In vitro and in silico docking and molecular dynamic of antimicrobial activities, alpha-glucosidase, and anti-inflammatory activity of compounds from the aerial parts of Mussaenda saigonensis.

Twelve compounds were isolated from Mussaenda saigonensis aerial parts through phytochemical analysis and the genus Mussaenda is the first place where the compounds 4-6 and 11-12 have been found. Based on the ability to inhibit NO production in RAW264.7 cells, compound 2 has demonstrated the strongest anti-inflammatory activity in vitro with an IC50 of 7.6 µM, as opposed to L-NMMA's IC50 of 41.3 µM. Compound 12 was found to be the most effective inhibitor of alpha-glucosidase enzyme in vitro, with an IC50 value of 42.4 µM (compared to 168 µM for acarbose). Compounds 1-12 were evaluated in vitro for antimicrobial activity using the paper dish method. Compound 11 demonstrated strong antifungal activity against M. gypseum with a MIC value of 50 µM. In silico docking for antimicrobial activity, pose 90 or compound 11 docked well to the 2VF5 enzyme, PDB, which explains why compound 11 had the highest activity in vitro. Entry 2/pose 280 demonstrated excellent anti-inflammatory activity in silico. The stability of the complex between pose 280 and the 4WCU enzyme for anti-inflammatory activity has been assessed using molecular dynamics over a simulation course ranging from 0 to 100 ns. It has been found to be stable from 60 and 100 ns. The Tyr 159 (95%, H-bond via water bridge), Asp 318 (200%, multiple contacts), Met 273 (75%, hydrophobic interaction via water bridge), and Gln 369 (75%, H-bond via water bridge) interacted well within the time range of 0 to 100 ns. It has more hydrophilic or polar pharmacokinetics.

Proanthocyanidins and Phenolic Compounds from the Twigs of Salix chaenomeloides and Their Anti-Lipogenic Effects on 3T3-L1 Preadipocytes.

The present study investigated potential bioactive natural products from the EtOH extract of Salix chaenomeloides twigs using column chromatography, leading to the isolation of six compounds (1-6), which were characterized as two proanthocyanidins, procyanidin B2 (1) and procyanidin B1 (2), and four phenolic compounds, 4-hydroxybenzoic acid ß-D-glucosyl ester (3), di-O-methylcrenatin (4), p-coumaric acid glucoside (5), and syringin (6) by the comparison of their NMR spectra with the reported data and high-resolution (HR)-electrospray ionization mass spectroscopy (ESI-MS) analysis. We investigated the potential of six compounds (1-6) to inhibit adipogenesis in 3T3-L1 preadipocytes, which showed that the compounds (1-6) significantly reduced lipid accumulation in 3T3-L1 adipocytes without affecting cell proliferation. Notably, compound 1 demonstrated a remarkable 60% and 90% reduction in lipid levels with 50 and 100 µM treatments, respectively. Oil Red O staining results indicated that compound 1 significantly inhibits the formation of lipid droplets, comparable to the effect of T863, an inhibitor of triglyceride used as a positive control, in adipocytes. Compound 1 had no effect on the regulators PPARγ, C/EBPα, and SREBF1 of adipocyte differentiation in 3T3-L1 preadipocytes, but compound 1 activated the fatty acid oxidation regulator, PPARα, compared to the lipogenic-induced control. It also suppressed fatty acid synthesis by downregulating the expression of fatty acid synthase (FAS). Finally, compound 1 induced the mRNA and protein levels of CPT1A, an initial marker of mitochondrial fatty acid oxidation in 3T3-L1. This finding substantiates the anti-lipogenic and lipolytic effects of procyanidin B2 (1) in 3T3-L1 preadipocytes, emphasizing its pivotal role in modulating obesity-related markers.

Adaptive response of Pseudomonas aeruginosa under serial ciprofloxacin exposure.

