Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

Los receptores acoplados a proteínas G como blanco terapéutico / G protein-coupled receptors as therapeutic target

Resumen Los receptores son proteínas codificadas por el ADN, algunos de los cuales ya han sido cristalizados, lo que permite conocer los detalles de su estructura a nivel atómico y algunos aspectos de su función. Esta revisión se enfoca en los más diversos y abundantes, los receptores acoplados a la proteína G. Esta familia de receptores reconoce y media la acción de varios ligandos endógenos (hormonas, neurotransmisores, factores de crecimiento y hormonas locales) y también interviene en la patogenia de diversas enfermedades, por lo que son el blanco terapéutico de aproximadamente 30 a 40 % de los medicamentos que se emplean en la práctica clínica cotidiana y de diversas drogas ilegales. La cristalografía de rayos X es una de las herramientas clave que ha permitido observar la estructura de estos receptores en los aminoácidos que participan en esta interacción, lo que posibilita conocer el sitio de unión del ligando endógeno y de moléculas sintéticas que actúan sobre ellos para modular su acción. El modelado molecular es también una herramienta bioinformática computacional que apoya la investigación sobre la unión receptor-ligando, que hace posible el diseño y desarrollo de fármacos cada vez más específicos. A estos desarrollos se suman importantes cambios en los conceptos farmacodinámicos fundamentales.

Abstract Receptors are proteins coded by DNA, some of which have already been crystalized, thus allowing the details of their structure at the atomic level and some aspects of their function to be known. This review focuses on the most diverse and abundant family of receptors, G protein-coupled receptors. This family of receptors recognizes and mediates the action of several endogenous ligands (hormones, neurotransmitters, growth factors and local hormones) and also intervenes in the pathogenesis of various diseases, which is why they are targeted by approximately 30 to 40% of medications that are used in daily clinical practice and of various illegal drugs as well. X-ray crystallography is one of the essential tools that has allowed to observe the structure of these receptors in the amino acids that participate in this interaction, which allows to know the binding site of the endogenous ligand and of synthetic molecules that act on them to modulate their action. Molecular modeling or "docking" is also a computational bioinformatics tool that supports research on receptor-ligand binding, which allows the design and development of increasingly specific drugs. These developments have brought along significant changes in fundamental pharmacodynamic concepts.

Evaluating performance and determining optimum sample size for regression tree and automatic linear modeling / [Avaliando o desempenho e determinando o tamanho ideal da amostra para árvore de regressão e modelagem linear automática]

This study was carried out for two purposes: comparing performances of Regression Tree and Automatic Linear Modeling and determining optimum sample size for these methods under different experimental conditions. A comprehensive Monte Carlo Simulation Study was designed for these purposes. Results of simulation study showed that percentage of explained variation estimates of both Regression Tree and Automatic Linear Modeling was influenced by sample size, number of variables, and structure of variance-covariance matrix. Automatic Linear Modeling had higher performance than Regression Tree under all experimental conditions. It was concluded that the Regression Tree required much larger samples to make stable estimates when comparing to Automatic Linear Modeling.(AU)

Este estudo foi realizado com dois objetivos: comparar os desempenhos da Árvore de Regressão e da Modelagem Linear Automática e determinar o tamanho ideal da amostra para estes métodos sob diferentes condições experimentais. Um abrangente Estudo de Simulação de Monte Carlo foi projetado para estes propósitos. Os resultados do estudo de simulação mostraram que a porcentagem de estimativas de variação explicada tanto da Árvore de Regressão como da Modelagem Linear Automática foi influenciada pelo tamanho da amostra, número de variáveis e estrutura da matriz de variância-covariância. A Modelagem Linear Automática teve um desempenho superior ao da Árvore de Regressão em todas as condições experimentais. Concluiu-se que a Árvore de Regressão exigia amostras muito maiores para fazer estimativas estáveis quando comparada à Modelagem Linear Automática.(AU)

Oliceridine - Breakthrough in the Management of Pain

Oliceridine an intravenous opioid approved in 2020 by the Food and Drug Administration (FDA) to treat moderate-to-severe pain. Oliceridin developed with a novel mechanism that is biased agonism toward G-protein-coupled receptors pathway. Being biased agonist, it does not activate beta arrestin pathway responsible for opioid-related adverse events (ORAE), especially respiratory depression. Because of the novel mechanism, oliceridine has paved a pathway to decrease ORAE. Oliceridine has received breakthrough status by FDA. However, FDA denied oliceridine approval and withdrew breakthrough status by 2019. FDA made this decision because of the inadequacy of the safety data. Abuse potential and QT prolongation studies are conducted as per FDA recommendation in the year 2019; oliceridine was approved for moderate to severe pain in adults. This review will briefly summarize the pharmacological properties and study results of oliceridine in the management of pain. Thorough literature search was done for the efficacy and safety of oliceridine, search was done in electronic database of PubMed and Cochrane from inception till June 2021. Oliceridine was found to be effective in acute severe pain with less OREA when compared to morphine. Oliceridine has many drawbacks than what is hypothesized earlier, but this approach has opened new options for patients suffering from severe pain. Long?term effect of oliceridine has to be monitored to assess the effects of biased agonism.

Single-cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet β Cells / 基因组蛋白质组与生物信息学报·英文版

Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.

Planejamento e desenvolvimento de ligantes não peptídicos com atividade agonista enviesada no receptor de angiotensina II tipo 1 empregando-se técnicas de modelagem molecular e ensaios in vitro / Drug design of non-peptidic biased agonists for angiotensin II type 1 receptor using molecular modeling techniques and in vitro tests

A insuficiência cardíaca (IC) é uma síndrome de elevada morbimortalidade, correspondendo a um grave problema de saúde pública. Uma das abordagens terapêuticas para IC consiste no uso de antagonistas do receptor de angiotensina II do tipo 1 (AT1R), conhecidos como sartanas. Estudos apontam que uma nova classe de compostos, os agonistas enviesados, é capaz de induzir a sinalização da via da ß-arrestina sem ativação da via da proteína G. Essa seletividade funcional é particularmente interessante, pois a via dependente da proteína G é responsável pelo aumento da pressão arterial, morte celular e fibrose tecidual, levando a hipertrofia cardíaca e progressão da IC. No entanto, a via da ß-arrestina está associada com renovação celular e aumento do inotropismo. Além disso, estudos in vivo sugerem que agonistas enviesados poderiam corresponder a uma terapia superior à dos antagonistas convencionais, que bloqueiam ambas as vias. Apesar do potencial terapêutico, esses compostos possuem estrutura peptídica e, por isso, tem sua administração restrita à via intravenosa. A resolução da estrutura cristalográfica do AT1R permitiu estudos de modelagem molecular mais acurados. Tendo isso em mente, nesse trabalho foram propostos agonistas enviesados de natureza não peptídica para o AT1R por meio de técnicas de modelagem molecular e validação das hipóteses levantadas por ensaios in vitro. Foram realizados estudos de dinâmica molecular com o AT1R (PDB ID: 4YAY) em uma bicamada lipídica e ensaios de ancoramento molecular da angiotensina II (AngII) e do ligante enviesado TRV027. As poses de ancoramento molecular selecionadas foram utilizadas em dinâmicas de complexo, que revelaram diferenças entre os sistemas apo (sem nenhum ligante) e holo (com o ligante no sitio de ligação). Nossos resultados sugerem que o TRV027 induz um padrão exclusivo de ligações de hidrogênio e de estrutura secundária, enquanto que a AngII afeta os resíduos do bolso hidrofóbico do sitio de ligação, principalmente a conformação do Trp2536.48. Com base nas simulações, três farmacóforos foram criados e utilizados de maneira complementar em triagens virtuais na base de dados ZINC15, resultando na seleção de cinco compostos. Um desses compostos apresentou afinidade pelo receptor AT1R e, ainda que estudos complementares de ativação de vias especificas sejam necessários para que o composto possa ser classificado como agonista enviesado, já se constitui em molécula potencialmente promissora. Além disso, esses estudos permitiram a proposição de estruturas inéditas que podem vir a ser hits no processo de desenvolvimento de agonistas enviesados para AT1R. Portanto, como continuidade desse trabalho, essas moléculas serão sintetizadas e investigadas quanto à possível interação com o receptor.

