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The results of a consistent computational and experimental study of acoustic self-oscillations in an annular cavity surrounding a circular pipe with a local narrowing are given. In the experiment, pressure fluctuations were measured on the outer wall of the annular cavity for various volume flow rates; air entered the pipe at the atmospheric pressure. It was found that the flow regime with excitation of acoustic self-oscillations in the cavity is implemented in a certain range of flow rates. The oscillation frequency corresponds to the first natural frequency, and the root-mean-square values of pressure fluctuations reach a level of 2300 Pa. Numerical simulation based on the RANS approach, carried out for the geometry and conditions of experiment, reproduces the observed effect of acoustic excitation of the cavity and gives similar values of the fluctuation amplitude. The oscillation modes developed at various volumetric flow rates are analyzed based on the obtained calculated data.

A significant fraction of carbon stored in the Earth's soil moves through arbuscular mycorrhiza (AM) and ectomycorrhiza (EM). The impacts of AM and EM on the soil carbon budget are poorly understood. We propose a method to quantify the mycorrhizal contribution to carbon cycling, explicitly accounting for the abundance of plant-associated and extraradical mycorrhizal mycelium. We discuss the need to acquire additional data to use our method, and present our new global database holding information on plant species-by-site intensity of root colonization by mycorrhizas. We demonstrate that the degree of mycorrhizal fungal colonization has globally consistent patterns across plant species. This suggests that the level of plant species-specific root colonization can be used as a plant trait. To exemplify our method, we assessed the differential impacts of AM : EM ratio and EM shrub encroachment on carbon stocks in sub-arctic tundra. AM and EM affect tundra carbon stocks at different magnitudes, and via partly distinct dominant pathways: via extraradical mycelium (both EM and AM) and via mycorrhizal impacts on above- and belowground biomass carbon (mostly AM). Our method provides a powerful tool for the quantitative assessment of mycorrhizal impact on local and global carbon cycling processes, paving the way towards an improved understanding of the role of mycorrhizas in the Earth's carbon cycle.

Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ and GNA11 genes, which convey oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway. Despite promising early results, safe doses of pharmacological inhibitors of the MAPK cascade failed to effectively control uveal melanoma in human trials. Considering the role of the RAC/PAK signaling axis as a co-regulator of the MAPK cascade, we set forth to investigate whether the efficacy of MAPK cascade inhibitors in pre-clinical models may be enhanced by direct inhibition of RAC and PAK proteins, or by indirect control of RAC via inhibition of guanylate biosynthesis. We observed that pharmacological inhibition of RAC, PAK and the key guanylate biosynthesis enzyme IMPDH significantly synergized with various inhibitors of the MAPK cascade in suppressing oncogenic signaling and the growth of uveal melanoma cells. In a mouse model, the addition of an IMPDH inhibitor to the treatment regimen significantly enhanced the ability of a MAPK cascade inhibitor to improve the survival of tumor-bearing animals. Targeting of the RAC/PAK axis provides a new strategy to increase the efficacy of targeted therapies in uveal melanoma. While RAC and PAK inhibitors are still undergoing pre-clinical development, clinically available inhibitors of IMPDH offer an opportunity to test the efficacy of this novel synergistic combination in the context of human disease.

Semiconductor quantum well electroabsorption modulators are widely used to modulate near-infrared (NIR) radiation at frequencies below 0.1 terahertz (THz). Here, the NIR absorption of undoped quantum wells was modulated by strong electric fields with frequencies between 1.5 and 3.9 THz. The THz field coupled two excited states (excitons) of the quantum wells, as manifested by a new THz frequency- and power-dependent NIR absorption line. Nonperturbative theory and experiment indicate that the THz field generated a coherent quantum superposition of an absorbing and a nonabsorbing exciton. This quantum coherence may yield new applications for quantum well modulators in optical communications.

Objective: Rifampicin (RIF)-resistance, a surrogate marker for multidrug-resistant tuberculosis (TB), is mediated by mutations in the rpoB gene. We aimed to investigate the prevalence of mutations pattern in the entire rpoB gene of Mycobacterium tuberculosis clinical isolates and their association with resistance level to RIF. Methods: Among 465 clinical isolates collected from the Guangzhou Chest Hospital, drug-susceptibility of 175 confirmed Mtb strains was performed via the proportion method and Bactec MGIT 960 system. GeneXpert MTB/RIF and sanger sequencing facilitated in genetic characterization, whereas the MICs of RIF were determined by Alamar blue assay. Results: We found 150/175 (85.71%) RIF-resistant strains (MIC: 4 to >64 [micro]g/mL) of which 57 were MDR and 81 pre- XDR TB. Genetic analysis identified 17 types of mutations 146/150 (97.33%) within RRDR (codons 426-452) of rpoB, mainly at L430 (P), D435 (V, E, G, N), H445 (N, D, Y, R, L), S450 (L, F) and L452 (P). D435V 12/146 (8.2%), H445N 16/146 (10.9%), and S450L 70/146 (47.94%) were the most frequently encountered mutations. Mutations Q432K, M434V, and N437D are rarely identified in RRDR. Deletions at (1284- 1289 CCAGCT,1295-1303 AATTCATGG), and insertion at (1300-1302 TTC) were detected within RRDR of three RIFr strains for the first time. We detected 47 types of mutations and insertions/deletions (indels) outside the RRDR. Four RIFr strains were detected with only novel mutations/indels outside the RRDR. Two of the four had (K274Q + C897 del + I491M) and (A286V + L494P), respectively. The other two had (G1687del + P454L) and (TT1835-6 ins + I491L) individually. Compared with phenotypic characterization, diagnostic sensitivities of GeneXpert MTB/RIF and sequencing analysis were 95.33% (143/150), and 100% (150/150) respectively. Conclusion: Our findings underscore the key role of RRDR mutations and the contribution of non-RRDR mutations in rapid molecular diagnosis of RIFr clinical isolates. Such insights will support early detection of disease and recommend the appropriate anti-TB regimens in high-burden settings. Keywords: rifampicin-resistance, Mycobacterium tuberculosis, rpoB, GeneXpert MTB/RIF, resistance-determining region