Understanding the evolution of antibiotic resistance is important for combating drug-resistant bacteria. In this work, we investigated the adaptive response of Pseudomonas aeruginosa to ciprofloxacin. Ciprofloxacin-susceptible P. aeruginosa ATCC 9027, CIP-E1 (P. aeruginosa ATCC 9027 exposed to ciprofloxacin for 14 days) and CIP-E2 (CIP-E1 cultured in antibiotic-free broth for 10 days) were compared. Phenotypic responses including cell morphology, antibiotic susceptibility, and production of pyoverdine, pyocyanin and rhamnolipid were assessed. Proteomic responses were evaluated using comparative iTRAQ labelling LC-MS/MS to identify differentially expressed proteins (DEPs). Expression of associated genes coding for notable DEPs and their related regulatory genes were checked using quantitative reverse transcriptase PCR. CIP-E1 displayed a heterogeneous morphology, featuring both filamentous cells and cells with reduced length and width. By contrast, although filaments were not present, CIP-E2 still exhibited size reduction. Considering the MIC values, ciprofloxacin-exposed strains developed resistance to fluoroquinolone antibiotics but maintained susceptibility to other antibiotic classes, except for carbapenems. Pyoverdine and pyocyanin production showed insignificant decreases, whereas there was a significant decrease in rhamnolipid production. A total of 1039 proteins were identified, of which approximately 25 % were DEPs. In general, there were more downregulated proteins than upregulated proteins. Noted changes included decreased OprD and PilP, and increased MexEF-OprN, MvaT and Vfr, as well as proteins of ribosome machinery and metabolism clusters. Gene expression analysis confirmed the proteomic data and indicated the downregulation of rpoB and rpoS. In summary, the response to CIP involved approximately a quarter of the proteome, primarily associated with ribosome machinery and metabolic processes. Potential targets for bacterial interference encompassed outer membrane proteins and global regulators, such as MvaT.

One-step synthesis of diaryloxadiazoles as potent inhibitors of BCRP.

Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.

Correction: Antimicrobial and alpha-glucosidase inhibitory flavonoid glycosides from the plant Mussaenda recurvata: in vitro and in silico approaches.

[This corrects the article DOI: 10.1039/D4RA00666F.].

Classification and application of metal-based nanoantioxidants in medicine and healthcare.

Antioxidants play an important role in the prevention of oxidative stress and have been widely used in medicine and healthcare. However, natural antioxidants have several limitations such as low stability, difficult long-term storage, and high cost of large-scale production. Along with significant advances in nanotechnology, nanomaterials have emerged as a promising solution to improve the limitations of natural antioxidants because of their high stability, easy storage, time effectiveness, and low cost. Among various types of nanomaterials exhibiting antioxidant activity, metal-based nanoantioxidants show excellent reactivity because of the presence of an unpaired electron in their atomic structure. In this review, we summarize some novel metal-based nanoantioxidants and classify them into two main categories, namely chain-breaking and preventive antioxidant nanomaterials. In addition, the applications of antioxidant nanomaterials in medicine and healthcare are also discussed. This review provides a deeper understanding of the mechanisms of metal-based nanoantioxidants and a guideline for using these nanomaterials in medicine and healthcare.

Comprehensive machine learning boosts structure-based virtual screening for PARP1 inhibitors.

Poly ADP-ribose polymerase 1 (PARP1) is an attractive therapeutic target for cancer treatment. Machine-learning scoring functions constitute a promising approach to discovering novel PARP1 inhibitors. Cutting-edge PARP1-specific machine-learning scoring functions were investigated using semi-synthetic training data from docking activity-labelled molecules: known PARP1 inhibitors, hard-to-discriminate decoys property-matched to them with generative graph neural networks and confirmed inactives. We further made test sets harder by including only molecules dissimilar to those in the training set. Comprehensive analysis of these datasets using five supervised learning algorithms, and protein-ligand fingerprints extracted from docking poses and ligand only features revealed one highly predictive scoring function. This is the PARP1-specific support vector machine-based regressor, when employing PLEC fingerprints, which achieved a high Normalized Enrichment Factor at the top 1% on the hardest test set (NEF1% = 0.588, median of 10 repetitions), and was more predictive than any other investigated scoring function, especially the classical scoring function employed as baseline.