Heart Failure (HF) is a common syndrome with high morbimortality, being considered a serious public health problem. One of the therapeutic approaches for HF consists in the use of the sartan class, which are angiotensin II type 1 receptor (AT1R) antagonists. Recent studies have shown that a new class of compounds, known as biased agonists, is able to induce signaling via ß-arrestin without G-protein activation. This functional selectivity is particularly interesting since G-protein dependent signaling is responsible for cell death and cardiac tissue fibrosis, which leads to cardiac muscle hypertophy and HF progression. On the other hand, ß-arrestin signaling is associated with cellular renewal and increased inotropism. In vivo studies suggests that biased agonists could correspond to a superior therapy over conventional angiotensin II type 1 receptor antagonists, which blocks cell signaling as a whole, however their peptidic structure restricts their use to intravenous administration. Moreover, the AT1R crystal structure determination holds great promise for more accurate molecular modeling studies. With that being said, the aim of this work was to plan and develop new non-peptidic biased agonists for ATR1 employing molecular modeling techniques and in vitro tests for hypothesis validation. Molecular dynamics (MD) simulations of the refined AT1R crystal (PDB ID: 4YAY) embedded in a lipid bilayer and molecular docking studies with angiotensin II (AngII) and TRV027 (biased agonist) were conducted. Selected docking poses from both ligands underwent complex MD simulations revealing differences between apo (ligand free) and holo (ligand in the binding site) systems. Our results suggest that TRV027 induces an exclusive hydrogen bond and secondary structure pattern, while AngII affects the hydrophobic pocket conformation, mainly Trp253. Based on the simulations, three pharmacophore models were created and used in virtual screenings in the ZINC15 database, resulting in the selection of five compounds that were tested in vitro. One of the compounds displayed affinity for AT1R and is a promising molecule. Nonetheless, it needs further pathway activation characterization in order to be a classified as a biased agonist. Furthermore, these results have contributed significantly for the proposition of new structures that could be hits with biased agonist activity for AT1R. Thus, for future works, we point out the necessity for synthesis and characterization of this new compounds

Data Analysis of Health-related Information of Kurobe Local Resident by Constitution Theory of Traditional Chinese Medicine / 日本補完代替医療学会誌

With the cooperation of Kurobe City, we conducted a basic survey using the nine classification of constitution and an intervention survey using a constitutional guidance program. The basic survey was conducted by the Kurobe group (Kurobe River alluvial fan spring water drinker n=155, 60.6±10.4 years old) and the non-Kurobe group (normal tap water drinker n=99, 50.7±12.8 living in the Hokuriku region without Kurobe City). A total of three surveys were conducted using the constitution Questionnaire (CCMQ-J). As a result, the Gentleness type, which is usually called the healthy constitution, was clearly higher in the Kurobe group, with 44.6 % in the Kurobe group and 22.5 % in the non-Kurobe group. In the proportion of each biased constitution(Mibyo constitution), the Kurobe group had less Wet-heat type (4.5 % vs 11.8 %), Qi-depression type (5.4 % vs 10.7 %), Yin-deficiency type (7.1 % vs 12.3 %) , and Phlegm-wetness type (5.8 % vs 9.6 %) than the non-Kurobe group. After the basic survey was completed, the Kurobe group was randomly divided into two groups, an intervention group (n=65, 62.3±9.3 years old) and a non-intervention group (n=68, 62.7±9.8 years old), and compared with the non-Kurobe group (control group) (n=80, 51.9±13.6 years old). The survey design was a simple comparative study, and the primary endpoint was a comparative study of changes in constitutional scores before and after intervention. As a result, in the Yang-deficiency type, a significant difference was observed between the intervention group, the non-intervention group and the control group at the first time after the intervention (One-way ANOVA p=0.04). No change was seen in the second survey after the intervention. In the comparison of Phlegm-wetness type between the three groups, there was a tendency in the amount of change in the constitutional score (One-way ANOVA p=0.087). From the above, it was suggested that the constitutional survey can not only grasp the health and the pre-symptomatic state, but also improve the pre-symptomatic by combining the guidance methods according to the constitution.

Mechanisms of β-arrestin-biased GPCR signal transduction and advances in drug research / 药学学报

G protein-coupled receptors (GPCR) are a class of receptor superfamily that exist on the surface of cell membrane. With the intensive studies on the GPCR desensitization regulator—β-arrestins, it is found that activated GPCR can not only conduct signal transduction through G protein-dependent pathway, but also mediate via non-G protein-dependent pathway. In addition to mediate endocytosis and desensitization, β-arrestins also initiate a new series of signal transduction events. Therefore, the concept of "biased transduction" was put forward: the receptor activated by a specific ligand could selectively activate a specific signaling pathway, leading the signal to be transmitted downstream along a "preferential" pathway. We call the ligand that binds to the receptor and causes biased activation "biased ligand". It is generally believed that the phenomenon of bias results from different binding modes of ligands and receptors, including multiple receptor conformations, diverse sites that downstream signal proteins bind, and signal proteins’ own conformations, etc. Here we give a brief review focusing on the mechanisms of β-arrestin-biased GPCR signal transduction and the advances in the drug development on β-arrestin biased ligands.

The evolution and distribution of noxious species of scorpions (Arachnida: Scorpiones)

This contribution attempts to bring some general information on the evolution and, in particular, on the geographic distribution of scorpion species noxious to humans. Since 95% of the scorpions incidents are generated by specimens of the family Buthidae C. L. Koch, the analysis will be limited to this familial group. As in previous similar contributions, the content of this work is mostly addressed to non-specialists whose research embraces scorpions in several fields such as venom toxins and public health. Only in recent years, efforts have been made to create better links between 'academic scorpion experts' and other academic non-specialists who use scorpions in their research. Even if a larger progress can yet be expected from such exchanges, crossed information proved to be useful in most fields of scorpion studies. Since the taxonomy of scorpions is complex, misidentifications and even more serious errors concerning scorpion classification/ identification are often present in the general literature. Consequently, a precise knowledge of the distribution patterns presented by many scorpion groups and, in particular, those of infamous species, proves to be a key point in the interpretation of final results, leading to a better treatment of the problems caused by infamous scorpion species.(AU)

Treatment of Insomnia from the Biased Constitution of the Elderly / 浙江中医药大学学报

[Objective] This article elaborated the clinical experience of Professor HAN Xu in the treatment of insomnia by using the theory of biased constitution. [Methods]For the sake of elaborating Professor HAN's experience in the treatment of insomnia, the author summed up the characteristics of old people's constitution and explained the relationship between the two from excess and deficiency syndrome. In order to better describe Professor HAN's experience in insomnia, the author enumerated 7 classic cases from several different aspects, like etiology and pathogenesis, therapy and prescriptions.[Results] Professor HAN believes that the characteristics of insomnia include the two aspects of deficiency and excess. The deficiency constitution should distinguish the deficiency between Qi and blood, Yin and Yang. The ways to treat the disease are invigorating Qi and nourishing blood, warming Yang and dispersing the cold, nourishing Yin and latenting Yang, striking the fire down. The Chinese medicinal formulae to treat the disease may use Decoction for invigorating the spleen, Mahuang Fuzi Xixin Tang, Fire diversion soup, Qianyang Fengsui Dan. The excess constitution should pay attention to phlegmatic hygrosis, stagnant blood, Qi-depression, fire -evil. The ways to treat the disease are soothing liver and invigorating spleen, descending and eliminating phlegm, stimulating circulation to end stasis. The ways include Peipi Shugan Tang, dissipating phlegm, Xuefu Zhuyu Decoction. To distinguish the actual situation of their specimens to take methods of strengthening the body resistance and eliminating evil, clinically has good effects. [Conclusion] Professor HAN makes the program of deficiency and excess and divides the biased constitution of the aged into six different types, like the deficiency of Qi and blood, Yang deficiency and Yin excess, hyperactivity of deficient fire, Liver Qi stagnation, phlegmatic hygrosis, blood stasis. The theory shows promising clinical outcome and is worth of a wide application.

Conceptual Progress for the Improvements in the Selectivity and Efficacy of G Protein-Coupled Receptor Therapeutics: An Overview

No abstract available.

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

Finding clues to the riddle of sex determination in zebrafish.

How sex is determined has been one of the most intriguing puzzles in biology since antiquity. Although a fundamental process in most metazoans, there seems to be myriad of ways in which sex can be determined – from genetic to environmental sex determination. This variation is limited mainly to upstream triggers with the core of sex determination pathway being conserved. Zebrafish has gained prominence as a vertebrate model system to study development and disease. However, very little is known about its primary sex determination mechanism. Here we review our current understanding of the sex determination in zebrafish. Zebrafish lack identifiable heteromorphic sex chromosomes and sex is determined by multiple genes, with some influence from the environment. Recently, chromosome 4 has been identified as sex chromosome along with few sex-linked loci on chromosomes 5 and 16. The identities of candidate sex-linked genes, however, have remained elusive. Sex in zebrafish is also influenced by the number of meiotic oocytes in the juvenile ovary, which appear to instruct retention of the ovarian fate. The mechanism and identity of this instructive signal remain unknown. We hypothesize that sex in zebrafish is a culmination of combinatorial effects of the genome, germ cells and the environment with inputs from epigenetic factors translating the biological meaning of this interaction.

Scorpion incidents, misidentification cases and possible implications for the final interpretation of results

The aim of this contribution is to bring general information on the classification and in particular on the specific identification of scorpion species dangerous to humans. Several generic groups are taken into consideration, but the Neotropical genus Tityus C. L. Koch, 1836 is used as a major example. The content of this paper is mostly addressed to non-specialists whose research embraces scorpions in several fields such as venom toxins and public health. Although efforts have been made in the last 20 years to create better links between 'true scorpion experts' and non-specialists who use scorpions in their research, such exchanges had never led to a consensus among those different branches of biological and medical research. Consequently, many cases of species misidentification and even more serious errors concerning scorpion classification/identification are often present in the specialized literature. In conclusion, it is suggested here that the frequent cases of misidentification observed in several reports may induce mistakes in the final interpretation of results, leading only to more inefficacity in the treatment of problems caused by infamous scorpion species.(AU)

Scorpion incidents, misidentification cases and possible implications for the final interpretation of results

The aim of this contribution is to bring general information on the classification and in particular on the specific identification of scorpion species dangerous to humans. Several generic groups are taken into consideration, but the Neotropical genus Tityus C. L. Koch, 1836 is used as a major example. The content of this paper is mostly addressed to non-specialists whose research embraces scorpions in several fields such as venom toxins and public health. Although efforts have been made in the last 20 years to create better links between true scorpion experts and non-specialists who use scorpions in their research, such exchanges had never led to a consensus among those different branches of biological and medical research. Consequently, many cases of species misidentification and even more serious errors concerning scorpion classification/identification are often present in the specialized literature. In conclusion, it is suggested here that the frequent cases of misidentification observed in several reports may induce mistakes in the final interpretation of results, leading only to more inefficacity in the treatment of problems caused by infamous scorpion species.

An imputation-based method to reduce bias in model parameter estimates due to non-random censoring in oncology trials

In oncology trials, patients are withdrawn from study at the time when progressive disease (PD) is diagnosed, which is defined as 20% increase of tumor size from the minimum. Such informative censoring can lead to biased parameter estimates when nonlinear mixed effects models are fitted using NONMEM. In this work, we investigated how empirical Bayes estimates (EBE) could be exploited to impute missing tumor size observations and partially correct biases in the parameter estimates. 50 simulated datasets, each consisting of 100 patients, were generated based on the published model. From the simulated dataset, censoring due to PD diagnosis has been implemented. Using the post-hoc EBEs acquired from fitting the censored datasets using NONMEM, imputed values were generated from the tumor size model. Model fitting was carried out using censored and imputed datasets. Parameter estimates using both datasets were compared with true values. Tumor growth rate and cell kill rate were approximately 28% and 16% underestimated when fitted using the censored dataset, respectively. With the imputed datasets, relative biases of tumor growth rate and cell kill rate decreased to about 6% and 0%, respectively. Our work demonstrates that using EBEs acquired from fitting the model to the censored dataset and imputing the unknown tumor size observations with individual predictions beyond the PD time point is a viable option to solve the bias associated with structural parameter estimates. This approach, however, would not be helpful in getting better estimates of variance parameters.

Sweet Taste-Sensing Receptors Expressed in Pancreatic beta-Cells: Sweet Molecules Act as Biased Agonists

The sweet taste receptors present in the taste buds are heterodimers comprised of T1R2 and T1R3. This receptor is also expressed in pancreatic beta-cells. When the expression of receptor subunits is determined in beta-cells by quantitative reverse transcription polymerase chain reaction, the mRNA expression level of T1R2 is extremely low compared to that of T1R3. In fact, the expression of T1R2 is undetectable at the protein level. Furthermore, knockdown of T1R2 does not affect the effect of sweet molecules, whereas knockdown of T1R3 markedly attenuates the effect of sweet molecules. Consequently, a homodimer of T1R3 functions as a receptor sensing sweet molecules in beta-cells, which we designate as sweet taste-sensing receptors (STSRs). Various sweet molecules activate STSR in beta-cells and augment insulin secretion. With regard to intracellular signals, sweet molecules act on STSRs and increase cytoplasmic Ca2+ and/or cyclic AMP (cAMP). Specifically, when an STSR is stimulated by one of four different sweet molecules (sucralose, acesulfame potassium, sodium saccharin, or glycyrrhizin), distinct signaling pathways are activated. Patterns of changes in cytoplasmic Ca2+ and/or cAMP induced by these sweet molecules are all different from each other. Hence, sweet molecules activate STSRs by acting as biased agonists.

Wolbachia endosymbiont infection in two Indian butterflies and female-biased sex ratio in the Red Pierrot, Talicada nyseus.

The maternally inherited obligate bacteria Wolbachia is known to infect various lepidopteran insects. However, so far only a few butterfly species harbouring this bacterium have been thoroughly studied. The current study aims to identify the infection status of these bacteria in some of the commonly found butterfly species in India. A total of nine butterfly species belonging to four different families were screened using PCR with Wolbachia-specific wsp and ftsZ primers. The presence of the Wolbachia super group ‘B’ in the butterflies Red Pierrot, Talicada nyseus (Guerin) (Lepidoptera: Lycaenidae) and Blue Mormon, Papilio polymnestor Cramer (Papilionidae), is documented for the first time in India. The study also gives an account on the lifetime fecundity and female-biased sex ratio in T. nyseus, suggesting a putative role for Wolbachia in the observed female-biased sex ratio distortion.