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. Methods: This study combines chemical synthesis, molecular modelling, and inhibitory activity assays to characterise the structure–activity relationship of novel isomeric 1,2,4-oxadiazole-substituted derivatives of the 2-azabicyclo[2.2.1]heptane scaffold acylated with (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid. Results: In this article, we demonstrate the efficacy of new compounds as robust inhibitors of DPP-4. The attempts to further modify neogliptin (our lead compound described previously) resulted in a more potent DPP-4 inhibitor 9a (IC50 = 4.3 nM), which did not mediate any substantial inhibition of DPP-8 and DPP-9. Conclusions: This study demonstrates that pseudo peptides incorporating (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, a 2-aza-bicyclo[2.2.1]heptane moiety, and 1,2,4-oxadiazole substituents act as potent and selective DPP-4 inhibitors. By the stereochemical refinement of oxadiazole derivatives of neogliptin, we discovered compound 9a, a strong candidate for further development in T2DM treatment.

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example of the leap in the development of mRNA technologies was the mass vaccination against COVID-19 during the pandemic. The emergence of large-scale technology and positive experience of mRNA immunization sparked the development of antiviral and anti-cancer mRNA vaccines as well as therapeutic mRNA agents for genetic and other diseases. To facilitate mRNA delivery, lipid nanoparticles (LNPs) have been successfully employed. However, the diverse use of mRNA therapeutic approaches requires the development of adaptable LNP delivery systems that can control the kinetics of mRNA uptake and expression in target cells. Here, we report effective mRNA delivery into cultured mammalian cells (HEK293T, HeLa, DC2.4) and living mouse muscle tissues by liposomes containing either 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) or the newly applied 1,30-bis(cholest-5-en-3β-yloxycarbonylamino)-9,13,18,22-tetraaza-3,6,25,28-tetraoxatriacontane tetrahydrochloride (2X7) cationic lipids. Using end-point and real-time monitoring of Fluc mRNA expression, we showed that these LNPs exhibited an unusually delayed (of over 10 h in the case of the 2X7-based system) but had highly efficient and prolonged reporter activity in cells. Accordingly, both LNP formulations decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) provided efficient luciferase production in mice, peaking on day 3 after intramuscular injection. Notably, the bioluminescence was observed only at the site of injection in caudal thigh muscles, thereby demonstrating local expression of the model gene of interest. The developed mRNA delivery systems hold promise for prophylactic applications, where sustained synthesis of defensive proteins is required, and open doors to new possibilities in mRNA-based therapies.

Ulmus laciniata is a strategic food resource for Cervus elaphus xanthopygus , especially in autumn and spring. The results of a study of the seasonal content of water-soluble polysaccharides, their monosaccharide composition, extracted from the bark and bast of U. laciniata, are presented. Two maxima in the content of water-soluble polysaccharides were revealed: during the shoot growth period (June) and during a slightly lower one during the preparation for winter dormancy (October). The minimum content is observed during the beginning of the growing season (April–May). The content of pectin substances, unlike water-soluble polysaccharides, changed slightly during the year. The groups of substances studied are classified as the most bioavailable polysaccharides with extensive physiological activity. In addition, the data obtained may explain the feeding behavior of C. elaphus xanthopygus , which lives in Primorskii krai.

Spontaneous bioelectrical activity of the brain and the duration of gasping were recorded in mice during modeling of global strangulation ischemia of the brain against the background of preventive administration of citicoline. The maximum neuroprotective effect of citicoline was observed when it was administered 60 min before the simulation of ischemia and was completely prevented by preliminary administration of a selective P 2 Y 6 receptor antagonist MRS2578. The obtained experimental data attest to the leading role of receptor mechanisms in the implementation of neuroprotective activity of citicoline.

The World Health Organization (WHO) reports that tuberculosis (TB) is one of the top 10 leading causes of global mortality. The increasing incidence of multidrug-resistant TB highlights the urgent need for an intensified quest to discover innovative anti-TB medications In this study, we investigated four new derivatives from the quinoxaline-2-carboxylic acid 1,4-dioxide class. New 3-methylquinoxaline 1,4-dioxides with a variation in substituents at positions 2 and 6(7) were synthesized via nucleophilic aromatic substitution with amines and assessed against a Mycobacteria spp. Compound 4 showed high antimycobacterial activity (1.25 μg/mL against M. tuberculosis) and low toxicity in vivo in mice. Selection and whole-genomic sequencing of spontaneous drug-resistant M. smegmatis mutants revealed a high number of single-nucleotide polymorphisms, confirming the predicted mode of action of the quinoxaline-2-carboxylic acid 1,4-dioxide 4 as a DNA-damaging agent. Subsequent reverse genetics methods confirmed that mutations in the genes MSMEG_4646, MSMEG_5122, and MSMEG_1380 mediate resistance to these compounds. Overall, the derivatives of quinoxaline-2-carboxylic acid 1,4-dioxide present a promising scaffold for the development of innovative antimycobacterial drugs.