Antimicrobial and alpha-glucosidase inhibitory flavonoid glycosides from the plant Mussaenda recurvata: in vitro and in silico approaches.

Seven flavonoid glycosides were isolated from the aerial portions of Mussaenda recurvata during a phytochemical analysis. This comprised one novel component, ecurvoside, and six well-studied compounds, namely astragalin, isoquercitrin, nicotiflorin, rutin, hesperidin, and neohesperidin. The chemical structures of compounds were identified using spectroscopic techniques and a comparison with previously published studies. Alpha-glucosidase inhibition testing was carried out on all isolated compounds. The compounds evaluated have IC50 values between 35.6 and 239.1 g mL-1, indicating a moderate degree of inhibition. In vitro antimicrobial activities of compounds 1-7 have screened against the bacteria Pseudomonas aeruginosa (P. aeruginosa), methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus faecalis (Strep. faecalis), and fungi: Candida albicans (C. albicans), Trichophyton mentagrophytes (T. mentagrophytes), and Microsporum gypseum (M. gypseum), where compound 6 showed excellent activity against fungi T. mentagrophytes with an MIC value of 12.5 µM. In accordance with the molecular docking study, ecurvoside (1) or pose 472 interacted well with the 3TOP enzyme: PDB and the molecular dynamic simulations proved that the complex of ecurvoside and 3TOP has a stable simulation time of 50-100 ns and the significant residual amino acids in 3TOP are relative to interactions more than one time such as Asp 960, Glu 961, Lys 1088, Glu 1095, Arg 1097, Gly 1102, Thr 1103, Gln 1109, Glu 1178: A chain and Glu 1095, Thr 1101, and Asp 1107: B chain. The docking studies of compounds 1-7 to the enzyme 2VF5 explain the general mechanism to inhibit bacteria and proved that compound 6 (pose 370) inhibited stronger than compound 7 (pose 362) and compound 5 (pose 280), and compounds 1 to 4 do not interact well with 2VF5.

Risk Factors for Severe Seafood Allergy Among Adults in an Urban City in Vietnam.

Purpose: Increasing seafood consumption is associated with more frequent reports of food allergy. Little is known about seafood allergy (SFA) among adults in Vietnam. We investigated the characteristics of individuals with SFA and the risk factors for severe SFA. Patients and methods: A cross-sectional, web-based survey was conducted among individuals aged ≥ 18 years from universities in Ho Chi Minh City (Vietnam) between December 2021 and July 2022. The survey was based on a structured, validated questionnaire related to FA. Strict definitions of "convincing allergy" were used. Multivariate analysis was used to estimate the risk factors for severe SFA after adjusting for covariates. Data were analyzed using JASP (v.0.16.3) and SPSS (v.22.0). Results: Totally, 1038 out of 2137 (48.57%) individuals completed the questionnaire, of whom 285 (27.46%) had reported SFA. Convincing SFA accounted for 20.13% (209/1038) of the cases, with convincing shellfish allergy being more common than fish allergy. Participants with comorbid shellfish and fish allergy had higher prevalence of atopic dermatitis, peanut/nut allergy, other food allergy, and cutaneous and upper airway symptoms compared to participants with shellfish allergy (p < 0.05). The spectrum of reactive seafood was diverse and characterized by local species. The age of symptom onset was most commonly during late childhood and adolescence, with most reactions persisting into adulthood. A history of anaphylaxis, comorbid peanut, and tree nut allergy, and ≥3 allergens were associated with severe SFA. Conclusion: Features of causative, coexisting seafood allergy, and risk factors for severe SFA were demonstrated, which can provide a reference for future studies.

A Web-Based Dynamic Nomogram to Predict the Risk of Methicillin-Resistant Staphylococcal Infection in Patients with Pneumonia.

