Tailoring Drug Release Kinetics by the Design and Optimization of Substituents in Azobenzene Molecules in the Photosensitive Liposomal System.

A light-sensitive moiety, e.g., azobenzene, for the light-sensitive liposomal drug carrier has shown advantages as an advanced drug delivery system in site-specific smart therapy due to its reversible photoisomerization characteristics. In this work, a series of 4-position-cholesterol-functionalized azobenzene derivatives with 4'-position substituted pyridine, quinoline, isoquinoline, triethylamine, or ethylenediamine were synthesized, and the relationship between the molecular structure and drug release behaviors was clarified. We found that the charge and electrophilicity of substituents were two important factors (expressed as the characteristic time) that can precisely regulate the isomerization ratio in the liposomal system. There was an approximately linear correlation between the characteristic time of photoisomerization and the fitted first-order constant of photoinduced drug release rate. The photoinduced drug release could be achieved at the desired time and in an appropriate amount by tailoring the substituents at the 4'-position of azobenzene-cholesterol derivatives.

Using machine learning to classify the immunosuppressive activity of per- and polyfluoroalkyl substances.

Per- and polyfluoroalkyl substances (PFASs), one of the persistent organic pollutants, have immunosuppressive effects. The evaluation of this effect has been the focus of regulatory toxicology. In this investigation, 146 PFASs (immunosuppressive or nonimmunosuppressive) and corresponding concentration gradients were collected from literature, and their structures were characterized by using Dragon descriptors. Feature importance analysis and stepwise feature elimination are used for feature selection. Three machine learning (ML) methods, namely Random Forest (RF), Extreme Gradient Boosting Machine (XGB), and Categorical Boosting Machine (CB), were utilized for model development. The model interpretability was explored by feature importance analysis and correlation analysis. The findings indicated that the three models developed have exhibited excellent performance. Among them, the best-performing RF model has an average AUC score of 0.9720 for the testing set. The results of the feature importance analysis demonstrated that concentration, SpPosA_X, IVDE, R2s, and SIC2 were the crucial molecular features. Applicability domain analysis was also performed to determine reliable prediction boundaries for the model. In conclusion, this study is the first application of ML models to investigate the immunosuppressive activity of PFASs. The variables used in the models can help understand the mechanism of the immunosuppressive activity of PFASs, allow researchers to more effectively assess the immunosuppressive potential of a large number of PFASs, and thus better guide environmental and health risk assessment efforts.

Fully human single-domain antibody targeting a highly conserved cryptic epitope on the Nipah virus G protein.

Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development.

Pemphigoid diseases in patients with end-stage kidney diseases: pathogenesis and treatment.

Background: Pemphigoid diseases constitute a group of autoimmune blistering disorders characterized by subepithelial blistering. The association between pemphigoid diseases and both end-stage kidney disease (ESKD) and its treatment is notable. However, there is limited evidence about the management of pemphigoid diseases in patients with ESKD. This systematic review compiled case reports and relevant studies, summarized the underlying mechanisms of pemphigoid diseases in patients with ESKD, and summarized the efficacy of various therapies. Methods: A systematic search of PubMed and Embase was performed for articles published between 1982 to June 2, 2024. Results: Fifty-three case reports and eight relevant studies were included. Triggers for pemphigoids in patients with ESKD included materials used to treat ESKD, immune dysregulation of patients with ESKD, and rejection of renal allograft. Treatment for these patients included removing triggers, as well as administering of corticosteroids, mycophenolate mofetil (MMF), tetracyclines, rituximab, methotrexate, dapsone, azathioprine, cyclosporine, intravenous immunoglobin (IVIG), plasmapheresis, and Janus kinase inhibitors. Conclusion: Removing triggers is the most effective strategy. Despite their suboptimal efficacy, corticosteroids remain the most commonly used agents in this patient population. MMF, tetracyclines, and rituximab are less used but with benefits. There are significant adverse effects associated with methotrexate treatment. Other treatment may also be beneficial and require further investigation. These findings may enable clinicians to optimize the therapeutic approach for these patients.

Customized Music Therapy Combined With the Counseling and Follow-Up System: Stratified Results for Tinnitus Efficacy.

