Strengthened ozone adsorption through positive electric field-induced charge migration on various TiO2 crystal surfaces: A mechanistic and theoretical study.

This study investigates the enhancement of ozone adsorption on diverse TiO2 crystal interfaces through an innovative electrochemical modulation approach. The research focuses on the effects of applied electric field strength and reaction sites on ozone interfacial adsorption energies for Ti/Anatase TiO2 (0 0 1) and Ti/Rutile TiO2 (1 1 0) interfaces. The findings reveal that positive electric fields significantly enhance ozone adsorption on both interfaces, with adsorption energies increasing by up to 18% for Ti/Anatase TiO2 (0 0 1) and 15% for Ti/Rutile TiO2 (1 1 0). Notably, double water molecule sites (≡(H2O)2) play a crucial role in this enhancement process. The study demonstrates that the applied electric field alters the charge distribution at the TiO2 catalytic interface, thereby increasing interfacial charge density and promoting charge migration to ozone. Furthermore, this process leads to enhanced overlap and hybridization between ≡(H2O)2 sites and the s and p orbitals of ozone molecules, resulting in the formation of chemical bonds with lower Fermi levels. These comprehensive results demonstrate the broad applicability of the electrochemical interfacial ozone adsorption enhancement method across different crystal types and surfaces. Consequently, this study provides essential data to support the advancement of greener and more energy-efficient heterogeneous catalytic ozonation processes, potentially contributing to significant improvements in ozone-based water treatment technologies.

Zinc: a potential star for regulating peritoneal fibrosis.

Peritoneal dialysis (PD) is a commonly used renal replacement therapy for patients with end-stage renal disease (ESRD). During PD, the peritoneum (PM), a semi-permeable membrane, is exposed to nonbiocompatible PD solutions. Peritonitis can occur, leading to structural and functional PM disorders, resulting in peritoneal fibrosis and ultrafiltration failure, which are important reasons for patients with ESRD to discontinue PD. Increasing evidence suggests that oxidative stress (OS) plays a key role in the pathogenesis of peritoneal fibrosis. Furthermore, zinc deficiency is often present to a certain extent in patients undergoing PD. As an essential trace element, zinc is also an antioxidant, potentially playing an anti-OS role and slowing down peritoneal fibrosis progression. This study summarises and analyses recent research conducted by domestic and foreign scholars on the possible mechanisms through which zinc prevents peritoneal fibrosis.

Penidaleodiolides A and B, Cage-Like Polyketides with Neurotransmission-Regulating Activity from the Soil Fungus Penicillium daleae L3SO.

Penicillium daleae L3SO is a fungus isolated from the rhizospheric soil of the chloroplast-deficient plant Monotropa uniflora. A chemical study on the rice fermentation of this fungus led to the isolation and identification of two cage-like polyketides, penidaleodiolide A (1) and its biosynthetic-related congener penidaleodiolide B (2). The structures of 1 and 2 were determined by a combination of extensive spectroscopic analysis, biosynthetic consideration, chemical derivatization, and computational methods. Compound 1 harbors an unusual tricyclo[4.3.04,9]nonane scaffold, unprecedented in polyketide natural products. The hypothetical biosynthetic pathways for 1 and 2 were postulated and were supported by CRISPR/Cas9 genome editing results. Penidaleodiolide A (1) showed a significant inhibitory effect on the action potentials of murine hippocampal basket neurons and decreased the frequency of spontaneous excitatory postsynaptic currents in a concentration-dependent manner (the inhibition ratios were 0.30 ± 0.02 for 1 µM, 0.37 ± 0.03 for 10 µM, and 0.50 ± 0.07 for 20 µM) while being devoid of cytotoxicity against the nerve cells.

Proteogenomics offers a novel avenue in neoantigen identification for cancer immunotherapy.

Cancer neoantigens are tumor-specific non-synonymous mutant peptides that activate the immune system to produce an anti-tumor response. Personalized cancer vaccines based on neoantigens are currently one of the most promising therapeutic approaches for cancer treatment. By utilizing the unique mutations within each patient's tumor, these vaccines aim to elicit a strong and specific immune response against cancer cells. However, the identification of neoantigens remains challenging due to the low accuracy of current prediction tools and the high false-positive rate of candidate neoantigens. Since the concept of "proteogenomics" emerged in 2004, it has evolved rapidly with the increased sequencing depth of next-generation sequencing technologies and the maturation of mass spectrometry-based proteomics technologies to become a more comprehensive approach to neoantigen identification, allowing the discovery of high-confidence candidate neoantigens. In this review, we summarize the reason why cancer neoantigens have become attractive targets for immunotherapy, the mechanism of cancer vaccines and the advances in cancer immunotherapy. Considerations relevant to the application emerging of proteogenomics technologies for neoantigen identification and challenges in this field are described.