The aim of this study was to create a dynamic web-based tool to predict the risks of methicillin-resistant Staphylococcus spp. (MRS) infection in patients with pneumonia. We conducted an observational study of patients with pneumonia at Cho Ray Hospital from March 2021 to March 2023. The Bayesian model averaging method and stepwise selection were applied to identify different sets of independent predictors. The final model was internally validated using the bootstrap method. We used receiver operator characteristic (ROC) curve, calibration, and decision curve analyses to assess the nomogram model's predictive performance. Based on the American Thoracic Society, British Thoracic Society recommendations, and our data, we developed a model with significant risk factors, including tracheostomies or endotracheal tubes, skin infections, pleural effusions, and pneumatoceles, and used 0.3 as the optimal cut-off point. ROC curve analysis indicated an area under the curve of 0.7 (0.63-0.77) in the dataset and 0.71 (0.64-0.78) in 1000 bootstrap samples, with sensitivities of 92.39% and 91.11%, respectively. Calibration analysis demonstrated good agreement between the observed and predicted probability curves. When the threshold is above 0.3, we recommend empiric antibiotic therapy for MRS. The web-based dynamic interface also makes our model easier to use.

Inequities in Conversion Practice Exposure at the Intersection of Ethnoracial and Gender Identities.

Objectives. To examine inequities in conversion practice exposure across intersections of ethnoracial groups and gender identity in the United States. Methods. Data were obtained from The Population Research in Identity and Disparities for Equality Study of sexual and gender minority people from 2019 to 2021 (n = 9274). We considered 3 outcomes: lifetime exposure, age of first exposure, and period between first and last exposure among those exposed to conversion practices. We used log-binomial, Cox proportional hazards, and negative binomial models to examine inequities by ethnoracial groups and gender identity adjusting for confounders. We considered additive interaction. Results. Conversion practice prevalence was highest among minoritized ethnoracial transgender and nonbinary participants (TNB; 8.6%). Compared with White cisgender participants, minoritized ethnoracial TNB participants had twice the prevalence (prevalence ratio = 2.16; 95% confidence interval [CI] = 1.62, 2.86) and risk (hazard ratio = 2.04; 95% CI = 1.51, 2.69) of conversion practice exposure. Furthermore, there was evidence of a positive additive interaction for age of first exposure. Conclusions. Minoritized ethnoracial TNB participants were most likely to recall experiencing conversion practices. Public Health Implications. Policies banning conversion practices may reduce the disproportionate burden experienced by minoritized ethnoracial TNB participants. (Am J Public Health. 2024;114(4):424-434. https://doi.org/10.2105/AJPH.2024.307580).

A metagenomic investigation of phytoplasma diversity in Australian vegetable growing regions.

In this study, metagenomic sequence data was used to investigate the phytoplasma taxonomic diversity in vegetable-growing regions across Australia. Metagenomic sequencing was performed on 195 phytoplasma-positive samples, originating either from historic collections (n=46) or during collection efforts between January 2015 and June 2022 (n=149). The sampled hosts were classified as crop (n=155), weed (n=24), ornamental (n=7), native plant (n=6), and insect (n=3) species. Most samples came from Queensland (n=78), followed by Western Australia (n=46), the Northern Territory (n=32), New South Wales (n=17), and Victoria (n=10). Of the 195 draft phytoplasma genomes, 178 met our genome criteria for comparison using an average nucleotide identity approach. Ten distinct phytoplasma species were identified and could be classified within the 16SrII, 16SrXII (PCR only), 16SrXXV, and 16SrXXXVIII phytoplasma groups, which have all previously been recorded in Australia. The most commonly detected phytoplasma taxa in this study were species and subspecies classified within the 16SrII group (n=153), followed by strains within the 16SrXXXVIII group ('Ca. Phytoplasma stylosanthis'; n=6). Several geographic- and host-range expansions were reported, as well as mixed phytoplasma infections of 16SrII taxa and 'Ca. Phytoplasma stylosanthis'. Additionally, six previously unrecorded 16SrII taxa were identified, including five putative subspecies of 'Ca. Phytoplasma australasiaticum' and a new putative 16SrII species. PCR and sequencing of the 16S rRNA gene was a suitable triage tool for preliminary phytoplasma detection. Metagenomic sequencing, however, allowed for higher-resolution identification of the phytoplasmas, including mixed infections, than was afforded by only direct Sanger sequencing of the 16S rRNA gene. Since the metagenomic approach theoretically obtains sequences of all organisms in a sample, this approach was useful to confirm the host family, genus, and/or species. In addition to improving our understanding of the phytoplasma species that affect crop production in Australia, the study also significantly expands the genomic sequence data available in public sequence repositories to contribute to phytoplasma molecular epidemiology studies, revision of taxonomy, and improved diagnostics.

