Physiological TLR5 expression in the intestine is regulated by differential DNA binding of Sp1/Sp3 through simultaneous Sp1 dephosphorylation and Sp3 phosphorylation by two different PKC isoforms

Toll-like receptor 5 (TLR5) expression in the intestinal epithelial cells (IECs) is critical to maintain health, as underscored by multiple intestinal and extra-intestinal diseases in mice genetically engineered for IEC-specific TLR5 knockout. A gradient of expression exists in the colonic epithelial cells from the cecum to the distal colon. Intriguingly, an identical gradient for the dietary metabolite, butyrate also exists in the luminal contents. However, both being critical for intestinal homeostasis and immune response, no studies examined the role of butyrate in the regulation of TLR5 expression. We showed that butyrate transcriptionally upregulates TLR5 in the IECs and augments flagellin-induced immune responses. Both basal and butyrate-induced transcription is regulated by differential binding of Sp-family transcription factors to the GC-box sequences over the TLR5 promoter. Butyrate activates two different protein kinase C isoforms to dephosphorylate/acetylate Sp1 by serine/threonine phosphatases and phosphorylate Sp3 by ERK-MAPK, respectively. This resulted in Sp1 displacement from the promoter and binding of Sp3 to it, leading to p300 recruitment and histone acetylation, activating transcription. This is the first study addressing the mechanisms of physiological TLR5 expression in the intestine. Additionally, a novel insight is gained into Sp1/Sp3-mediated gene regulation that may apply to other genes

EphH, a unique epoxide hydrolase encoded by Rv3338 is involved in the survival of Mycobacterium tuberculosis under in vitro stress and vacuolar pH-induced changes

IntroductionMycobacterium tuberculosis (Mtb), one of the deadliest human pathogen, has evolved with different strategies of survival inside the host, leading to a chronic state of infection. Phagosomally residing Mtb encounters a variety of stresses, including increasing acidic pH. To better understand the host-pathogen interaction, it is imperative to identify the role of various genes involved in the survivability of Mtb during acidic pH environment.MethodsBio-informatic and enzymatic analysis were used to identify Mtb gene, Rv3338, as epoxide hydrolase. Subsequently, CRISPRi knockdown strategy was used to decipher its role for Mtb survival during acidic stress, nutrient starvation and inside macrophages. Confocal microscopy was used to analyse its role in subverting phagosomal acidification within macrophage.ResultsThe present work describes the characterization of Rv3338 which was previously known to be associated with the aprABC locus induced while encountering acidic stress within the macrophage. Bio-informatic analysis demonstrated its similarity to epoxide hydrolase, which was confirmed by enzymatic assays, thus, renamed EphH. Subsequently, we have deciphered its indispensable role for Mtb in protection from acidic stress by using the CRISPRi knockdown strategy. Our data demonstrated the pH dependent role of EphH for the survival of Mtb during nutrient starvation and in conferring resistance against elevated endogenous ROS levels during stress environment.ConclusionTo the best of our knowledge, this is the first report of an EH of Mtb as a crucial protein for bacterial fitness inside the host, a phenomenon central to its pathogenesis

Quasi-viscous accretion flow -- I: Equilibrium conditions and asymptotic behaviour

In a novel approach to studying viscous accretion flows, viscosity has been introduced as a perturbative effect, involving a first-order correction in the $\alpha$-viscosity parameter. This method reduces the problem of solving a second-order nonlinear differential equation (Navier-Stokes equation) to that of an effective first-order equation. Viscosity breaks down the invariance of the equilibrium conditions for stationary inflow and outflow solutions, and distinguishes accretion from wind. Under a dynamical systems classification, the only feasible critical points of this "quasi-viscous" flow are saddle points and spirals. A linearised and radially propagating time-dependent perturbation gives rise to secular instability on large spatial scales of the disc. Further, on these same length scales, the velocity evolution equation of the quasi-viscous flow has been transformed to bear a formal closeness with Schr\"odinger's equation with a repulsive potential. Compatible with the transport of angular momentum to the outer regions of the disc, a viscosity-limited length scale has been defined for the full spatial extent over which the accretion process would be viable.Comment: 15 page

Three new species of Russula (Russulales) from India

Abstract Since 2008, macrofungal explorations have been undertaken in a mycologically underexplored West district of Sikkim (India), located in the Eastern Himalaya. Three species, namely Russula sharmae, R. dubdiana and R. sikkimensis are proposed herein as new taxa. Macro-and micromorphological illustrated descriptions of these species are given along with their taxonomic positions and relations to allied species

An analytical review on schizophrenia pharmaceutical treatment along with intelligent retrieval

Suicidal thoughts, higher use of resources like hospitalisation and related costs, and clinical deterioration may occur if schizophrenia patients fail to adhere to their drug regimens, according to a new study. We are analysing data from clinical trials of therapy that aim to boost the proportion of patients with schizophrenia who adhere to their medication. Nonadherence to therapy is a problem that affects both patients and healthcare providers. Behavioral treatment, long acting injectables (LAI), and antipsychotics based on methamphetamine LAI technology are a few examples. Only a small number of smartphone applications, such as medicine monitors and voice assistants, have been integrated with AI. The inclusion of clinically relevant samples in randomised, controlled, and blinded studies is necessary to measure not just adherence but also clinically important and long-lasting treatment outcomes for schizophrenia patients

Immune thrombocytopenia: An updated review from etiopathophysiology, laboratory investigations and current therapy

An inherited condition with isolated thrombocytopenia, immune thrombocytopenia (ITP) is still unknown in terms of the cause. A primary or secondary ITP diagnosis is determined by whether or not an underlying treatable cause exists. Diagnosis of primary ITP is based on the exclusion and hence does not have a gold standard test to validate it. Before classifying a patient as primary ITP, recent medication use, infections, lymphoproliferative illnesses, and connective tissue disorders should be checked out. An in-depth look at the most recent developments in ITP diagnostics and treatment is provided in this study. Our research was supported by GOOGLE Scholar, PUBMED, and ClinicalTrial.gov databases. Idiopathic thrombocytopenic purpura was also included in the search, as was "immune-mediated thrombocytopenia," "idiopathic thrombocytopenic purpura," and "isolated thrombocytopenia." It was found that more research is needed to better understand the underlying mechanisms of ITP. For example, corticosteroids have both short- and long-term side effects when used in the first place. In light of this, future research may need a rethinking of ITP treatment recommendations and the use of viable alternative drugs