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Molecular basis of protein stability at different temperatures is a fundamental problem in protein science that is substantially far from being accurately and quantitatively solved as it requires an explicit knowledge of the temperature dependence of folding free energy of amino acid residues. In the present study, we attempted to gain insights into the thermodynamic stability of SazCA and its implications on protein folding/unfolding. We report molecular dynamics simulations of water solvated SazCA in a temperature range of 293-393 K to study the relationship between the thermostability and flexibility. Our structural analysis shows that the protein maintains the highest structural stability at 353 K and the protein conformations are highly flexible at temperatures above 353 K. Larger exposure of hydrophobic surface residues to the solvent medium for conformations beyond 353 K were identified from H-bond analysis. Higher number of secondary structure contents exhibited by SazCA at 353 K corroborated the conformations at 353 K to exhibit the highest thermal stability. The analysis of thermodynamics of protein stability revealed that the conformations that denature at higher melting temperatures tend to have greater maximum thermal stability. Our analysis shows that 353 K conformations have the highest melting temperature, which was found to be close to the experimental optimum temperature. The enhanced protein stability at 353 K due the least value of heat capacity at unfolding suggested an increase in folding. Comparative Gibbs free energy analysis and funnel shaped energy landscape confirmed a transition in folding/unfolding pathway of SazCA at 353 K.

Plasmonic metasurfaces, which can be considered as the two-dimensional analog of metal-based metamaterials, have attracted progressively increasing attention in recent years because of the ease of fabrication and unprecedented control over the reflected or transmitted light while featuring relatively low losses even at optical wavelengths. Among all the different design approaches, gap-surface plasmon metasurfaces – a specific branch of plasmonic metasurfaces – which consist of a subwavelength thin dielectric spacer sandwiched between an optically thick metal film and arrays of metal subwavelength elements arranged in a strictly or quasi-periodic fashion, have gained awareness from researchers working at practically any frequency regime as its realization only requires a single lithographic step, yet with the possibility to fully control the amplitude, phase, and polarization of the reflected light. In this paper, we review the fundamentals, recent developments, and opportunities of gap-surface plasmon metasurfaces. Starting with introducing the concept of gap-surface plasmon metasurfaces, we present three typical gap-surface plasmon resonators, introduce generalized Snell’s law, and explain the concept of Pancharatnam-Berry phase. We then overview the main applications of gap-surface plasmon metasurfaces, including beam-steerers, flat lenses, holograms, absorbers, color printing, polarization control, surface wave couplers, and dynamically reconfigurable metasurfaces. The review is ended with a short summary and outlook on possible future developments.

Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter “autophagy”) is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were immunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (P < 0.001) and reticular basement membrane (P < 0.0001), greater lamina propria depth (P < 0.005), and increased airway smooth muscle bundles (P < 0.001) with higher expression of Beclin-1 (P < 0.01) and ATG5 (autophagy-related gene 5) (P < 0.05) together with reduced p62 (P < 0.05) compared with nonasthmatic control tissues. Beclin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (P < 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context–dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.

The series Li 7−4 x Ge x La 3 Zr 2 O 12 has been synthesized using conventional solid-state reaction method by substituting Germanium (Ge) at the Li site with the varying content of Ge ( x ) from 0.05 to 0.20. The conducting cubic phase is confirmed using XRD analysis. The surface morphology and elemental distribution have been studied with the help of SEM characterization. The densities of the samples were calculated. For the confirmation of functional groups present, IR spectroscopy has been studied. The modulus and ac conductivity studies have also been examined. A complex impedance study has been carried out in the frequency range 20 Hz to 20 MHz .The highest ionic conductivity has been observed for 0.10 Ge. The minimum activation energy of 0.56 eV is associated with the highest conductivity value of 7.23 × 10 −6 S/cm at room temperature. The increment in ionic conductivity by one order at room temperature makes 0.10 Ge containing ceramic sample a promising candidate as a solid electrolyte.

Meiotic recombination is initiated by SPO11-induced double-strand breaks (DSBs). In most mammals, the methyltransferase PRDM9 guides SPO11 targeting, and the ATM kinase controls meiotic DSB numbers. Following MRE11 nuclease removal of SPO11, the DSB is resected and loaded with DMC1 filaments for homolog invasion. Here, we demonstrate the direct detection of meiotic DSBs and resection using END-seq on mouse spermatocytes with low sample input. We find that DMC1 limits both minimum and maximum resection lengths, whereas 53BP1, BRCA1 and EXO1 play surprisingly minimal roles. Through enzymatic modifications to END-seq, we identify a SPO11-bound meiotic recombination intermediate (SPO11-RI) present at all hotspots. We propose that SPO11-RI forms because chromatin-bound PRDM9 asymmetrically blocks MRE11 from releasing SPO11. In Atm –/– spermatocytes, trapped SPO11 cleavage complexes accumulate due to defective MRE11 initiation of resection. Thus, in addition to governing SPO11 breakage, ATM and PRDM9 are critical local regulators of mammalian SPO11 processing. Recombination requires DNA break formation by SPO11, following which SPO11 is thought to be released. Here, the authors show that meiotic hotspots retain SPO11 through a recombination intermediate dependent on the methyltransferase PRDM9, and that the ATM kinase governs the release of SPO11.

Shock propagation at microscales has been an area of utmost interest in recent years due to the recent developments in the fields of micro-electro-mechanical systems (MEMS) and medical science. In the present investigation, post-shock boundary layer flow is numerically examined for shock wave propagation in micro-ducts of 1000 μ m × 150 μ m, 1000 μ m × 300 μ m, and 1000 μ m × 400 μ m cross sections at incident shock Mach numbers ranging from 1.97 to 2.31, similar to the experimental investigations of Giordano et al. (Shock Waves 28:1251–1262, 2018). The shock is introduced using the stagnation properties corresponding to the Mach number of shock-induced flow. The shock position and the shock wave attenuation parameter are compared with the experimental findings of Giordano et al. Numerical results suggest the existence of a turbulent boundary layer behind the shock wave similar to the experimental findings.

Omega 3 (n3) and Omega 6 (n6) polyunsaturated fatty acids (PUFAs) have been reported to exhibit opposing roles in cancer progression. Our objective was to determine whether different ratios of n6/n3 (AA/EPA+DHA) FAs could modulate the cell viability, lipid peroxidation, total cellular fatty acid composition and expression of tumor regulatory Matrix Attachment Region binding proteins (MARBPs) in breast cancer cell lines and in non-cancerous, MCF10A cells. Low ratios of n6/n3 (1:2.5, 1:4, 1:5, 1:10) FA decreased the viability and growth of MDA-MB-231 and MCF7 significantly compared to the non-cancerous cells (MCF10A). Contrarily, higher n6/n3 FA (2.5:1, 4:1, 5:1, 10:1) decreased the survival of both the cancerous and non-cancerous cell types. Lower ratios of n6/n3 selectively induced LPO in the breast cancer cells whereas the higher ratios induced in both cancerous and non-cancerous cell types. Interestingly, compared to higher n6/n3 FA ratios, lower ratios increased the expression of tumor suppressor MARBP, SMAR1 and decreased the expression of tumor activator Cux/CDP in both breast cancer and non-cancerous, MCF10A cells. Low n6/n3 FAs significantly increased SMAR1 expression which resulted into activation of p21WAF1/CIP1 in MDA-MB-231 and MCF7, the increase being ratio dependent in MDA-MB-231. These results suggest that increased intake of n3 fatty acids in our diet could help both in the prevention as well as management of breast cancer.

This Analysis compares four commonly used assays to measure food intake in flies and identifies radioisotope-labeling and the capillary feeder (CAFE) as the most reproducible and sensitive. Food intake is a fundamental parameter in animal studies. Despite the prevalent use of Drosophila in laboratory research, precise measurements of food intake remain challenging in this model organism. Here, we compare several common Drosophila feeding assays: the capillary feeder (CAFE), food labeling with a radioactive tracer or colorimetric dye and observations of proboscis extension (PE). We show that the CAFE and radioisotope labeling provide the most consistent results, have the highest sensitivity and can resolve differences in feeding that dye labeling and PE fail to distinguish. We conclude that performing the radiolabeling and CAFE assays in parallel is currently the best approach for quantifying Drosophila food intake. Understanding the strengths and limitations of methods for measuring food intake will greatly advance Drosophila studies of nutrition, behavior and disease.

Reactive arthritis (ReA) is typically preceded by sexually transmitted disease or gastrointestinal infection. An association has also been reported with bacterial and viral respiratory infections. Herein, we report the first case of ReA after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This male patient is in his 50s who was admitted with COVID-19 pneumonia. On the second day of admission, SARS-CoV-2 PCR was positive from nasopharyngeal swab specimen. Despite starting standard dose of favipiravir, his respiratory condition deteriorated during hospitalisation. On the fourth hospital day, he developed acute respiratory distress syndrome and was intubated. On day 11, he was successfully extubated, subsequently completing a 14-day course of favipiravir. On day 21, 1 day after starting physical therapy, he developed acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon, without rash, conjunctivitis, or preceding diarrhoea or urethritis. Arthrocentesis of his left ankle revealed mild inflammatory fluid without monosodium urate or calcium pyrophosphate crystals. Culture of synovial fluid was negative. Plain X-rays of his ankles and feet showed no erosive changes or enthesophytes. Tests for syphilis, HIV, anti-streptolysin O (ASO), Mycoplasma, Chlamydia pneumoniae, antinuclear antibody, rheumatoid factor, anticyclic citrullinated peptide antibody and Human Leukocyte Antigen-B27 (HLA-B27) were negative. Gonococcal and Chlamydia trachomatis urine PCR were also negative. He was diagnosed with ReA. Nonsteroidal Anti-Inflammatory Drug (NSAID)s and intra-articular corticosteroid injection resulted in moderate improvement.

At least 120 non-olfactory G-protein-coupled receptors in the human genome are ‘orphans’ for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs. Yeast-based screening identifies the benzodiazepine drug lorazepam as a non-selective positive allosteric modulator of the G-protein-coupled receptor (GPCR) GPR68; homology modelling and molecular docking of 3.1 million molecules found a new compound, ‘ogerin’, as a potent GPR68 modulator, which suppressed recall in fear conditioning in wild-type mice, and the general method of combining physical and structure-based screening may lead to the discovery of selective ligands for other GPCRs. Finding ligands for GPCR orphans At least 120 non-olfactory G-protein-coupled receptors (GPCRs) in the human genome are 'orphans', meaning that their endogenous ligands are not known. Bryan Roth and colleagues use yeast-based screening to identify the benzodiazepine drug lorazepam as a non-selective positive allosteric modulator of GPR68, a proton receptor with no known small-molecule modulators. Homology modelling and molecular docking of 3.1 million molecules identified a new compound 'ogerin', as a potent GPR68 modulator. Ogerin suppressed recall in fear conditioning in wild-type mice. The procedures used in this work, combining physical and structure-based screening, may serve as a general method for identifying selective ligands for other GPCRs.