Decoding the Structural Diversity: A New Horizon in Antimicrobial Prospecting and Mechanistic Investigation.

The escalating crisis of antimicrobial resistance (AMR) underscores the urgent need for novel antimicrobials. One promising strategy is the exploration of structural diversity, as diverse structures can lead to diverse biological activities and mechanisms of action. This review delves into the role of structural diversity in antimicrobial discovery, highlighting its influence on factors such as target selectivity, binding affinity, pharmacokinetic properties, and the ability to overcome resistance mechanisms. We discuss various approaches for exploring structural diversity, including combinatorial chemistry, diversity-oriented synthesis, and natural product screening, and provide an overview of the common mechanisms of action of antimicrobials. We also describe techniques for investigating these mechanisms, such as genomics, proteomics, and structural biology. Despite significant progress, several challenges remain, including the synthesis of diverse compound libraries, the identification of active compounds, the elucidation of complex mechanisms of action, the emergence of AMR, and the translation of laboratory discoveries to clinical applications. However, emerging trends and technologies, such as artificial intelligence, high-throughput screening, next-generation sequencing, and open-source drug discovery, offer new avenues to overcome these challenges. Looking ahead, we envisage an exciting future for structural diversity-oriented antimicrobial discovery, with opportunities for expanding the chemical space, harnessing the power of nature, deepening our understanding of mechanisms of action, and moving toward personalized medicine and collaborative drug discovery. As we face the continued challenge of AMR, the exploration of structural diversity will be crucial in our search for new and effective antimicrobials.

Challenges and Solutions in the Recombinant Expression of Membrane Proteins.

Membrane proteins are important components of the proteome and play key roles in many biological processes, such as signal transduction, material transport, cell recognition, etc. Membrane proteins are involved in several fields, and more and more researchers want to understand them. However, the structural properties of membrane proteins make their recombinant expression yield low. This adversely affects the study of the structure and function of membrane proteins. Therefore, it is crucial to have a comprehensive and up-to-date understanding of membrane protein recombinant expression. Based on the current stage of research on membrane proteins, the article describes the current challenges faced by membrane protein recombinant expression and the solutions that can be applied to lay the foundation for a better study of membrane proteins in the future.

The Predictive Value of Three Variables in Patients with Metastatic Renal Cell Carcinoma Treated with Immune-Based Combination Therapies in Randomized Clinical Trials: A Systematic Review and Meta-Analysis.

Background: Sex, age, and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic risk may influence the immune response. Nonetheless, the correlation between these factors and the survival benefits of immune-based combination therapies in patients with metastatic renal cell carcinoma (mRCC) is controversial and undefined. As a result, the purpose of this research is to evaluate the potential differences of immune-based combination therapies on survival benefits from mRCC subgroups. Methods: PubMed, Cochrane Library, Embase, and http://www.clinicaltrials.gov were searched from inception to March 17, 2022. Randomized clinical trials (RCTs) comparing overall survival (OS) or progression-free survival (PFS) in patients with mRCC treated by immune-based combinations vs. contemporary first-line therapies were included. Results: Five RCTs with a total of 4206 subjects were included. An OS and PFS benefit of immune-based combinations were found for patients of different sex, age, and IMDC intermediate/poor risk. No obvious difference in relative PFS benefit from immune-based combinations over the control group was found in patients of different genders (P=0.71, I2 = 0%), ages (P=0.55, I2 = 0%), or IMDC prognostic risks (P=0.38, I2 = 0%). However, the difference in OS benefit was significant regarding age (P=0.009, I2 = 85.5%) and IMDC prognostic risk (P=0.004, I2 = 82.2%). Conclusions: This meta-analysis found that immune-based combination therapies should not be restricted to certain patients with mRCC in gender categories. However, age and IMDC prognostic risk of mRCC patients are associated with different outcomes of OS and thus help identify those patients most probably to benefit from immune-based combination therapies.

Strategies for Optimizing the Production of Proteins and Peptides with Multiple Disulfide Bonds.

Bacteria can produce recombinant proteins quickly and cost effectively. However, their physiological properties limit their use for the production of proteins in their native form, especially polypeptides that are subjected to major post-translational modifications. Proteins that rely on disulfide bridges for their stability are difficult to produce in Escherichia coli. The bacterium offers the least costly, simplest, and fastest method for protein production. However, it is difficult to produce proteins with a very large size. Saccharomyces cerevisiae and Pichia pastoris are the most commonly used yeast species for protein production. At a low expense, yeasts can offer high protein yields, generate proteins with a molecular weight greater than 50 kDa, extract signal sequences, and glycosylate proteins. Both eukaryotic and prokaryotic species maintain reducing conditions in the cytoplasm. Hence, the formation of disulfide bonds is inhibited. These bonds are formed in eukaryotic cells during the export cycle, under the oxidizing conditions of the endoplasmic reticulum. Bacteria do not have an advanced subcellular space, but in the oxidizing periplasm, they exhibit both export systems and enzymatic activities directed at the formation and quality of disulfide bonds. Here, we discuss current techniques used to target eukaryotic and prokaryotic species for the generation of correctly folded proteins with disulfide bonds.