Response surface methodology for aqueous two-phase system extraction: An unprecedented approach for the specific flavonoid-rich extraction of Houttuynia cordata Thunb. leaves towards acne treatment.

Background: Houttuynia cordata Thunb. has long been widely used as a daily vegetable and traditional medicine. The flavonoid component of H. cordata has plenty of pharmacological effects, such as antibacterial, anti-inflammatory, and antioxidant. In this study, we applied the aqueous two-phase system (ATPS) combined with ultrasonic extraction for extracting H. cordata leaves. Methods: We optimized the extraction process to improve the extraction efficiency of the two flavonoids, hyperin and quercitrin, by Surface Method Response - Central Composite Design (RSM-CCD). Next, we investigated the antibacterial ability of H. cordata ATPS extract from optimal conditions against two bacterial strains, Cutibacterium acnes and Staphylococcus epidermidis. Results: The results showed that using 10% (NH4)2SO4 and 35% ethanol for ATPS extraction resulted in the highest hyperin and quercitrin contents. From the RSM-CCD results, the optimal extraction conditions were determined to be ultrasonic extraction at 50 °C for 30 min, giving results consistent with the predicted model and obtaining hyperin and quercitrin contents at 1.5681 ± 0.0114 and 4.6225 ± 0.0327 mg/g, respectively.Furthermore, ATPS extract has excellent antibacterial activity with a minimum inhibitory concentration (MIC) value of 250 µg/mL on both C. acnes and S. epidermidis. This MIC is significantly lower than the H. cordata ultrasound-assisted (UA) extract, with MICs of 1500.00 and 156.25 µg/mL on C. acnes and S. epidermidis, respectively. In addition, the results from the disk diffusion assay also showed that ATPS extraction has superior internal antibacterial activity with a zone of inhibition diameter at 250 µg/mL of 8.67 ± 1.15 and 5.00 ± 2.00 mm. Meanwhile, those of UA extract on C. acnes is 5.67 ± 1.53 mm (at 1500 µg/mL), and on S. epidermidis is 1.34 ± 0.58 mm (at 156.25 µg/mL). Conclusion: To sum up, our research highlights the potential of H. cordata ATPS extracts as the starting material for topical preparations for effectively treating acne.

COVID-19 Vaccine Coverage and Factors Associated with Vaccine Hesitancy: A Cross-Sectional Survey in the City of Kinshasa, Democratic Republic of Congo.

Vaccination against COVID-19 has been the main strategy used by most countries to limit the spread of the virus. However, vaccine uptake has been low in Africa, leading to the implementation of several interventions in order to improve vaccine coverage. This study was conducted due to the lack of information about COVID-19 vaccine coverage and the factors associated with vaccine hesitancy. This cross-sectional study was carried out in Kinshasa city using multi-stage random sampling. A total of 2160 households were included in this study. The data were analyzed using Stata 17 software. The means and standard deviations were computed for continuous data that followed a normal distribution, whereas proportions together with their 95% confidence intervals (CIs) were computed for categorical variables. The connections between dependent variables and each independent variable were tested using either Pearson's chi-square test or Fisher's exact test. The logistic regression method was employed to determine the factors that are linked to hesitation in obtaining the COVID-19 immunization. The majority of respondents were aged between 25 and 34 and 35 and 49 (28.9%). During this study, 15% (95% CI [13.25-17.9]) of respondents had received at least one dose of the COVID-19 vaccine. The prevalence of vaccine hesitancy was 67% (CI95%:64.9-69.1). Among the reasons given for refusing to be vaccinated, most respondents cited concerns about the vaccine being unsafe or causing adverse reactions (45%). Among the reasons given for accepting the vaccine, 26% thought that the vaccine prevented superinfection. The factors associated with hesitancy toward the COVID-19 vaccine were female gender, an age of less than 35 years, and living in non-slum households. Despite the interventions implemented across the country, the reluctance to be vaccinated remains a problem; this could lead to poor health outcomes, especially among the elderly and those with pre-existing conditions. It is important to step up awareness-raising campaigns in the community in order to increase the uptake of vaccination.