Objective: Chronic subjective tinnitus is a worldwide intractable problem. In our previous studies, customized music therapy combined with a follow-up system can reduce tinnitus perception and improve anxiety/depression. This study aims to explore which characteristics of tinnitus patients are more likely to benefit from our therapy. Study Design: This study included 1031 patients with chronic subjective tinnitus, all of whom completed customized music therapy with the follow-up system. Population demographics, tinnitus characteristics, and tinnitus-related scales at pretherapy and posttherapy were collected. Setting: Huadong Hospital affiliated Fudan University, Department of Otorhinolaryngology-Head & Neck Surgery from 2018 to 2022. Methods: A paired t test and the one-way analysis of variance were utilized to the overall efficacy and stratified difference based on tinnitus duration/age/tinnitus frequency. Results: There were significant statistical differences in the Tinnitus Handicap Inventory (THI), Tinnitus Loudness Visual Analog Scale (VAS), and Hospital Anxiety and Depression Scale (HADS)-A/D scores between pretherapy and 3 months posttherapy. THI and HADS (A/D) scores decreased the most in the 1-year duration tinnitus group. The most significant decrease in THI and VAS scores was observed in the 31- to 50-year-old tinnitus group. Patients with high-frequency tinnitus and extended high-frequency tinnitus had greater decreases generally than those with low-frequency tinnitus though no significance. Conclusion: Group with severe and prolonged tinnitus, shorter duration of tinnitus onset, and 31 to 50 years old benefit more from our therapy. Therefore, standardized personalized music and consulting and follow-up systems while promoting early treatment can reduce tinnitus and its comorbidities.

Methane-Driven Perchlorate Reduction by a Microbial Consortium.

The phenomenon of methane oxidation linked to perchlorate reduction has been reported in multiple studies; yet, the underlying microbial mechanisms remain unclear. Here, we enriched suspended cultures by performing methane-driven perchlorate reduction under oxygen-limiting conditions in a membrane bioreactor (MBR). Batch test results proved that perchlorate reduction was coupled to methane oxidation, in which acetate was predicted as the potential intermediate and oxygen played an essential role in activating methane. By combining DNA-based stable isotope probing incubation and high-throughput sequencing analyses of 16S rRNA gene and functional genes (pmoA, pcrA, and narG), we found that synergistic interactions between aerobic methanotrophs (Methylococcus and Methylocystis) and perchlorate-reducing bacteria (PRB; Denitratisoma and Dechloromonas) played active roles in mediating methane-driven perchlorate reduction. This partnership was further demonstrated by coculture experiments in which the aerobic methanotroph could produce acetate to support PRB to complete perchlorate reduction. Our findings advance the understanding of the methane-driven perchlorate reduction process and have implications for similar microbial consortia linking methane and chlorine biogeochemical cycles in natural environments.

3-ketoacyl-CoA synthase 19 contributes to the biosynthesis of seed lipids and cuticular wax in Arabidopsis and abiotic stress tolerance.

Very-long-chain fatty acids (VLCFAs) are essential precursors for plant membrane lipids, cuticular waxes, suberin, and storage oils. Integral to the fatty acid elongase (FAE) complex, 3-ketoacyl-CoA synthases (KCSs) function as crucial enzymes in the VLCFA pathway, determining the chain length of VLCFA. This study explores the in-planta role of the KCS19 gene. KCS19 is predominantly expressed in leaves and stem epidermis, sepals, styles, early silique walls, beaks, pedicels, and mature embryos. Localized in the endoplasmic reticulum, KCS19 interacts with other FAE proteins. kcs19 knockout mutants displayed reduced total wax and wax crystals, particularly alkanes, while KCS19 overexpression increased these components and wax crystals. Moreover, the cuticle permeability was higher for the kcs19 mutants compared to the wild type, rendering them more susceptible to drought and salt stress, whereas KCS19 overexpression enhanced drought and salt tolerance. Disrupting KCS19 increased C18 species and decreased C20 and longer species in seed fatty acids, indicating its role in elongating C18 to C20 VLCFAs, potentially up to C24 for seed storage lipids. Collectively, KCS19-mediated VLCFA synthesis is required for cuticular wax biosynthesis and seed storage lipids, impacting plant responses to abiotic stress.

Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma.

Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.

Analysis of the effects of eating and emotions on reproductive axis function in patients with functional hypothalamic amenorrhea.

Objective: To investigate the effects of eating and emotions on reproductive axis function in patients with functional hypothalamic amenorrhea (FHA).Methods: A retrospective cohort study was conducted to summarize the clinical and endocrine characteristics of 58 patients with FHA at initial diagnosis and to follow up the recovery of ovulation and spontaneous menstruation in the patients to investigate these biochemical indicators and their effects on recovery outcomes.Results: Among patients with FHA, 13.8% (8/58) and 15.5% (9/58) had above moderately severe depressive and severe anxiety symptoms respectively, and 25.9% (15/58) were at high risk for eating disorders. 34.5% (20/58) were included assessed as having recovered. The non-recovered group had higher scores on the Patient Health Questionnaire (PHQ-9) (p = .022) and higher scores on the Eating Attitude Test-26 (EAT-26) (p = .03) as well as bulimia and food preoccupation (p = .041). Follicle diameter >5 mm at initial diagnosis was an independent factor influencing recovery of reproductive axis function (odds ratio = 7.532; 95% confidence interval, 1.321-42.930; p = .023).Conculsions: Mood disorders and a certain risk of eating disorders were present in FHA.These, together with weight loss, endocrine and follicle size, could influence the outcome.

Research Progress on the Treatment of Geriatric Intertrochanteric Femur Fractures with Proximal Femur Bionic Nails (PFBNs).

Intertrochanteric femur fracture is the most common hip fracture in elderly people, and the academic community has reached a consensus that early surgery is imperative. Proximal femoral nail anti-rotation (PFNA) and InterTan are the preferred internal fixation devices for intertrochanteric femur fractures in elderly individuals due to their advantages, such as a short lever arm, minimal stress shielding, and resistance to rotation. However, PFNA is associated with complications such as nail back-out and helical blade cut-out due to stress concentration. As a new internal fixation device for intertrochanteric femur fractures, the proximal femoral biodegradable nail (PFBN) addresses the issue of nail back-out and offers more stable fracture fixation, a shorter lever arm, and stress distribution compared to PFNA and InterTan. Clinical studies have shown that compared to PFNA, PFBNs lead to faster recovery of hip joint function, shorter non-weight-bearing time, and faster fracture healing. This article provides a literature review of the structural characteristics, biomechanical analysis, and clinical studies of PFBNs, aiming to provide a theoretical basis for the selection of internal fixation devices for the treatment of intertrochanteric femur fractures in elderly patients and to improve the quality of life of patients during the postoperative period.

The effect of systematic couple group therapy on families with depressed juveniles: a pilot trial.

Background: Depression is a primary cause of illness and disability among teenagers, and the incidence of depression and the number of untreated young people have increased in recent years. Effective intervention for those youths could decrease the disease burden and suicide or self-harm risk during preadolescence and adolescence. Objective: To verify the short efficacy of the systemic couple group therapy (SCGT) on youths' depression changes and families with depressed adolescents. Methods: The study was a self-control trial; only within-group changes were evaluated. Participants were couples with a depressed child who was resistant to psychotherapy; they were recruited non-randomly through convenient sampling. The paired-sample t-test and Wilcoxon signed-rank test were used to compare differences before and after interventions. The effect sizes were also estimated using Cohen's d. Spearman's correlation analysis was used to examine associations between changes. Results: A downward trend was seen in depressive symptoms after treatment, and Cohen's d was 0.33 (p = 0.258). The adolescents perceived fewer interparental conflicts, and the effect sizes were medium for perceived conflict frequency (0.66, p = 0.043), conflict intensity (0.73, p = 0.028), conflict solutions (0.75, p = 0.025), coping efficacy (0.68, p = 0.038), and perceived threat (0.57, p = 0.072). For parents, global communication quality, constructive communication patterns, and subjective marital satisfaction significantly improved after interventions, with large effect sizes (1.11, 0.85, and 1.03, respectively; all p < 0.001). Other destructive communication patterns such as demand/withdraw (p = 0.003) and mutual avoidance (p = 0.018) and communication strategies like verbal aggression (p = 0.012), stonewalling (p = 0.002), avoidance-capitulation (p = 0.036), and child involvement (p = 0.001) also reduced, with medium effect sizes (0.69, 0.52, 0.55, 0.71, 0.46, and 0.79, respectively). Meanwhile, the associations between depression changes and changes in interparental conflicts (p < 0.001) and marital satisfaction (p = 0.001) were significant. Conclusions and clinical relevance: The SCGT offers the possibility for the treatment of families with depressed children who are unwilling to seek treatment. Helping parents improve communication and marital quality may have benefits on children's depressive symptoms.

MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration.

Metabolic remodeling is a strategy for tumor survival under stress. However, the molecular mechanisms during the metabolic remodeling of colorectal cancer (CRC) remain unclear. Melanocyte proliferating gene 1 (MYG1) is a 3'-5' RNA exonuclease and plays a key role in mitochondrial functions. Here, we uncover that MYG1 expression is upregulated in CRC progression and highly expressed MYG1 promotes glycolysis and CRC progression independent of its exonuclease activity. Mechanistically, nuclear MYG1 recruits HSP90/GSK3ß complex to promote PKM2 phosphorylation, increasing its stability. PKM2 transcriptionally activates MYC and promotes MYC-medicated glycolysis. Conversely, c-Myc also transcriptionally upregulates MYG1, driving the progression of CRC. Meanwhile, mitochondrial MYG1 on the one hand inhibits oxidative phosphorylation (OXPHOS), and on the other hand blocks the release of Cyt c from mitochondria and inhibits cell apoptosis. Clinically, patients with KRAS mutation show high expression of MYG1, indicating a high level of glycolysis and a poor prognosis. Targeting MYG1 may disturb metabolic balance of CRC and serve as a potential target for the diagnosis and treatment of CRC.

CSRP1 gene: a potential novel prognostic marker in acute myeloid leukemia with implications for immune response.

BACKGROUND: Acute myeloid leukemia, constituting a majority of leukemias, grapples with a 24% 5-year survival rate. Recent strides in research have unveiled fresh targets for drug therapies. LIM-only, a pivotal transcription factor within LIM proteins, oversees cell development and is implicated in tumor formation. Among these critical LIM proteins, CSRP1, a Cysteine-rich protein, emerges as a significant player in various diseases. Despite its recognition as a potential prognostic factor and therapeutic target in various cancers, the specific link between CSRP1 and acute myeloid leukemia remains unexplored. Our previous work, identifying CSRP1 in a prognostic model for AML patients, instigates a dedicated exploration into the nuanced role of CSRP1 in acute myeloid leukemia. METHODS: R tool was conducted to analyze the public data. qPCR was applied to evaluate the expression of CSRP1 mRNA for clinical samples and cell line. Unpaired t test, Wilcoxon Rank Sum test, KM curves, spearman correlation test and Pearson correlation test were included in this study. RESULTS: CSRP1 displays notable expression variations between normal and tumor samples in acute myeloid leukemia (AML). It stands out as an independent prognostic factor for AML patients, showing correlations with clinical factors like age and cytogenetics risk. Additionally, CSRP1 correlates with immune-related pathways, immune cells, and immune checkpoints in AML. Furthermore, the alteration of CSRP1 mRNA levels is observed upon treatment with a DNMT1 inhibitor for THP1 cells. CONCLUSION: The CSRP1 has potential as a novel prognostic factor and appears to influence the immune response in acute myeloid leukemia. Additionally, there is an observed association between CSRP1 and DNA methylation in acute myeloid leukemia.

Tinnitus pitch does not always fall within the frequency range of hearing loss - a cross-sectional study on the mechanism of tinnitus production.

