Nodulisporic acid produces direct activation and positive allosteric modulation of AVR-14B, a glutamate-gated chloride channel from adult Brugia malayi.

Glutamate-gated chloride channels (GluCls) are unique to invertebrates and are targeted by macrocyclic lactones. In this study, we cloned an AVR-14B GluCl subunit from adult Brugia malayi, a causative agent of lymphatic filariasis in humans. To elucidate this channel's pharmacological properties, we used Xenopus laevis oocytes for expression and performed two-electrode voltage-clamp electrophysiology. The receptor was gated by the natural ligand L-glutamate (effective concentration, 50% [EC50] = 0.4 mM) and ivermectin (IVM; EC50 = 1.8 nM). We also characterized the effects of nodulisporic acid (NA) on Bma-AVR-14B and NA-produced dual effects on the receptor as an agonist and a type II positive allosteric modulator. Here we report characterization of the complex activity of NA on a nematode GluCl. Bma-AVR-14B demonstrated some unique pharmacological characteristics. IVM did not produce potentiation of L-glutamate-mediated responses but instead, reduced the channel's sensitivity for the ligand. Further electrophysiological exploration showed that IVM (at a moderate concentration of 0.1 nM) functioned as an inhibitor of both agonist and positive allosteric modulatory effects of NA. This suggests that IVM and NA share a complex interaction. The pharmacological properties of Bma-AVR-14B indicate that the channel is an important target of IVM and NA. In addition, the unique electrophysiological characteristics of Bma-AVR-14B could explain the observed variation in drug sensitivities of various nematode parasites. We have also shown the inhibitory effects of IVM and NA on adult worm motility using Worminator. RNA interference (RNAi) knockdown suggests that AVR-14 plays a role in influencing locomotion in B. malayi.

Copper/Zinc-Catalyzed Stitching of 2-Carbonylanilines with Bis(ynamides): Access to Pyrrolo[2,3-b]quinolines and Its Photophysical Studies.

Herein, a one-pot desulfonylative protocol enabled by copper(II)/zinc(II) salts to access pyrrolo[2,3-b]quinolines in good to excellent yields from 2-carbonylanilines and ynamide-derived buta-1,3-diynes has been reported. Significantly, various 2-carbonylanilines carrying reactive functional groups are well tolerated. Moreover, a gram-scale synthesis and synthetic application highlight the practical utility of the current protocol. Notably, the fluorescence properties of pyrrolo[2,3-b]quinolines have been recorded, and their potential use as a fluorescent probe in the imaging of live cells has been demonstrated.

Leveraging Zn(II) Catalyst: Synthesis of Amidoquinolines via (3 + 3) Heteroannulation of Aromatic Amines and Ynamides.

Herein, we present a Zn(II)-catalyzed (3 + 3) heteroannulation reaction between aromatic amines and 1,3-diynamides for the synthesis of amidoquinolines. A large number of aromatic amines are well tolerated, furnishing quinoline derivatives in up to excellent yield. Notably, various reactive functional groups have survived under the optimal reaction conditions, highlighting the mildness of the developed protocol. In addition, amines derived from bioactive molecules show modest reactivity.

One-Pot, Tandem Reductive Amination/Alkylation-Cycloamidation for Lactam Synthesis from Keto or Amino Acids.

Monotrifluoroacetoxyborane-amines, prepared by treating borane-amines with trifluoroacetic acid, have been shown to be efficient reagents for a one-pot, tandem reductive amination/alkylation-cycloamidation of keto or amino acids to achieve the synthesis of 5-aryl or 5-methyl pyrrolidin-2-ones and 6-aryl or 6-methyl piperidin-2-ones.

EAT-18 is an essential auxiliary protein interacting with the non-alpha nAChR subunit EAT-2 to form a functional receptor.

Nematode parasites infect approximately 1.5 billion people globally and are a significant public health concern. There is an accepted need for new, more effective anthelmintic drugs. Nicotinic acetylcholine receptors on parasite nerve and somatic muscle are targets of the cholinomimetic anthelmintics, while glutamate-gated chloride channels in the pharynx of the nematode are affected by the avermectins. Here we describe a novel nicotinic acetylcholine receptor on the nematode pharynx that is a potential new drug target. This homomeric receptor is comprised of five non-α EAT-2 subunits and is not sensitive to existing cholinomimetic anthelmintics. We found that EAT-18, a novel auxiliary subunit protein, is essential for functional expression of the receptor. EAT-18 directly interacts with the mature receptor, and different homologs alter the pharmacological properties. Thus we have described not only a novel potential drug target but also a new type of obligate auxiliary protein for nAChRs.

