this study in three separate samples from India, Italy, and the UK. Articulatory features were extracted from recorded conversations between a total of 85 same-sex pairs of participants and correlated with their self-reported perceived closeness (CR) to the other member of the pair and with the individual Autism Spectrum Quotient (AQ). Results indicated a significant positive correlation between interpersonal closeness and articulation area in all three samples. A significant negative correlation between AQ and articulation area was observed only in the UK sample. This study thus provides novel insights into determinants of interpersonal vocal communication and a test of their cultural generalizability.

animal behavior and cognition↗