Orexin neurons mediate temptation-resistant voluntary exercise.

Despite the well-known health benefits of physical activity, many people underexercise; what drives the prioritization of exercise over alternative options is unclear. We developed a task that enabled us to study how mice freely and rapidly alternate between wheel running and other voluntary activities, such as eating palatable food. When multiple alternatives were available, mice chose to spend a substantial amount of time wheel running without any extrinsic reward and maintained this behavior even when palatable food was added as an option. Causal manipulations and correlative analyses of appetitive and consummatory processes revealed this preference for wheel running to be instantiated by hypothalamic hypocretin/orexin neurons (HONs). The effect of HON manipulations on wheel running and eating was strongly context-dependent, being the largest in the scenario where both options were available. Overall, these data suggest that HON activity enables an eat-run arbitration that results in choosing exercise over food.

GhEXL3 participates in brassinosteroids regulation of fiber elongation in Gossypium hirsutum.

Cotton fiber (Gossypium hirsutum) serves as an ideal model for investigating the molecular mechanisms of plant cell elongation at the single-cell level. Brassinosteroids (BRs) play a crucial role in regulating plant growth and development. However, the mechanism by which BR influences cotton fiber elongation remains incompletely understood. In this study, we identified EXORDIUM-like (GhEXL3) through transcriptome analysis of fibers from BR-deficient cotton mutant pagoda 1 (pag1) and BRI1-EMS-SUPPRESSOR 1 (GhBES1.4, encoding a central transcription factor of BR signaling) overexpression cotton lines. Knockout of GhEXL3 using CRISPR/Cas9 was found to impede cotton fiber elongation, while its overexpression promoted fiber elongation, suggesting a positive regulatory function for GhEXL3 in fiber elongation. Furthermore, in vitro ovule culture experiments revealed that the overexpression of GhEXL3 partially counteracted the inhibitory effects of brassinazole (BRZ) on cotton fiber elongation, providing additional evidence of GhEXL3 involvement in BR signaling pathways. Moreover, our findings demonstrate that GhBES1.4 directly binds to the E-box (CACGTG) motif in the GhEXL3 promoter region and enhances its transcription. RNA-seq analysis revealed that overexpression of GhEXL3 upregulated the expression of EXPs, XTHs, and other genes associated with fiber cell elongation. Overall, our study contributes to understanding the mechanism by which BR regulates the elongation of cotton fibers through the direct modulation of GhEXL3 expression by GhBES1.4.

Using Respondent-Driven Sampling (RDS) to Recruit Women With Criminal Legal System-Involvement (CLSI) During the COVID-19 Pandemic.

Recruiting women participants with criminal legal system involvement (CLSI) has always presented challenges, whether gaining access to them in prisons and jails or locating them after release. This research brief describes how the COVID-19 pandemic required us to change our recruitment strategies from previously successful approaches to a hybrid strategy using techniques from respondent-driven sampling (RDS) to recruit CLSI women. The RDS techniques, with internet social media, enabled us to capitalize on the community-based social networks of CLSI women to recruit 255 into our clinical trial of a health education intervention. This new avenue for recruitment can be useful beyond pandemic conditions.

Multiple Mechanisms of Haematococcus pluvialis-Derived Carotenoids to Inhibit Glycidyl Ester Formation in Rice Oil and a Chemical Model at High Temperatures.

The common presence of glycidyl esters (GEs) in refined vegetable oils has been a concern for food safety. The present study aimed to investigate the inhibitory effects of three carotenoids derived from Haematococcus pluvialis microalga on GE formation in both rice oil and a chemical model during heating. The addition of astaxanthin (AS), lutein (LU), and ß-carotene (CA) at 0.6 mg/g in rice oil can reduce GE formation by 65.0%, 57.1%, and 57.5%, respectively, which are significantly higher than those achieved by common antioxidants such as l-ascorbyl palmitate (39.0%), α-tocopherol (18.5%), tert-butyl hydroquinone (42.7%), and quercetin (26.2%). UPLC-Q-TOF-MS/MS analysis showed that two new compounds, that is, propylene glycol monoester and diester of palmitic acid, were formed in the CA-added chemical model, which provided direct experimental evidence for the inhibition of antioxidants including AS, LU, and CA against GE formation not only by indirect antioxidative action but also by direct radical reactions to competitively prevent the formation of cyclic acyloxonium intermediates. Furthermore, it was interestingly found that only AS could react with the GEs. The adduct of AS with GEs, astaxanthin-3-O-propanetriol esters, was preliminarily identified using Q-TOF-MS/MS in the heated AS-GE model, suggesting that reacting with GEs might represent another distinct mechanism of AS to eliminate GEs.

Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents.

A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.

Patient regional index: a new way to rank clinical specialties based on outpatient clinics big data.

BACKGROUND: Many existing healthcare ranking systems are notably intricate. The standards for peer review and evaluation often differ across specialties, leading to contradictory results among various ranking systems. There is a significant need for a comprehensible and consistent mode of specialty assessment. METHODS: This quantitative study aimed to assess the influence of clinical specialties on the regional distribution of patient origins based on 10,097,795 outpatient records of a large comprehensive hospital in South China. We proposed the patient regional index (PRI), a novel metric to quantify the regional influence of hospital specialties, using the principle of representative points of a statistical distribution. Additionally, a two-dimensional measure was constructed to gauge the significance of hospital specialties by integrating the PRI and outpatient volume. RESULTS: We calculated the PRI for each of the 16 specialties of interest over eight consecutive years. The longitudinal changes in the PRI accurately captured the impact of the 2017 Chinese healthcare reforms and the 2020 COVID-19 pandemic on hospital specialties. At last, the two-dimensional assessment model we devised effectively illustrates the distinct characteristics across hospital specialties. CONCLUSION: We propose a novel, straightforward, and interpretable index for quantifying the influence of hospital specialties. This index, built on outpatient data, requires only the patients' origin, thereby facilitating its widespread adoption and comparison across specialties of varying backgrounds. This data-driven method offers a patient-centric view of specialty influence, diverging from the traditional reliance on expert opinions. As such, it serves as a valuable augmentation to existing ranking systems.

Hydrophobic Microenvironment Modulation of Ru Nanoparticles in Metal-Organic Frameworks for Enhanced Electrocatalytic N2 Reduction.

The modulation of the chemical microenvironment surrounding metal nanoparticles (NPs) is an effective means to enhance the selectivity and activity of catalytic reactions. Herein, a post-synthetic modification strategy is developed to modulate the hydrophobic microenvironment of Ru nanoparticles encapsulated in a metal-organic framework (MOF), MIP-206, namely Ru@MIP-Fx (where x represents perfluoroalkyl chain lengths of 3, 5, 7, 11, and 15), in order to systematically explore the effect of the hydrophobic microenvironment on the electrocatalytic activity. The increase of perfluoroalkyl chain length can gradually enhance the hydrophobicity of the catalyst, which effectively suppresses the competitive hydrogen evolution reaction (HER). Moreover, the electrocatalytic production rate of ammonia and the corresponding Faraday efficiency display a volcano-like pattern with increasing hydrophobicity, with Ru@MIP-F7 showing the highest activity. Theoretical calculations and experiments jointly show that modification of perfluoroalkyl chains of different lengths on MIP-206 modulates the electronic state of Ru nanoparticles and reduces the rate-determining step for the formation of the key intermediate of N2H2 *, leading to superior electrocatalytic performance.

Rank-In Integrated Machine Learning and Bioinformatic Analysis Identified the Key Genes in HFPO-DA (GenX) Exposure to Human, Mouse, and Rat Organisms.

Hexafluoropropylene Oxide Dimer Acid (HFPO-DA or GenX) is a pervasive perfluorinated compound with scant understood toxic effects. Toxicological studies on GenX have been conducted using animal models. To research deeper into the potential toxicity of GenX in humans and animals, we undertook a comprehensive analysis of transcriptome datasets across different species. A rank-in approach was utilized to merge different transcriptome datasets, and machine learning algorithms were employed to identify key genetic mechanisms common among various species and humans. We identified seven genes-TTR, ATP6V1B1, EPHX1, ITIH3, ATXN10, UBXN1, and HPX-as potential variables for classification of GenX-exposed samples, and the seven genes were verified in separate datasets of human, mouse, and rat samples. Bioinformatic analysis of the gene dataset further revealed that mitochondrial function and metabolic processes may be modulated by GenX through these key genes. Our findings provide insights into the underlying genetic mechanisms and toxicological impacts of GenX exposure across different species and offer valuable references for future studies using animal models to examine human exposure to GenX.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P < 0.0005). Further, we verified its biological activity using the human hepatoma cells G2 model, where the B11-H2-Fc exhibited almost 100% efficiency in PCSK9 inhibition at only 0.75 µM. The immunoblotting results of low-density lipoprotein cholesterol (LDL-c) uptake assay also demonstrated the excellent performance of B11-H2-Fc on recovering the LDL-c receptor (LDLR), as strong as the Repatha (P > 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.