Cu(II)-catalyzed [4 + 1] and [4 + 3] annulation reactions: a modular approach to N-aryl/alkyl substituted 2,5-diamidopyrroles and diazepines.

A one-pot copper-catalyzed [4 + 1] annulation reaction of primary amines with ynamide-derived buta-1,3-diynes for the synthesis of 2,5-diamido bearing N-aryl/alkyl pyrroles in up to excellent yields has been showcased. A broad range of primary amines having highly reactive functional groups are well tolerated. Notably, sterically demanding aniline and primary aliphatic amines are excellent amine sources. Furthermore, the current protocol may yield structurally unique diazepine derivatives. The scale-up reaction and fruitful chemical elaboration of pyrrole motifs highlight the importance of this reaction.

Trimethyl Borate-Catalyzed, Solvent-Free Reductive Amination.

Solvent-free reductive amination of aldehydes and ketones with aliphatic and aromatic amines in high-to-excellent yields has been achieved with sub-stoichiometric trimethyl borate as promoter and ammonia borane as reductant.

Incremental Learning in Modelling Process Analysis Technology (PAT)-An Important Tool in the Measuring and Control Circuit on the Way to the Smart Factory.

To meet the demands of the chemical and pharmaceutical process industry for a combination of high measurement accuracy, product selectivity, and low cost of ownership, the existing measurement and evaluation methods have to be further developed. This paper demonstrates the attempt to combine future Raman photometers with promising evaluation methods. As part of the investigations presented here, a new and easy-to-use evaluation method based on a self-learning algorithm is presented. This method can be applied to various measurement methods and is carried out here using an example of a Raman spectrometer system and an alcohol-water mixture as demonstration fluid. The spectra's chosen bands can be later transformed to low priced and even more robust Raman photometers. The evaluation method gives more precise results than the evaluation through classical methods like one primarily used in the software package Unscrambler. This technique increases the accuracy of detection and proves the concept of Raman process monitoring for determining concentrations. In the example of alcohol/water, the computation time is less, and it can be applied to continuous column monitoring.

Gold-catalyzed homo- and cross-annulation of alkynyl carboxylic acids: a facile access to substituted 4-hydroxy 2H-pyrones and total synthesis of pseudopyronine A.

A Au(i)-catalyzed homo- and cross-annulation reaction of alkynyl carboxylic acids offering 3,6-disubstituted 4-hydroxy 2H-pyrones has been demonstrated. The reaction tolerates various substituted alkynyl carboxylic acids and moderate to good yields of α-pyrone scaffolds have been observed. Later, a gram-scale reaction of the acid and the total synthesis of the natural product pseudopyronine A have been carried out successfully.

Comparative study of different glycating agents on human plasma and vascular cells.

Diabetic complications are associated with the glycation and formation of advanced glycation end products (AGEs) which leads to structural modifications of biomolecules further affecting cells. Carbonyl compounds such as methylglyoxal and glyceraldehyde-3-phosphate are highly reactive and form an elevated amount of AGEs as compared to glucose and fructose. The investigation of glycation modifications by different compounds may be important to assess the specific pattern of biomolecular and cellular modifications and compare their glycation potential. The present work aims to comprehensively and comparatively examine the effect of glycating agents (glucose, fructose, ribose, methylglyoxal, and glyceraldehyde) on plasma, erythrocytes, platelets, and blood DNA. Glycation of plasma, cells, and DNA was initiated by incubating them with glycating agents for 24-48 h at 37 °C. Negative control samples (without glycating agents) were maintained simultaneously. After treatment, plasma and DNA samples were dialyzed and cell lysate was prepared. Markers of glycation (fructosamine), structural modifications (free amino, ß-amyloid, absorption spectra), antioxidant indices (catalase activity, glutathione) and erythrocyte hemolysis were estimated. In the presence of glycating agents, there was a significant increase in the formation of fructosamine, structural modification markers and depletion in antioxidant indices. Overall results suggest that among all glycating agents; methylglyoxal and glyceraldehyde have more potency of glycation induced structural modifications in plasma and vascular cells. This indicates the specific glycation modifications in plasma and vascular cells by various glycating agents may be investigated further for controlling diabetic pathological changes.

Incidence and antimicrobial susceptibility of Staphylococcus aureus isolated from ready-to-eat foods of animal origin from tourist destinations of North-western Himalayas, Himachal Pradesh, India.

This study was aimed to determine the incidence of Staphylococcus aureus in ready-to-eat (RTE) milk (n = 120) and meat (n = 120) products from various tourist places in north western Himalayas, Himachal Pradesh, India. S. aureus isolates and its enterotoxins; A, B, D and E were characterized by conventional and molecular methods. Antimicrobial susceptibility (AMS) profiles of S. aureus isolates were determined by disk diffusion method using Clinical and Laboratory Standards Institute criteria. Overall, 6.7% (n = 16/240) food samples were positive for S. aureus. PCR amplification of nucA confirmed all biochemically characterized isolates as S. aureus. Incidence of S. aureus was higher (10.0%) in RTE milk products than meat products (3.3%). S. aureus contamination levels were highest in milk cake/khoa (26.0%, p = 0.0002) followed by ice cream/kulfi (10.0%, p = 0.4), mutton momo (10.0%, p = 0.4), burfi (3.3%, p = 0.7) and chicken momo (3.3%, p = 0.7). None of the isolates carried genes for S. aureus enterotoxins; A, B, D and E. AMS testing revealed seven different resistance patterns and 81.3% multi drug resistance. All the isolates were resistant to ampicillin. High resistance levels were observed against methicillin (93.7%), clindamycin (68.8%), erythromycin (56.3%) and vancomycin (43.8%). Vancomycin resistant (n = 7) isolates were also resistant to methicillin. All isolates were susceptible to novobiocin.

Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.

Getting around the roundworms: Identifying knowledge gaps and research priorities for the ascarids.

The ascarids are a large group of parasitic nematodes that infect a wide range of animal species. In humans, they cause neglected diseases of poverty; many animal parasites also cause zoonotic infections in people. Control measures include hygiene and anthelmintic treatments, but they are not always appropriate or effective and this creates a continuing need to search for better ways to reduce the human, welfare and economic costs of these infections. To this end, Le Studium Institute of Advanced Studies organized a two-day conference to identify major gaps in our understanding of ascarid parasites with a view to setting research priorities that would allow for improved control. The participants identified several key areas for future focus, comprising of advances in genomic analysis and the use of model organisms, especially Caenorhabditis elegans, a more thorough appreciation of the complexity of host-parasite (and parasite-parasite) communications, a search for novel anthelmintic drugs and the development of effective vaccines. The participants agreed to try and maintain informal links in the future that could form the basis for collaborative projects, and to co-operate to organize future meetings and workshops to promote ascarid research.

Discrete symmetries tested at 10-4 precision using linear polarization of photons from positronium annihilations.

Discrete symmetries play an important role in particle physics with violation of CP connected to the matter-antimatter imbalance in the Universe. We report the most precise test of P, T and CP invariance in decays of ortho-positronium, performed with methodology involving polarization of photons from these decays. Positronium, the simplest bound state of an electron and positron, is of recent interest with discrepancies reported between measured hyperfine energy structure and theory at the level of 10-4 signaling a need for better understanding of the positronium system at this level. We test discrete symmetries using photon polarizations determined via Compton scattering in the dedicated J-PET tomograph on an event-by-event basis and without the need to control the spin of the positronium with an external magnetic field, in contrast to previous experiments. Our result is consistent with QED expectations at the level of 0.0007 and one standard deviation.

Nitrogen Atom Transfer Enables the (5+1) Annulation Reaction to Access Aminoisoquinolines.

Herein, a catalytic synthetic transformation offering a series of -NH2 group-bearing aminoisoquinolines with moderate to good yields has been showcased. Interestingly, the nitrogen atom of the isoquinoline ring is coming from the reaction medium upon metal-assisted C≡N bond cleavage. Moreover, this (5+1) annulation reaction shows broad substrate variation. Furthermore, the derivatization of the isoquinoline core via functional group interconversions and mechanistic studies to identify the reaction intermediate have been carried out successfully.

Twofold Heteroannulation Reactions Enabled by Gold(I)/Zinc(II) Catalysts: Synthesis of Amine-Substituted Diaryl[c,h][1,6]naphthyridines.

A straightforward and atom-economical one-pot protocol catalyzed by gold(I) and zinc(II) for the synthesis of amine-substituted diaryl[c,h][1,6]naphthyridines from two different aromatic nitriles has been showcased. This dual-catalytic strategy is highly efficient, offering an array of tetracyclic heteroaromatic products in good to excellent yields. Furthermore, the base can efficiently catalyze the second annulation step, yielding structurally unique thiophene-fused [1,6]naphthyridines in good yields.

