Notes

Boron nitride nanotube forerunners formation during high-temperature combination: kinetic and also thermodynamic acting.
The field of membrane structural biology represents a fast-moving field with exciting developments including native nanodiscs that allow preparation of complexes of post-translationally modified proteins bound to biological lipids. This has led to conceptual advances including biological membraneprotein assemblies or "memteins" as the fundamental functional units of biological membranes. Tools including cryo-electron microscopy and X-ray crystallography are maturing such that it is becoming increasingly feasible to solve structures of large, multicomponent complexes, while complementary methods including nuclear magnetic resonance spectroscopy yield unique insights into interactions and dynamics. Challenges remain, including elucidating exactly how lipids and ligands are recognized at atomic resolution and transduce signals across asymmetric bilayers. In this special volume some of the latest thinking and methods are gathered through the analysis of a range of transmembrane targets. Ongoing work on areas including polymer design, protein labelling and microfluidic technologies will ensure continued progress on improving resolution and throughput, providing deeper understanding of this most important group of targets.Depression is the most common psychiatric comorbidity to be diagnosed following traumatic brain injury (TBI). In clinical populations, TBI-induced depression may be particularly difficult to treat due to both unique underlying causes and the propensity for treatment resistance. Preclinical assays are needed to characterize depressive-like behavior in models of TBI and evaluate treatments. In the current study, two traditionally-acute assays of depressive-like behaviors, the Forced Swim Task and Saccharin Preference, were extended longitudinally to evaluate chronic TBI-induced depressive-like behaviors in male rats. Two chronic measures of motivation, the Progressive Ratio (PR) task and Effort Discounting Task (EDT), were also tested. The PR measures motivation to exert effort, while the EDT parametrically evaluates choice between low- and high-effort requirements. The EDT was the only assay which captured chronic depressive-like behavior after TBI, albeit with a degree of recovery over time. We found that traditionally-acute measures (Forced Swim Task, Saccharin Preference), and even our other chronic measure (PR), failed to capture long-term deficits. We also challenged serotonin and dopamine systems (via fluoxetine and bupropion) to evaluate how TBI-induced changes to these systems might drive depressive-like behaviors. Although we found no effect of fluoxetine, high-dose bupropion differentially impaired TBI rats. These findings suggest that (1) TBI-induced depressive symptoms remain difficult to measure at the preclinical level, (2) treatment for TBI-induced depression requires further exploration, and (3) obstacles at the preclinical level may translate to treatment failure at the clinical level.Studies have shown that epigenetic changes such as alteration in histone acetylation and DNA methylation in various brain regions play an essential role in anxiety behavior. According to the critical role of calcium/calmodulin protein kinaseII (CaMKII) in these processes, the present study examined the effect of CaMKII inhibitor (KN93) on neuronal activity and level of c-fos in the amygdala and nucleus accumbens (NAC) in the offspring of morphine-exposed parents. Adult male and female Wistar rats received morphine orally (for 21 days). After the washout period (10 days), rats were mated with either drug-naïve or morphine-exposed rats. KN93 was microinjected into the brain of male offspring. The anxiety-like behavior, the neuronal firing rate in the NAC and the amygdala and level of c-fos were assessed by related techniques. Data showed the offspring with one and/or two morphine-abstinent parent(s) had more anxiety-like behavior than the control group. However, the administration of KN-93 decreased anxiety in the offspring of morphine-exposed rats compared with saline-treated groups. The expression level of the c-fos was not significantly altered by the inhibition of CaMKII in the amygdala, but the c-fos level was reduced in the NAC. The neuronal firing rate of these groups was associated with an increase in the amygdala in comparison to the saline groups but was decreased in the NAC. Results showed that CaMKII had a role in anxiety-like behavior in the offspring of morphine-exposed parents, and changes in neuronal firing rate and c-fos level in the NAC might be involved in this process.Cladribine (2-chloro-2'-deoxy-β-d-adenosine) is a 2'-deoxyadenosine analogue, approved by the FDA for the treatment of hairy cell leukemia and more recently has been proved for therapeutic against many autoimmune diseases as multiple sclerosis. The biosynthesis of this compound using Thermomonospora alba CECT 3324 as biocatalyst is herein reported. Selleckchem IOX2 This thermophilic microorganism was successfully entrapped in polyacrylamide gel supplemented with nanoclays such as bentonite. The immobilized biocatalyst (T. alba-Ac-Bent 1.00 %), was able to biosynthesize cladribine with a conversion of 89 % in 1 h of reaction and retains its activity for more than 270 reuses without significantly activity loss, showing better operational stability and mechanical properties than the natural matrix. A microscale assay using the developed system, could allow the production of at least 181 mg of cladribine in successive bioprocesses.Previously, we showed a differential regulation of the human delta-opioid receptor (hDOPr) by etorphine and [D-Pen2, D-Pen5] enkephalin (DPDPE). To understand the molecular basis of such differences, we introduced 3 alanine mutations at the residues T161. Y318 and S363. Both wild type (WT) and hDOPr mutants were expressed in HEK cells containing endogenous arrestins or CFP-tagged arrestin 3, then desensitization, internalization, recycling and phosphorylation were studied. In a context of endogenous arrestin expression, a major difference in DOPr desensitization was observed between agonists that was modified with the T161A mutation upon etorphine and with the S363A substitution upon DPDPE exposure. While both agonists induced a major receptor internalization, T161A and S363A impaired DOPr sequestration only for etorphine. However, similar level of S363 phosphorylation was measured between agonists. When CFP-tagged arrestin 3 was over-expressed, a similar profile of desensitization was measured for both agonists. In this context, all the 3 alanine mutations decreased etorphine-induced receptor desensitization. Using FRET, we showed similar interactions between WT hDOPr and arrestin 3 under DPDPE and etorphine stimulation which were delayed by both the Y318A and the S363A substitutions for etorphine. Finally, hDOPr recycling was qualitatively evaluated by microscopy and showed neither arrestin 3/hDOPr colocalization nor major impact of alanine mutations except for the S363A which impaired internalization and recycling for etorphine. The T161, Y318 and S363 residues of hDOPr could underlie the differential regulation promoted by DPDPE and etorphine.The gut microbiome profoundly affects human health and disease, and their infecting viruses are likely as important, but often missed because of reference database limitations. Here, we (1) built a human Gut Virome Database (GVD) from 2,697 viral particle or microbial metagenomes from 1,986 individuals representing 16 countries, (2) assess its effectiveness, and (3) report a meta-analysis that reveals age-dependent patterns across healthy Westerners. The GVD contains 33,242 unique viral populations (approximately species-level taxa) and improves average viral detection rates over viral RefSeq and IMG/VR nearly 182-fold and 2.6-fold, respectively. GVD meta-analyses show highly personalized viromes, reveal that inter-study variability from technical artifacts is larger than any "disease" effect at the population level, and document how viral diversity changes from human infancy into senescence. Together, this compact foundational resource, these standardization guidelines, and these meta-analysis findings provide a systematic toolkit to help maximize our understanding of viral roles in health and disease.The SARS-CoV-2 betacoronavirus uses its highly glycosylated trimeric Spike protein to bind to the cell surface receptor angiotensin converting enzyme 2 (ACE2) glycoprotein and facilitate host cell entry. We utilized glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. We combined this information with bioinformatics analyses of natural variants and with existing 3D structures of both glycoproteins to generate molecular dynamics simulations of each glycoprotein both alone and interacting with one another. Our results highlight roles for glycans in sterically masking polypeptide epitopes and directly modulating Spike-ACE2 interactions. Furthermore, our results illustrate the impact of viral evolution and divergence on Spike glycosylation, as well as the influence of natural variants on ACE2 receptor glycosylation. Taken together, these data can facilitate immunogen design to achieve antibody neutralization and inform therapeutic strategies to inhibit viral infection.Alveolar macrophages are among the first immune cells that respond to inhaled pathogens. However, numerous pathogens block macrophage-intrinsic immune responses, making it unclear how robust antimicrobial responses are generated. The intracellular bacterium Legionella pneumophila inhibits host translation, thereby impairing cytokine production by infected macrophages. Nevertheless, Legionella-infected macrophages induce an interleukin-1 (IL-1)-dependent inflammatory cytokine response by recruited monocytes and other cells that controls infection. How IL-1 directs these cells to produce inflammatory cytokines is unknown. Here, we show that collaboration with the alveolar epithelium is critical for controlling infection. IL-1 induces the alveolar epithelium to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). Intriguingly, GM-CSF signaling amplifies inflammatory cytokine production in recruited monocytes by enhancing Toll-like receptor (TLR)-induced glycolysis. Our findings reveal that alveolar macrophages engage alveolar epithelial signals to metabolically reprogram monocytes for antibacterial inflammation.Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Here we integrated topological maps for colon tumors and normal colons with epigenetic, transcriptional, and imaging data to characterize alterations to chromatin loops, topologically associated domains, and large-scale compartments. We found that spatial partitioning of the open and closed genome compartments is profoundly compromised in tumors. This reorganization is accompanied by compartment-specific hypomethylation and chromatin changes. Additionally, we identify a compartment at the interface between the canonical A and B compartments that is reorganized in tumors. Remarkably, similar shifts were evident in non-malignant cells that have accumulated excess divisions. Our analyses suggest that these topological changes repress stemness and invasion programs while inducing anti-tumor immunity genes and may therefore restrain malignant progression. Our findings call into question the conventional view that tumor-associated epigenomic alterations are primarily oncogenic.
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