Hyperoside Ameliorates Diabetic Retinopathy via Anti-Oxidation, Inhibiting Cell Damage and Apoptosis Induced by High Glucose.

BACKGROUND: Hyperoside (Hyp) is a flavonoid substance extracted from plants, which has the functions of anti-cancer, anti-inflammatory, and anti-oxidation. In the previous study, we found that Hyp reduced the injury of rat retinal vascular endothelial cells (RVECs) induced by H2O2. METHOD: In the present research, we evaluated the protective effect of Hyp on the pathological damage of retina caused by high glucose of diabetes mellitus (DM) in in vitro and in vivo experiments. The effect of Hyp on cell viability, oxidative stress level, and apoptosis of RVECs was assessed. RESULTS: Hyp significantly reduced the of RVECs damage, oxidative stress level, and cell apoptosis induced by high glucose in vitro. In DM model rats, Hyp treatment could significantly reduce blood glucose levels and the pathological damage of retina caused by DM and increase the proliferation of RVECs while exerting the inhibition on apoptotic activity. Furthermore, Hyp treatment decreased the expressions of apoptotic proteins including caspase-3, caspase-9, and Bax in RVECs of DM rats, while increased the expression of anti-apoptotic protein Bcl-2. CONCLUSION: Hyp may have protective effect on diabetes-induced retinopathy by reducing oxidative stress, inhibiting cell damage, and apoptosis induced by high glucose.

Short-term effect and safety of a new generation of monoclonal antibodies targeting interleukin-23p19 for treatment of psoriasis: a systematic review and meta-analysis.

The effect and safety of monoclonal antibodies (mAbs) targeting the interleukin-23 (IL-23) p19 subunit for treatment of psoriasis has not previously been systematically evaluated. To perform a systematic review and meta-analysis of randomized clinical trials (RCTs) (including Phase I-III trials) to evaluate the efficacy and safety of these mAbs for treatment of psoriasis. The databases of PubMed, Baidu Scholar, and Cochrane Library of Clinical Trials were searched from inception of the databases to January 1st, 2018. A systematic review and meta-analysis was conducted using Review Manager Software version 5.3 (RevMan 5.3). Nine RCTs with a total of 2,478 subjects met our inclusion criteria. A significant increase in PASI 75 (RR: 11.65; 95% CI: 9.01-15.06), PASI 90 (RR: 21.74; 95% CI: 14.28-33.10), PASI 100 (RR: 31.56; 95% CI: 14.66-67.96), PGA 0/1 (OR: 23.21; 95% CI: 14.61-36.89), and DLQI 0/1 (RR: 10.29; 95% CI: 7.52-14.09) was identified for anti-IL-23p19 mAb vs. placebo, and PASI 75 (RR: 1.25; 95% CI: 1.18-1.32), PASI 90 (OR: 2.56; 95% CI: 2.13-3.09), PASI 100 (OR: 2.38, 95% CI: 1.89-2.99), and DLQI 0/1 (RR: 1.33; 95% CI: 1.20-1.47) vs. tumour necrosis factor (TNF) antagonists for the treatment of psoriasis. Furthermore, there was no significant difference in adverse events between placebo and TNF antagonists. Anti-IL-23p19 mAbs are effective with acceptable safety as therapy for psoriasis, and may be superior to TNF antagonists. More RCTs with a larger sample size are required to verify the current findings.

A case of Phaeohyphomycosis caused by Corynespora cassiicola infection.

BACKGROUND: Corynespora cassiicola infection is common in plants, but the human Corynespora cassiicola infection in our report is rare according to the literature. CASE PRESENTATION: We report a case of subcutaneous phaeohyphomycosis caused by a plant pathogen in a patient with acute heart failure. The organism was isolated and identified as Corynespora cassiicola according to its morphological characteristics and gene analysis. The patient was treated successfully with systemic voriconazole. CONCLUSIONS: This is the third reported case of subcutaneous infection caused by Corynespora cassiicola and the first reported case with accompanied renal impairment, which was associated with acute heart failure. Our case also suggests the importance of renal function monitoring in patients receiving intravenous voriconazole treatment.

Determination of boron content and isotopic composition in gypsum by inductively coupled plasma optical emission spectroscopy and positive thermal ionization mass spectrometry using phase transformation.

As a stable isotope, boron plays an important role in hydrogeology, environmental geochemistry, ore deposit geochemistry and marine paleoclimatology. However, there is no report of boron isotopic composition in gypsum. This is mainly confined to complete dissolution of Gypsum by water or acid. In this study, gypsum was converted to calcium carbonate (CaCO3) with ammonium bicarbonate(NH4HCO3) by two steps at 50°C. In every step, the mass ratio of NH4HCO3/CaSO4·2H2O was twice, and conversion rate reached more than 98%. Converted CaCO3 was totally dissolved with hydrochloric acid (the dissolution rate was over 99%). In order to overcome the difficulties of the matrix interference and the detection limit of Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), we use Amberlite IRA 743 resin to purify and enrichment the boron at first, then eluting boron from the resin with 10mL 0.1mol/L hydrochloric acid at 75°C. The boron isotopic composition of natural gypsum samples was determined using positive thermal ionization mass spectrometry (P-TIMS). The boron isotopic composition of gypsum may be an excellent indicator for the formation environment.

Production of disulfide bond-rich peptides by fusion expression using small transmembrane proteins of Escherichia coli.

Recombinant expression in Escherichia coli allows the simple, economical, and effective production of bioactive peptides. On the other hand, the production of native peptides, particularly those rich in disulfide bonds, is a major problem. Previous studies have reported that the use of carrier proteins for fusion expression can result in good peptide yields, but few are folded correctly. In this study, two transmembrane small proteins in E. coli, YoaJ and YkgR, which both orientate with their N-termini in cytoplasm and their C-termini in periplasm, were used for fusion expression. The recombinant production of two peptides, asteropsin A (ASPA) and ß-defensin (BD), was induced in the periplasm of E. coli using a selected carrier protein. Both peptides were expressed at high levels, at yields of approximately 5-10 mg/L of culture. Mass spectrometry showed that the resulting peptide had the same molecular weight as their natural forms. After purification, single peaks were observed by reversed phase high-performance liquid chromatography (RP-HPLC), demonstrating the absence of isoforms. Furthermore, cytoplasmically expressed fusion proteins with a carrier at their C-termini did not contain disulfide bonds. This study provides new carrier proteins for fusion expression of disulfide bond-rich peptides in E. coli.

Accurate and precise determination of boron isotopic ratios at low concentration by positive thermal ionization mass spectrometry using static multicollection of Cs2BO2+ ions.

A static double-collector system for accurate, precise, and rapid boron isotope analysis has been established by employing a newly fixed Faraday H3 and H4 cup enabling simultaneously collected Cs2BO2(+) ion beams (m/z = 308 and 309) on a Finnigan-MAT Triton thermal ionization mass spectrometer of boron (Triton B). The experimental result indicated that Cs2BO2(+) ion beams (m/z = 308 and 309) were simultaneously collected using a fixed Faraday H3 and H4 cup without using the "Zoom Quad" function and reduced accelerating voltage. Furthermore, the method enabled the measurement of samples containing as little as 20 ng of boron. An analysis of the National Institute of Standards and Technology standard reference material (NIST SRM) 951 standard showed external reproducibility (2RSD) of ±0.013‰, ± 0.013‰, and ±0.019‰ for 100, 50, and 20 ng of boron, respectively. The present method of static multicollection of Cs2BO2(+) ions is applicable to a wide field of boron isotopic research that requires high precision and accuracy to analyze samples with low boron concentrations, including pore fluids, foraminifera, rivers, rainwater, and other natural samples.

Effective elimination of organic matter interference in boron isotopic analysis by thermal ionization mass spectrometry of coral/foraminifera: micro-sublimation technology combined with ion exchange.

In order to better estimate the effectiveness of micro-sublimation technology on the elimination of organic matter interference during boron isotopic analysis, a series of improved experiments was carried out using simple apparatus. Recovery rates after micro-sublimation were measured for boric acid solutions with different B contents or different B/organic matter ratios. The improved micro-sublimation procedure combined with ion-exchange technology was then used to test natural samples (coral and foraminifera) for the separation of boron. Our results show that the time taken for 100% recovery of different amounts of B differed and that the proportions of B/organic matter within the natural organic matter have little effect on the relationship between the recovery rates of B and the micro-sublimation times. The experiments further confirm that the organic matter does indeed have an effect on boron isotope analyses by positive thermal ionization mass spectrometry and that the use of micro-sublimation can effectively remove interferences from the organic matter during boron isotopic analysis.

[Up-conversion luminescent properties of SrAl2O4: Eu2+, Dy3+ phosphors].

Strong green up-conversion emission was observed for the first time in europium and dysprosium co-doped strontium aluminate (SrAl2O4: Eu2+, Dy3+) phosphor under 980 nm infrared excitation at room temperature. The up-conversion emission spectrum of phosphors was quite different from that of down-conversion emission spectrum excited by ultraviolet or visible lights. The two kinds of emission spectra implied that there are different mechanisms of emission. The X-ray diffraction (XRD) results revealed that the prepared phosphor has the same crystal lattice and composition as that reported previously.