Efficiency determination of J-PET: first plastic scintillators-based PET scanner.

BACKGROUND: The Jagiellonian Positron Emission Tomograph is the 3-layer prototype of the first scanner based on plastic scintillators, consisting of 192 half-metre-long strips with readouts at both ends. Compared to crystal-based detectors, plastic scintillators are several times cheaper and could be considered as a more economical alternative to crystal scintillators in future PETs. JPET is also a first multi-photon PET prototype. For the development of multi-photon detection, with photon characterized by the continuous energy spectrum, it is important to estimate the efficiency of J-PET as a function of energy deposition. The aim of this work is to determine the registration efficiency of the J-PET tomograph as a function of energy deposition by incident photons and the intrinsic efficiency of the J-PET scanner in detecting photons of different incident energies. In this study, 3-hit events are investigated, where 2-hits are caused by 511 keV photons emitted in [Formula: see text] annihilations, while the third hit is caused by one of the scattered photons. The scattered photon is used to accurately measure the scattering angle and thus the energy deposition. Two hits by a primary and a scattered photon are sufficient to calculate the scattering angle of a photon, while the third hit ensures the precise labeling of the 511 keV photons. RESULTS: By comparing experimental and simulated energy distribution spectra, the registration efficiency of the J-PET scanner was determined in the energy deposition range of 70-270 keV, where it varies between 20 and 100[Formula: see text]. In addition, the intrinsic efficiency of the J-PET was also determined as a function of the energy of the incident photons. CONCLUSION: A method for determining registration efficiency as a function of energy deposition and intrinsic efficiency as a function of incident photon energy of the J-PET scanner was demonstrated. This study is crucial for evaluating the performance of the scanner based on plastic scintillators and its applications as a standard and multi-photon PET systems. The method may be also used in the calibration of Compton-cameras developed for the ion-beam therapy monitoring and simultaneous multi-radionuclide imaging in nuclear medicine.

Monotrifluoroacetoxyborane-amines: chemoselective reagents for challenging reductive aminations.

Borane-amines undergo exclusive monoacetoxylation to trifluoroacetoxyborane-amines (TFAB-amines), which serve as chemoselective reagents for direct reductive amination of aldehydes and ketones. TFAB-NEt3 has been established as mild and highly selective compared to widely-used NaBH3CN and Na(AcO)3BH, even at higher temperatures with challenging substrates. A mechanism involving polyaminoborane formed via dehydroacetoxylation of TFAB-NH3 has been described.

Synergetic copper/zinc catalysis: synthesis of aryl/heteroaryl-fused 1H-pyrrolo[3,2-c]pyridines.

Scaffolds having a 1H-pyrrolo[3,2-c]pyridine core show significant biological activity. Herein, we report a synergetic copper/zinc-catalyzed one-step annulation reaction of 2-amino (hetero)arylnitriles with ynamide-derived buta-1,3-diynes to deliver 1H-pyrrolo[3,2-c]quinoline-2,4-diamine derivatives in moderate to good yields. The annulation reaction follows a double cyclization pathway. The gram-scale synthesis of 1H-pyrrolo[3,2-c]quinoline-2,4-diamine proves the practicality of this protocol.

Advances in our understanding of nematode ion channels as potential anthelmintic targets.

Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In nematodes, the physiological behaviors including locomotion, navigation, feeding and reproduction, are regulated by these protein entities. Majority of the antinematodal chemotherapeutics target the ion channels to disrupt essential biological functions. Here, we have summarized current advances in our understanding of nematode ion channel pharmacology. We review cys-loop ligand gated ion channels (LGICs), including nicotinic acetylcholine receptors (nAChRs), acetylcholine-chloride gated ion channels (ACCs), glutamate-gated chloride channels (GluCls), and GABA (γ-aminobutyric acid) receptors, and other ionotropic receptors (transient receptor potential (TRP) channels and potassium ion channels). We have provided an update on the pharmacological properties of these channels from various nematodes. This article catalogs the differences in ion channel composition and resulting pharmacology in the phylum Nematoda. This diversity in ion channel subunit repertoire and pharmacology emphasizes the importance of pursuing species-specific drug target research. In this review, we have provided an overview of recent advances in techniques and functional assays available for screening ion channel properties and their application.