COVID-19 and influenza vaccine uptake in women with criminal-legal system involvement.

OBJECTIVE: Given their vulnerable health status and resource constraints, the perspectives of women with criminal-legal involvement (WCLI) are important but not usually represented in the literature on vaccine interest and vaccine hesitancy. This study aims to examine how the COVID-19 pandemic and vaccine affected the influenza vaccine uptake among WCLI. METHODS: A cross-sectional secondary analysis was conducted using data collected from the Tri-City study, which followed WCLI in three U.S. cities from 2019 to 2023. We mapped the distribution of influenza vaccine uptake in 2019-2023 and developed a composite outcome that reflected participants' patterns of Y/N to influenza vaccine, which were categorized into four groups: Influenza Vaccine Supportive, Influenza Vaccine Adaptive, Influenza Vaccine Discontinued, and Influenza Vaccine Resistant. RESULTS: Out of 507 people: 23.7% were Supportive, 8.5% Adaptive, 15.2% Discontinued and 38.3% Resistant. People who received the COVID vaccine had significantly lower odds of being identified as Discontinued (OR = 0.42, 95%CI = 0.20-0.87, p = .020) and Resistant (OR = 0.23, 95%CI = 0.13-0.43, p < .001), compared to the Supportive group. Mistrust toward COVID-19-related information was a significant independent predictor of being Adaptive (OR = 1.59, 95%CI = 1.08-2.35, p = .019), Discontinued (OR = 1.61, 95%CI = 1.15-2.25, p = .006), and Resistant (OR = 1.54, 95%CI = 1.19-2.00, p < .001) relative to Supportive. CONCLUSIONS: Vaccine hesitancy poses significant challenges to public health efforts, with apparent dampening effect across vaccines. Public health messaging and clinical interactions informed by best practices in communication tailored to the lived experience of all people, including women with criminal-legal system involvement, will be necessary to inform future interventions aimed at increasing vaccine uptake.

Succinylation of 14-3-3 theta by CPT1A promotes survival and paclitaxel resistance in nasal type extranodal natural killer/T-cell lymphoma.

BACKGROUND: The aggressive and refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT) is a subtype of non-Hodgkin's lymphoma. Succinylation promotes progression in a variety of tumors, but its mechanism in ENKTL-NT is unclear. METHODS: Bioinformatic analysis was performed to screen differentially expressed genes in the ENKTL dataset. Cell transfection techniques were used for knockdown and overexpression of genes. The mRNA and protein expression were detected using RT-qPCR and western blot, respectively. Immunohistochemical staining was used to assess protein expression in situ. For the detection of cell proliferation activity, CCK-8, clonal formation, and EDU staining assays were used. Flow cytometry was employed to detect apoptosis. Co-immunoprecipitation was utilized for the identification of protein interactions and succinylation modifications. RESULTS: Succinyltransferase CPT1A was highly elevated in ENKTL-NT and was associated with a dismal prognosis. CPT1A knockdown suppressed SNK-6 cells' proliferation and induced apoptosis, while these effects were reversed by the overexpression of 14-3-3theta. Co-immunoprecipitation results showed that CPT1A caused succinylation of 14-3-3theta at site of K85, thereby enhancing the protein stability. Suppression of CPT1A-induced succinylation of 14-3-3theta by ST1326 resulted in the inhibition of SNK-6 cell proliferation and increased apoptosis. Paclitaxel combined with knockdown of CPT1A significantly inhibited the proliferation of ENKTL-NT compared to paclitaxel alone. CONCLUSION: CPT1A induces succinylation of 14-3-3theta at the K85 site, promoting ENKTL-NT proliferation. The anti-ENKTL activity of paclitaxel was improved when combined with CPT1A knockdown.

Bariatric surgery partially reverses subclinical proarrhythmic structural, electrophysiological, and autonomic changes in obesity.

BACKGROUND: Obesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown. OBJECTIVE: The purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi). METHODS: Sixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 (81%) female participants; BMI 46.7 ± 5.5 kg/m2) had ECGi pre-bariatric surgery, of whom 12 (75%) had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m2). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m2) acted as controls and had ECGi only once. RESULTS: Obesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization time gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm3 vs 64.5 cm3; P = .0010) and left ventricular mass (33 g/m2.7 vs 25 g/m2.7; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgical obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts. CONCLUSION: Obesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies.