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Defenses increasing nutraceuticals: Existing developments as well as difficulties.
SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance of proper ChC function is further underscored by the association of ChC connectivity defects with various neurological conditions. Despite this, the cellular mechanisms governing ChC axo-axonic synapse formation remain poorly understood. Here, we identify microglia as key regulators of ChC axonal morphogenesis and AIS synaptogenesis, and show that disease-induced aberrant microglial activation perturbs proper ChC synaptic development/connectivity in the neocortex. In doing so, such findings highlight the therapeutic potential of manipulating microglia to ensure proper brain wiring.SignificanceA gene regulatory system is an important tool for the engineering of biosynthetic pathways of organisms. Here, we report the development of an inducible-ON/OFF regulatory system using a malO operator as a key element. We identified and modulated sequence, position, numbers, and spacing distance of malO operators, generating a series of activating or repressive promoters with tunable strength. The stringency and robustness are both guaranteed in this system, a maximal induction factor of 790-fold was achieved, and nine proteins from different organisms were expressed with high yields. This system can be utilized as a gene switch, promoter enhancer, or metabolic valve in synthetic biology applications. This operator-based engineering strategy can be employed for developing similar regulatory systems in different microorganisms.SignificanceHepatitis C virus chronically infects approximately 1% of the world's population, making an effective vaccine for hepatitis C virus a major unmet public health need. The membrane-associated E1E2 envelope glycoprotein has been used in clinical studies as a vaccine candidate. However, limited neutralization breadth and difficulty in producing large amounts of homogeneous membrane-associated E1E2 have hampered efforts to develop an E1E2-based vaccine. Our previous work described the design and biochemical validation of a native-like soluble secreted form of E1E2 (sE1E2). Here, we describe the immunogenic characterization of the sE1E2 complex. sE1E2 elicited broadly neutralizing antibodies in immunized mice, with increased neutralization breadth relative to the membrane-associated E1E2, thereby validating this platform as a promising model system for vaccine development.SignificanceThe photosensitizer is one of the important components in the photocatalytic system. Molecular photosensitizers have well-defined structures, which is beneficial in revealing the catalysis mechanism and helpful for further structural design and performance optimization. However, separation and recycling of the molecular photosensitizers is a great problem. Loading them into/on two/three-dimensional supports through covalent bonds, electrostatic interactions, and supramolecular interactions is a method that enhances their separation and recycling capability. Nonetheless, the structures of the resulting composites are unclear. Thus, the development of highly crystalline heterogeneity methods for molecular photosensitizers, albeit greatly challenging, is meaningful and desirable in photocatalysis, through which heterogeneous photosensitizers with well-defined structures, definite catalysis mechanisms, and good catalytic performance would be expected.Colistin is considered the last-line antimicrobial for the treatment of multidrug-resistant gram-negative bacterial infections. The emergence and spread of superbugs carrying the mobile colistin resistance gene (mcr) have become the most serious and urgent threat to healthcare. Here, we discover that silver (Ag+), including silver nanoparticles, could restore colistin efficacy against mcr-positive bacteria. We show that Ag+ inhibits the activity of the MCR-1 enzyme via substitution of Zn2+ in the active site. Unexpectedly, a tetra-silver center was found in the active-site pocket of MCR-1 as revealed by the X-ray structure of the Ag-bound MCR-1, resulting in the prevention of substrate binding. Moreover, Ag+effectively slows down the development of higher-level resistance and reduces mutation frequency. Importantly, the combined use of Ag+ at a low concentration with colistin could relieve dermonecrotic lesions and reduce the bacterial load of mice infected with mcr-1–carrying pathogens. This study depicts a mechanism of Ag+ inhibition of MCR enzymes and demonstrates the potentials of Ag+ as broad-spectrum inhibitors for the treatment of mcr-positive bacterial infection in combination with colistin.SignificanceIn this work, we explore the hypothesis that biological neural networks optimize their architecture, through evolution, for learning. We study early olfactory circuits of mammals and insects, which have relatively similar structure but a huge diversity in size. We approximate these circuits as three-layer networks and estimate, analytically, the scaling of the optimal hidden-layer size with input-layer size. We find that both longevity and information in the genome constrain the hidden-layer size, so a range of allometric scalings is possible. However, the experimentally observed allometric scalings in mammals and insects are consistent with biologically plausible values. This analysis should pave the way for a deeper understanding of both biological and artificial networks.Circular RNAs (CircRNAs) have attracted increasing attention in the diagnosis and treatment of human cancers. CircUBAP2 has been identified to promote the progression of triple-negative breast cancer (TNBC), but the function of circUBAP2 in the cisplatin (DDP) resistance of TNBC remains obscure. Our investigation showed that circUBAP2 was significantly upregulated in DDP-resistant TNBC and TNBC sensitivity to DDP could be enhanced by silencing of circUBAP2. D609 Moreover, circUBAP2 was revealed to be a ceRNA for miR-300 to upregulate the expression of anti-silencing function 1B histone chaperone (ASF1B). The effect of circUBAP2/miR-300/ASF1B axis on DDP resistance of TNBC was evaluated by rescue experiments, which demonstrated that circUBAP2 inhibited TNBC sensitivity to DDP through miR-300/ASF1B axis. Furthermore, it was discovered that ASF1B activated PI3K/AKT/mTOR signaling to facilitate the DDP resistance of TNBC cells. In summary, this research revealed a novel regulatory mechanism that circUBAP2 functioned as ceRNA of miR-300 to upregulate ASF1B, which further triggered the PI3K/AKT/mTOR (PAM) signaling to enhance the DDP resistance of TNBC.Akkermansia muciniphila is a commensal bacterium using mucin as its sole carbon and nitrogen source. A. muciniphila is a promising candidate for next-generation probiotics to prevent inflammatory and metabolic disorders, including diabetes and obesity, and to increase the response to cancer immunotherapy. In this study, a comparative pan-genome analysis was conducted to investigate the genomic diversity and evolutionary relationships between complete genomes of 27 A. muciniphila strains, including KGMB strains isolated from healthy Koreans. The analysis showed that A. muciniphila strains formed two clades of group A and B in a phylogenetic tree constructed using 1,219 orthologous single-copy core genes. Interestingly, group A comprised of strains from human feces in Korea, whereas most of group B comprised strains from human feces in Europe and China, and from mouse feces. As group A and B branched, mucin hydrolysis played an important role in the stability of the core genome and drove evolution in the direction of defense against invading pathogens, survival in, and colonization in the mucus layer. In addition, WapA and anSME, which function in competition and post-translational modification of sulfatase, respectively, have been a particularly important selective pressure in the evolution of group A. KGMB strains in group A with anSME gene showed sulfatase activity, but KCTC 15667T in group B without anSME did not. Our findings revealed that KGMB strains evolved to gain an edge in the competition with other gut bacteria by increasing the utilization of sulfated mucin, which will allow it to become highly colonized in the gut environment.Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder and chronic intermittent hypoxia (CIH) is an important pathological characteristic of OSAS. Injuries on renal tubular epithelial cells were observed under the condition of CIH. Pyroptosis is a programmed mode of cell death following cell apoptosis and cell necrosis, which is mediated by NLRP3 signaling. The present study aims to investigate the effects of CIH on the pyroptosis of renal tubular epithelial cells and the underlying mechanism. Firstly, CIH was induced in two renal tubular epithelial cell lines, HK-2 cells and TCMK-1 cells. As the aggravation of hypoxia, an increasing trend of elevated apoptotic rate was observed in HK-2 cells and TCMK-1 cells, accompanied by the excessive release of ROS and LDH, and upregulation of NLRP3. Subsequently, the CIH model was established on rats. The pathological analysis results indicated that in CIH rats, the glomerular bottom membrane and mesangium were slightly thickened and edema was observed in the renal tubule epithelium. More serious injury was observed in the moderate intermittent hypoxia group. The expression level of IL-1β and IL-18 was promoted as the aggravation of hypoxia, accompanied by the elevated production of LDH and ROS. The expression level of cleaved Caspase-1, Caspase-1, GSDMD, TLR4, MyD88, NF-κB, p-NF-κB, and NLRP3 was found significantly upregulated as the aggravation of hypoxia. Lastly, the pathological changes in rats induced by CIH were dramatically abolished by MCC950, a specific inhibitor of NLRP3. Collectively, CIH triggered the pyroptosis of renal tubular epithelial cells by activating the NLRP3 inflammasome.There are several approaches to incorporating uncertainty in power analysis. We review these approaches and highlight the Bayesian-classical hybrid approach that has been implemented in the R package hybridpower. Calculating Bayesian-classical hybrid power circumvents the problem of local optimality in which calculated power is valid if and only if the specified inputs are perfectly correct. hybridpower can compute classical and Bayesian-classical hybrid power for popular testing procedures including the t-test, correlation, simple linear regression, one-way ANOVA (with equal or unequal variances), and the sign test. Using several examples, we demonstrate features of hybridpower and illustrate how to elicit subjective priors, how to determine sample size from the Bayesian-classical approach, and how this approach is distinct from related methods. hybridpower can conduct power analysis for the classical approach, and more importantly, the novel Bayesian-classical hybrid approach that returns more realistic calculations by taking into account local optimality that the classical approach ignores. For users unfamiliar with R, we provide a limited number of RShiny applications based on hybridpower to promote the accessibility of this novel approach to power analysis. We end with a discussion on future developments in hybridpower.
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