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Background and objectives A2A adenosine receptor (A2AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with A2AAR agonist and A3 adenosine receptor (A3AR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms. Methods Immortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses. Results In vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the A2AAR agonist or A3AR antagonist. In vivo, LJ-4378 treatment increased energy expenditure by 17.0% (P value P value P value = 0.0044), respectively, and improved glucose tolerance in the HFD-fed mice. LJ-4378 increased the expression levels of brown adipocyte markers and mitochondrial proteins in interscapular brown and inguinal white adipose tissue. Conclusion These findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

Portable, interoperable, and flexible are the objectives of following generations of computer-controlled technologies G-codes have long been used by CNC production instruments for component programmers and are now seen as a roadblock in the construction of next Automation. STEP-NC is a new data structure for a younger breed of CNC machine equipment. The data architecture is a simple standards aimed particularly at sophisticated CNC manufacturing machines, putting closer to reality the goal of a standardized CNC controllers and NC code generating facilities. STEP-NC CNC machines are regarded to be the cornerstone for a more open and adaptable design. The future of STEP-NC is depicted in this research, which includes autonomously manufactured machines, STEP compliance data understanding, intelligence constituent programming generation, diagnostic and upkeep, supervision, and job capacity planning.

AImmortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses.In vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the AThese findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

Background: Avian metapneumovirus (aMPV) is an important viral agent in chicken and turkey production industry and is most commonly associated with acute upper respiratory tract infection and swollen head syndrome. The disease is of significant economic concern as it is highly contagious and can lead to production losses in chicken and turkey flocks, especially when associated with secondary bacterial pathogens. Methods: Herein, we have performed a survey on layer farms in selected areas of Madhya Pradesh State, India to ascertain the aMPV status in laying birds, choanal cleft swabs and sera samples were collected for ELISA and RT-PCR assay. A total of 263 sera and 169 choanal cleft swabs from five districts of Madhya Pradesh State (Indore, Bhopal, Sagar, Guna and Bhind) from layer birds of age group 20-72 weeks were screened for aMPV antibodies and for genome. Result: Out of these Indore had maximum sero-postivity (73.33%), followed by Sagar (5.00%) and Bhopal (4.08%), respectively. Other two districts did not show any seropostivity against aMPV. RT-PCR assay using published primers and in vitro transcribed RNA of nucleoprotein (N) gene as positive control was carried out in 169 choanal cleft samples from four districts (Indore, Bhopal, Sagar and Guna). All the samples were found negative for aMPV genome by RT-PCR assay. Overall, 26/263 (9.88%) sera were positive to aMPV antibodies. As the chickens in India are not vaccinated against avian metapneumovirus therefore, this study indicates that layers are exposed to this important poultry pathogen. This study warrants further investigation in wider geographical area and isolation of aMPV to design the control strategies for aMPV.

Synthesis of azepane annulated bicyclo[2.2.2]octenone via oxidative dearomatization and intramolecular π4s + π2s cycloaddition has been described. Manipulation of the adduct led to tricyclic compounds having a β,γ-enone chromophore whose photoreaction upon triplet and singlet excitation furnished polycyclic systems having azepane ring systems.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the lack of treatments to combat infections with human or (potentially) zoonotic CoVs. Thus, it is critical to develop and evaluate antiviral compounds that either directly target CoV functions or modulate host functions involved in viral replication. Here, we demonstrate that low-micromolar concentrations of 6′,6′-difluoro-aristeromycin (DFA), an adenosine nucleoside analogue, strongly inhibit the replication of Middle East respiratory syndrome coronavirus (MERS-CoV) in a cell-based infection assay. DFA was designed to target S-adenosylhomocysteine (SAH) hydrolase and, consequently, may affect intracellular levels of the methyl donor S-adenosylmethionine, which is used by two CoV methyltransferases involved in the capping of the 5’ end of the viral mRNAs. Passaging of wild-type MERS-CoV in the presence of DFA selected a virus population with a ∼100-fold decreased DFA sensitivity, which carried various amino acid substitutions in viral nonstructural proteins (nsps). Specifically, mutations were present in the RNA polymerase subunit (nsp12) and in nsp13, the helicase subunit containing a nucleoside triphosphate hydrolase activity that has been implicated in CoV capping. We hypothesize that DFA directly or indirectly affects viral cap methylation, either by inhibiting the viral enzymes involved or by binding to SAH hydrolase. We also evaluated the antiviral activity of DFA against other betacoronaviruses, but found it to have limited impact on their replication, while being quite cytotoxic to the Calu-3 cells used for this comparison. Nevertheless, our results justify the further characterization of DFA derivatives as an inhibitor of MERS-CoV replication.ImportanceCurrently, there is a lack of antiviral drugs with proven efficacy against human CoV infections including the MERS-CoV that is endemic in the Middle East, the pandemic SARS-CoV-2 and potential future zoonotic CoV. This highlights the importance to investigate new drug targets and identify compounds that can be used to inhibit CoV replication. In this study, we characterize the inhibitory effect of DFA on MERS-CoV replication by phenotypic studies, time-of-addition studies, and the generation and genotyping of a DFA-resistant virus population. Our results revealed that DFA needs further improvement to reduce its cytotoxic side-effects and potentially enhance its broad-spectrum activity. Despite this observation, we think that DFA can be used to understand the function and metabolic interactions of the CoV RNA-synthesizing machinery, or as a starting point for the design of new compounds of the same class.

Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A1AR, A2AAR, A2BAR, and A3AR. A2AAR agonists protect against inflammation, and A3AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2AAR agonist and an A3AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.

A regio- and stereoselective cycloaddition of 6,6-spiroepoxycyclohexa-2,4-dienones with indene leading to benzo-annulated spiroepoxytricyclo[5.2.2.02,6]undec-10-en-9-ones has been described. Manipulation of the oxirane ring in adducts furnished benzotricyclo[5.2.2.02,6]undecanes endowed with a β,γ-enone chromophore. Photochemical reaction of β,γ-enones upon direct irradiation (1S) gave annulated bicyclo[4.2.0]octenones as a consequence of a stereoselective 1,3-acyl shift. Triplet excitation of chromophoric systems led to oxa-di-π-methane reaction and gave pentacyclic products which upon cleavage of cyclopropane ring furnished benzoannulated triquinanes. An interesting effect of substituent on the photoreaction has also been observed.