A pleiotropic chemoreceptor facilitates the functional coupling of pheromone production and perception

Optimal mating decisions depend on the robust coupling of signal production and perception because independent changes in either could carry a fitness cost. However, since the perception and production of mating signals are often mediated by different tissues and cell types, the mechanisms that drive and maintain their coupling remain unknown for most animal species. Here, we show that in Drosophila, sensory perception and production of an inhibitory mating pheromone are co-regulated by Gr8a, a member of the Gustatory receptor gene family. Specifically, we found that the pleiotropic action of Gr8a independently regulates the perception of pheromones by the chemosensory systems of males and females, as well as their production in the fat body and oenocytes of males. These findings provide a relatively simple molecular explanation for how pleiotropic receptors maintain robust mating signaling systems at the population and species levels.

PORTABLE SEISMIC SYSTEMS (OVERVIEW)

The review presents a survey of the current state of development of portable (transportable) guard and reconnaissance-signaling seismic systems. The features of application and advantages of such systems over stationary are shown, the general trends in the design of the portable guard and reconnaissance-signaling systems are to described. Their main design features and characteristics serially produced for civilian and military use are given.

Sequestration of histidine kinases by non-cognate response regulators establishes a threshold level of stimulation for bacterial two-component signaling

Two-component signaling systems (TCSs) in bacteria are often positively auto-regulated, where the histidine kinase (HK) and response regulator (RR) proteins comprising a TCS are expressed downstream of the signal they transduce. This auto-regulation improves the sensitivity of the TCS to stimuli and amplifies adaptive responses. The downside, however, is that the TCS may mount disproportionately large responses to weak or fleeting signals. How bacteria prevent such disproportionate responses is not known. Here, we show that sequestration of phosphorylated HKs by non-cognate RRs serves as a design to prevent such disproportionate responses. Using TCSs of M. tuberculosis as model systems, we found that with every one of the five HKs we studied, there was at least one non-cognate RR with higher affinity than that of the cognate RR for the HK. Phosphorylated HKs would thus preferentially bind the non-cognate RRs, suppressing signal transduction through the cognate pathways, which we demonstrated in vitro. Using mathematical modeling of TCS signaling in vivo, we predicted that this sequestration would introduce a threshold level of stimulation for a significant response, preventing responses to signals below this threshold. Finally, we showed in vivo using tunable expression systems in M. bovis that upregulation of a higher affinity non-cognate RR substantially suppressed the output from the cognate TCS pathway, presenting strong evidence of sequestration by non-cognate RRs as a design to regulate TCS signaling. Blocking this sequestration may be a novel intervention strategy, as it would compromise bacterial fitness by letting it respond unnecessarily to signals.

Members of the KCTD family are major regulators of cAMP signaling

Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger with an essential role in neuronal function. cAMP synthesis by adenylyl cyclases (AC) is controlled by G protein–coupled receptor (GPCR) signaling systems. However, the network of molecular players involved in the process is incompletely defined. Here, we used CRISPR/Cas9–based screening to identify that members of the potassium channel tetradimerization domain (KCTD) family are major regulators of cAMP signaling. Focusing on striatal neurons, we show that the dominant isoform KCTD5 exerts its effects through an unusual mechanism that modulates the influx of Zn2+ via the Zip14 transporter to exert unique allosteric effects on AC. We further show that KCTD5 controls the amplitude and sensitivity of stimulatory GPCR inputs to cAMP production by Gβγ-mediated AC regulation. Finally, we report that KCTD5 haploinsufficiency in mice leads to motor deficits that can be reversed by chelating Zn2+. Together, our findings uncover KCTD proteins as major regulators of neuronal cAMP signaling via diverse mechanisms.

Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton.

Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study

Farnesol, a self-secreted quorum-sensing molecule (QSM) of Candida albicans, has been known to limit yeast-to-hyphal transition by blocking the RAS1–cAMP–PKA pathway. In a similar fashion, certain bacterial QSMs have also been reported to be successful in attenuating C. albicans biofilm and hyphal formation at relatively high cell density. This prompted us to investigate the antihyphal efficacy of certain bacterial QSMs through virtual docking against seminal drug targets, viz., CYCc and RAS1, that have been reported to be the hallmark players in C. albicans dimorphic virulence cascade. Against this backdrop, 64 QSMs belonging to five different bacterial QS signaling systems were subjected to initial virtual screening with farnesol as reference. Data of the virtual screening unveiled QSMs belonging to diketopiperazines (DKPs), i.e., 3-benzyl-6-isobutylidene-2,5-piperazinedione (QSSM 1157) and cyclo(l-Pro-l-Leu) (QSSM 1112), as potential inhibitors of CYCc and RAS1 with binding energies of −8.2 and −7.3 kcal mol−1, respectively. Further, the molecular dynamics simulations (for 50 ns) of CYCc-QSSM 1157 and RAS1-QSSM 1112 complexes revealed the mean ligand root mean square deviation (RMSD) values of 0.35 and 0.27 Å, respectively, which endorsed the rigid nature, less fluctuation in binding stiffness, and conformation of binding complexes. Furthermore, the identified two QSMs were found to be good in solubility, absorption, and permeation and less toxic in nature, as revealed by pharmacokinetics and toxicity analyses. In addition, the in vitro antihyphal assays using liquid and solid media, germ-tube experiment, and microscopic analysis strongly validated DKP-QSSM 1112 as a promising inhibitor of hyphal transition. Taken together, the present study unequivocally proves that DKPs can be used as potent inhibitors of C. albicans virulence dimorphism.