Minimally Invasive Treatment of Chyle Leak After Thyroidectomy and Cervical Lymph Node Dissection in Patients with Thyroid Carcinoma: Results of a Study Involving 36 Patients.

Objective: Chyle leak (CL) after head and neck surgery is a rare but well-known complication. In patients with high-output leakage, the treatment can be complicated. This study aims to report on a recent innovation in lymphatic intervention for treating such patients. Materials and Methods: A retrospective review of 36 patients with chyle leak after neck surgery for thyroid cancer was conducted to assess the efficacy of percutaneous lymphatic embolization and thoracic duct (TD) disruption. Results: Antegrade catheterization of the thoracic duct was achieved in 31 of 36 patients (86.1%). Therefore, embolization of the thoracic duct and thoracic duct branches was performed in 26 and 5 patients, respectively. In 5 cases of unsuccessful antegrade catheterization into the thoracic duct, transcervical access embolization was performed in 2 patients, and TD disruption (TDD) was performed in 3 patients. The pooled overall technical success rate of lymphatic embolization was 33/36 patients (91.7%). One patient who underwent thoracic duct embolization (TDE) with technical success (1/33 patients) but clinical failure had additional treatment directly sclerosing the TD under computed tomography scan. Cervical fluid collection sclerotherapy was done in 7 patients as an additional treatment. Resolution of the chyle leak after procedures was observed in all patients (100%). The mean time to resolution was 3 days (1-7 days). There was no complication intra and after procedures. Conclusion: TDE, selective TD branches embolization and TDD are safe and effective minimally invasive treatments for CL post-surgery for thyroid carcinoma. Sclerosing cervical fluid collection contributes to clinical success.

Predictors of mortality among inpatients in COVID-19 treatment centers in the city of Butembo, North Kivu, Democratic Republic of Congo.

Determining the risk factors for severe disease and death among hospitalized Covid-19 patients is critical to optimize health outcomes and health services efficiency, especially in resource-constrained and humanitarian settings. This study aimed to identify the predictors of mortality of Covid-19 patients in North Kivu province in the Democratic Republic of Congo.A retrospective cohort study was conducted in 6 Covid-19 treatment centers in the city of Butembo from 1 January to 31 December 2021. The time to event (death), the outcome variable, was visualized by Kaplan-Meier curves and the log-rank test was used to confirm differences in trends. Cox regression was used for all the predictors in the bivariate analysis and multivariate analysis was done using predictors found statistically significant in the bivariate analysis. The following variables were considered for inclusion to the Cox regression model: Age, Sex, Disease length, Treatment site, History of at least one co-morbidity, Body mass index, Stage according to SpO2 and the NEWS-modified score.Among the 303 participants (mean age of 53 years), the fatality rate was 33.8 deaths per 1000 patient-days. Four predictors were independently associated with inpatient death: age category (≥ 60 years) (adjusted HR: 9.90; 95% CI: 2.68-36.27), presence of at least one comorbidity (adjusted HR: 11.39; 95% CI: 3.19-40.71); duration of illness of > 5 days before hospitalization (adjusted HR:1.70, 95% CI: 1.04-2.79) and peripheral capillary oxygen saturation (SpO2) < 90% (adjusted HR = 14.02, 95% CI: 2.23-88.32). In addition to advanced age, comorbidity, and length of disease before hospitalization, ambient air SpO2 measured by healthcare providers using low-tech, affordable and relatively accessible pulse oximetry could inform the care pathways of Covid-19 inpatients in resource-challenged health systems in humanitarian settings.

Investigating the effects of ultrafine bubbles on bacterial growth.

Several previous studies have considered ultrafine bubbles as a potential research target because their properties can be applied in many different research areas. In particular, the interaction between UFBs and microorganisms has always been one of the aspects that receives much attention due to the high difficulty in controlling a living system. The properties of UFBs, as mobile air-water interfaces, are greatly determined by their gas cores which play a critical role in regulating microbial growth. This study aims to investigate the effects of ultrafine bubbles on bacterial growth. Two well-studied organisms were chosen as models - Escherichia coli and Staphylococcus aureus. Their growing behavior was examined based on the growth rate, phenotype and biomass. Three types of Luria-Bertani cultures were tested, including a standard culture containing distilled water, an air ultrafine bubble culture, and a hydrogen ultrafine bubble culture. The UFBs were generated via ultrasonic cavitation and stabilized by 50 µM SDS, which was proven to have negligible effects on bacterial growth. By comparing among the three cultivation conditions, the bacterial growth rates were observed to be the highest in exposure to HUFBs. The results also signified that UFBs had an enhancement on cell proliferation. On the other hand, while proposing an increase in cell density, bacteria cultured in HUFB media have their sizes decreased uniformly and significantly (p-value < 0.05). This study confirmed that bacterial growth was promoted by UFBs; and better effects recorded were due to the HUFB present in the culture media. However, the average morphological size of bacteria was in negative correlation with their population size.

Inactive-enriched machine-learning models exploiting patent data improve structure-based virtual screening for PDL1 dimerizers.

INTRODUCTION: Small-molecule Programmable Cell Death Protein 1/Programmable Death-Ligand 1 (PD1/PDL1) inhibition via PDL1 dimerization has the potential to lead to inexpensive drugs with better cancer patient outcomes and milder side effects. However, this therapeutic approach has proven challenging, with only one PDL1 dimerizer reaching early clinical trials so far. There is hence a need for fast and accurate methods to develop alternative PDL1 dimerizers. OBJECTIVES: We aim to show that structure-based virtual screening (SBVS) based on PDL1-specific machine-learning (ML) scoring functions (SFs) is a powerful drug design tool for detecting PD1/PDL1 inhibitors via PDL1 dimerization. METHODS: By incorporating the latest MLSF advances, we generated and evaluated PDL1-specific MLSFs (classifiers and inactive-enriched regressors) on two demanding test sets. RESULTS: 60 PDL1-specific MLSFs (30 classifiers and 30 regressors) were generated. Our large-scale analysis provides highly predictive PDL1-specific MLSFs that benefitted from training with large volumes of docked inactives and enabling inactive-enriched regression. CONCLUSION: PDL1-specific MLSFs strongly outperformed generic SFs of various types on this target and are released here without restrictions.

Oxygen-evolving photosystem II structures during S1-S2-S3 transitions.

Photosystem II (PSII) catalyses the oxidation of water through a four-step cycle of Si states (i = 0-4) at the Mn4CaO5 cluster1-3, during which an extra oxygen (O6) is incorporated at the S3 state to form a possible dioxygen4-7. Structural changes of the metal cluster and its environment during the S-state transitions have been studied on the microsecond timescale. Here we use pump-probe serial femtosecond crystallography to reveal the structural dynamics of PSII from nanoseconds to milliseconds after illumination with one flash (1F) or two flashes (2F). YZ, a tyrosine residue that connects the reaction centre P680 and the Mn4CaO5 cluster, showed structural changes on a nanosecond timescale, as did its surrounding amino acid residues and water molecules, reflecting the fast transfer of electrons and protons after flash illumination. Notably, one water molecule emerged in the vicinity of Glu189 of the D1 subunit of PSII (D1-E189), and was bound to the Ca2+ ion on a sub-microsecond timescale after 2F illumination. This water molecule disappeared later with the concomitant increase of O6, suggesting that it is the origin of O6. We also observed concerted movements of water molecules in the O1, O4 and Cl-1 channels and their surrounding amino acid residues to complete the sequence of electron transfer, proton release and substrate water delivery. These results provide crucial insights into the structural dynamics of PSII during S-state transitions as well as O-O bond formation.