Probing PAC1 receptor activation across species with an engineered sensor.

Class-B1 G-protein-coupled receptors (GPCRs) are an important family of clinically relevant drug targets that remain difficult to investigate via high-throughput screening and in animal models. Here, we engineered PAClight1, a novel genetically encoded sensor based on a class-B1 GPCR (the human PAC1 receptor, hmPAC1R) endowed with high dynamic range (Δ/ = 1100%), excellent ligand selectivity, and rapid activation kinetics ( = 1.15 s).

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release.

Nociceptin/orphanin-FQ (N/OFQ) is a recently appreciated critical opioid peptide with key regulatory functions in several central behavioral processes including motivation, stress, feeding, and sleep. The functional relevance of N/OFQ action in the mammalian brain remains unclear due to a lack of high-resolution approaches to detect this neuropeptide with appropriate spatial and temporal resolution. Here we develop and characterize NOPLight, a genetically encoded sensor that sensitively reports changes in endogenous N/OFQ release.

ERK1/2-Dependent Phosphorylation of GABA(S867/T872), Controlled by CaMKIIβ, Is Required for GABA Receptor Degradation under Physiological and Pathological Conditions.

GABA receptor-mediated inhibition is indispensable for maintaining a healthy neuronal excitation/inhibition balance. Many neurological diseases are associated with a disturbed excitation/inhibition balance and downregulation of GABA receptors due to enhanced sorting of the receptors to lysosomal degradation. A key event triggering the downregulation of the receptors is the phosphorylation of S867 in the GABA subunit mediated by CaMKIIβ.

Adamtsl3 mediates DCC signaling to selectively promote GABAergic synapse function.

The molecular code that controls synapse formation and maintenance in vivo has remained quite sparse. Here, we identify that the secreted protein Adamtsl3 functions as critical hippocampal synapse organizer acting through the transmembrane receptor DCC (deleted in colorectal cancer). Traditionally, DCC function has been associated with glutamatergic synaptogenesis and plasticity in response to Netrin-1 signaling.

Sensitive multicolor indicators for monitoring norepinephrine in vivo.

Genetically encoded indicators engineered from G-protein-coupled receptors are important tools that enable high-resolution in vivo neuromodulator imaging. Here, we introduce a family of sensitive multicolor norepinephrine (NE) indicators, which includes nLightG (green) and nLightR (red). These tools report endogenous NE release in vitro, ex vivo and in vivo with improved sensitivity, ligand selectivity and kinetics, as well as a distinct pharmacological profile compared with previous state-of-the-art GRAB indicators.

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release.

Nociceptin/orphanin-FQ (N/OFQ) is a recently appreciated critical opioid peptide with key regulatory functions in several central behavioral processes including motivation, stress, feeding, and sleep. The functional relevance of N/OFQ action in the mammalian brain remains unclear due to a lack of high-resolution approaches to detect this neuropeptide with appropriate spatial and temporal resolution. Here we develop and characterize NOPLight, a genetically encoded sensor that sensitively reports changes in endogenous N/OFQ release.

Optical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution.

The glucagon-like peptide-1 receptor (GLP1R) is a broadly expressed target of peptide hormones with essential roles in energy and glucose homeostasis, as well as of the blockbuster weight-loss drugs semaglutide and liraglutide. Despite its large clinical relevance, tools to investigate the precise activation dynamics of this receptor with high spatiotemporal resolution are limited. Here, we introduce a novel genetically encoded sensor based on the engineering of a circularly permuted green fluorescent protein into the human GLP1R, named GLPLight1.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1.

Targeting the interaction of GABA receptors with CaMKII with an interfering peptide restores receptor expression after cerebral ischemia and inhibits progressive neuronal death in mouse brain cells and slices.

Cerebral ischemia is the leading cause for long-term disability and mortality in adults due to massive neuronal death. Currently, there is no pharmacological treatment available to limit progressive neuronal death after stroke. A major mechanism causing ischemia-induced neuronal death is the excessive release of glutamate and the associated overexcitation of neurons (excitotoxicity).