The Effect of 5-hydroxytryptamine on Smooth Muscles is Impacted by Broadband UV and LED UV and Blue Light

Due to their effects, similar to low-intensity therapy light sources such as light-emitting diodes (LED) and broadband spectrum lamps have recently become commonly used in the diagnosis and treatment of neurodegenerative pathologies, cancer, as well as ageing. Despite the proven positive effects of such therapies, deeper understanding of the light therapies’ biological effects remains unclear. Even more, the molecular mechanisms through which different neurotransmitters, namely serotonin (5-hydroxytryptamine, 5-HT), mediate the organism’s response to radiation are yet indistinct. In this paper, we present the design and development of a specialized system for irradiation of biological objects, which is composed of LED 365 nm and LED 470 nm and a broadband lamp source of UVA/B (350 nm) with intensity, power density and direction, which can be optimized experimentally. The system, named a “water organ bath (wob)”, is used in the current work to irradiate smooth muscle stomach strips of rats. The obtained results prove that the modulation of the spontaneous contractile smooth muscle activity and the potentiation of the effects of major neurotransmitters are executed by the emitted light. The probable explanation for the neurotransmitters photoactivation is that it is the resultant effect of electromagnetic radiation on intracellular enzymes signaling systems.

AGUSTIN DE BETANCOURT AS CREATOR OF OPTICAL TELEGRAPH MACHINE USED ON THE FIRST EUROPEAN RAILWAY LINES AND PRECURSOR OF RAILWAY SIGNALLING SYSTEMS

The origin of signalling principles, their purpose and development since the 4th century BC are described. Claude Chappe' s research on the peculiarities of human vision and the rationale for the choice of colors for the optical telegraph are presented. These principles are used in modern rail and road signaling systems with slight modifi cations to refl ect the development of technology. The transmission apparatus and the Claude Chappe alphabet are presented, documentary examples of its use in France are proposed, and the main disadvantages of this principle of data transmission are indicated. Further in the article, an alternative principle of data transmission using a single semaphore wing in an optical telegraph is presented. It was developed and introduced in 1798 between Madrid and Cadiz (Spain) by Agustin de Betancourt. The article shows the diagrams of the optical telegraph apparatus of Agustin de Betancourt, and also gives its comparison with fi rst mechanical signals used in railway transport. With references to historical documents and evidence, the evolution of the optical telegraph by Agustin de Betancourt from data transmission systems between cities to systems for the exchange of information between neighboring railway posts and stations on the fi rst railway lines is presented. The evolution of the telegraph from mechanical devices announcing the train approach to the railway post to the signals for train drivers thanks to the change of wing position is shown. As a transitional stage from mechanical to electrical signals in railway transport, the principle of operation of semaphores with kerosene lamps lit at night with light fi lters mechanically connected to the position of the wing is explained. Based on development of mechanical signals, the historical reasons for signal aspect with two lamps in diff erent modern signalling systems are presented. The article opens a new, previously little-known page of the activities by Agustin de Betancourt, who was not only the fi rst rector of the fi rst transport high school in Russia but also one of developers of data transmission systems used optical telegraph. His inventions such as mechanical signal with one wing are using in improved form in railway signalling systems up today.

Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices

Natural evolution produced polypeptides that selectively recognize chemical entities and their polymers, ranging from ions to proteins and nucleic acids. Such selective interactions serve as entry points to biological signaling and metabolic pathways. The ability to engineer artificial versions of such entry points is a key goal of synthetic biology, bioengineering and bioelectronics. We set out to map the optimal strategy for developing artificial small molecule:protein complexes that function as chemically induced dimerization (CID) systems. Using several starting points, we evolved CID systems controlled by a therapeutic drug methotrexate. Biophysical and structural analysis of methotrexate-controlled CID system reveals the critical role played by drug-induced conformational change in ligand-controlled protein complex assembly. We demonstrate utility of the developed CID by constructing electrochemical biosensors of methotrexate that enable quantification of methotrexate in human serum. Furthermore, using the methotrexate and functionally related biosensor of rapamycin we developed a multiplexed bioelectronic system that can perform repeated measurements of multiple analytes. The presented results open the door for construction of genetically encoded signaling systems for use in bioelectronics and diagnostics, as well as metabolic and signaling network engineering.