Targeting the Interaction of GABA Receptors With CHOP After an Ischemic Insult Restores Receptor Expression and Inhibits Progressive Neuronal Death.

GABA receptors control neuronal excitability via slow and prolonged inhibition in the central nervous system. One important function of GABA receptors under physiological condition is to prevent neurons from shifting into an overexcitation state which can lead to excitotoxic death. However, under ischemic conditions, GABA receptors are downregulated, fostering over-excitation and excitotoxicity.

Sustained Baclofen-Induced Activation of GABA Receptors After Cerebral Ischemia Restores Receptor Expression and Function and Limits Progressing Loss of Neurons.

One important function of GABA receptors is the control of neuronal activity to prevent overexcitation and thereby excitotoxic death, which is a hallmark of cerebral ischemia. Consequently, sustained activation of GABA receptors with the selective agonist baclofen provides neuroprotection in and models of cerebral ischemia. However, excitotoxic conditions severely downregulate the receptors, which would compromise the neuroprotective effectiveness of baclofen.

Molecular Evaluation of Exon 8 Cystathionine rs5742905T T>C Gene Polymorphism and Determination of its Frequency, Distribution Pattern, and Association with Susceptibility to Coronary Artery Disease in the North Indian Population.

Background: The protein coded by the cystathionine β synthase (CBS) gene acts as a catalyzer and converts homocysteine to cystathionine. Impairment of the CBS gene leads to homocystinuria by cystathionine β synthase deficiency which is linked to Coronary Artery Disease. A number of polymorphisms studies have been performed on the cystathionine β synthase gene.

Correction to: Ectopic PD-L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of STAT3 and STAT5.

In the original publication, third author name was incorrectly published as "Ab Rashid Mir". The correct name should read as "Rashid Mir".

Ectopic PD-L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of STAT3 and STAT5.

Escalated PD-L1 expression has been identified during malignant transformation in a number of cancer types and helps cancer cells escape an effective anti-tumor immune response. The mechanisms underlying escalated production of PD-L1 in many cancers, however, are still far from clear. We studied PD-L1, STAT3 and STAT5 mRNA expression using qRT-PCR in 72 BCR/ABL1 negative myeloproliferative neoplasm (MPN) patients (39 polycythemia vera and 33 essential thrombocythemia).

Clinical Importance of () Gene Polymorphisms and Their Expression Patterns in Coronary Artery Disease Patients: A Study from India.

The influence of Estrogen Receptor 1 (ESR1) gene -397T>C (PvuII) and -351A>G (XbaI) polymorphisms on the risk of development of coronary artery disease (CAD) in the north Indian population was analysed. We hypothesized that ESR1 gene polymorphisms may influence the susceptibility to CAD through variation in Estrogen Receptor α (ERα) expression. To assess this concept, we evaluated ERα mRNA expression in blood plasma of CAD patients.

Association of GABAA Receptor Gene with Epilepsy Syndromes.

GABA has always been an inviting target in the etiology and treatment of epilepsy. The GABRA1, GABRG2, and GABRD genes provide instructions for making α1, ϒ2, and δ subunits of GABAA receptor protein respectively. GABAA is considered as one of the most important proteins and has found to play an important role in many neurological disorders.

A review on heme oxygenase-1 induction: is it a necessary evil.

Heme oxygenase-1 (HO-1) is considered to be the main protein in diseases arising as a result of oxidative and inflammatory insults. Tremendous research has been carried out on HO-1 since years, pertaining its cytoprotective effect against oxidative injury and other cellular stresses. HO-1, by regulating intracellular levels of pro-oxidant heme, or by other benefits of its by-products such as carbon monoxide (CO) and biliverdin (BV) had become an important candidate protein to be up-regulated to combat diverse stressful events.