BACKGROUND: Clinically, we find that tinnitus patients often have hearing loss. According to the most accepted mechanism of tinnitus, that is, the spontaneous discharge and abnormal synchronization of neurons after afferent reduction, tinnitus frequency is closely related to the frequency of hearing loss. OBJECTIVE: The purpose of this study was to investigate the correlation of tinnitus pitch with the frequency of hearing loss. MATERIALS AND METHODS: A total of 500 patients with unilateral or bilateral chronic tinnitus were enrolled in this study. All patients underwent pure tone audiometry (PTA) and tinnitus acoustic examination. Hearing loss levels and frequencies were recorded. The relationship between tinnitus pitch and hearing loss level and frequency was statistically analyzed. RESULTS: Our results showed that 96.6% of the 500 tinnitus patients had hearing loss. Statistical analysis showed that low frequency (LF) tinnitus was correlated with LF hearing loss, but moderate frequency & high frequency (MF&HF) tinnitus was not significantly associated with MF&HF hearing loss. The coincidence of tinnitus pitch with the highest hearing threshold correlated with the degree of hearing loss. CONCLUSION AND SIGNIFICANCE: The vast majority of patients with chronic subjective tinnitus had hearing loss, and the frequency of tinnitus correlated with the degree and frequency of hearing loss but not exactly fall within the frequency range of hearing loss.

Construction of a Novel Vanillin-Induced Autoregulating Bidirectional Transport System in a Vanillin-Producing E. coli Cell Factory.

Vanillin is one of the world's most extensively used flavoring agents with high application value. However, the yield of vanillin biosynthesis remains limited due to the low efficiency of substrate uptake and the inhibitory effect on cell growth caused by vanillin. Here, we screened high-efficiency ferulic acid importer TodX and vanillin exporters PP_0178 and PP_0179 by overexpressing genes encoding candidate transporters in a vanillin-producing engineered Escherichia coli strain VA and further constructed an autoregulatory bidirectional transport system by coexpressing TodX and PP_0178/PP_0179 with a vanillin self-inducible promoter ADH7. Compared with strain VA, strain VA-TodX-PP_0179 can efficiently transport ferulic acid across the cell membrane and convert it to vanillin, which significantly increases the substrate utilization rate efficiency (14.86%) and vanillin titer (51.07%). This study demonstrated that the autoregulatory bidirectional transport system significantly enhances the substrate uptake efficiency while alleviating the vanillin toxicity issue, providing a promising viable route for vanillin biosynthesis.

Responses of Protozoan Communities to Multiple Environmental Stresses (Warming, Eutrophication, and Pesticide Pollution).

To explore the impacts of multiple environmental stressors on animal communities in aquatic ecosystems, we selected protozoa-a highly sensitive group of organisms-to assess the effect of environmental change. To conduct this simulation we conducted a three-factor, outdoor, mesocosm experiment from March to November 2021. Changes in the community structure and functional group composition of protozoan communities under the separate and combined effects of these three environmental stressors were investigated by warming and the addition of nitrogen, phosphorus, and pesticides. The results were as follows: (1) Both eutrophication and pesticides had a considerable promotional effect on the abundance and biomass of protozoa; the effect of warming was not considerable. When warming was combined with eutrophication and pesticides, there was a synergistic effect and antagonistic effect, respectively. (2) Eutrophication promoted α diversity of protozoa and affected their species richness and dominant species composition; the combination of warming and pesticides remarkably reduced the α diversity of protozoa. (3) Warming, eutrophication, and pesticides were important factors affecting the functional groups of protozoa. Interaction among different environmental factors could complicate changes in the aquatic ecological environment and its protozoan communities. Indeed, in the context of climate change, it might be more difficult to predict future trends in the protozoan community. Therefore, our results provide a scientific basis for the protection and restoration of shallow lake ecosystems; they also offer valuable insights in predicting changes in shallow lakes.

The Effect of Different Substances Embedded in Fullerene Cavity on Surfactant Self-Assembly Behavior through Molecular Dynamics Simulation.

Fullerene-based amphiphiles are new types of monomers that form self-assemblies with profound applications. The conical fullerene amphiphiles (CFAs) have attracted attention for their uniquely self-assembled structures and have opened up a new field for amphiphile research. The CFAs and CFAs with different substances embedded in cavities are designed and their self-assembly behaviors are investigated using molecular dynamics (MD) simulations. The surface and internal structures of the micelles are analyzed from various perspectives, including micelle size, shape, and solvent-accessible surface area (SASA). The systems studied are all oblate micelles. In comparison, embedding Cl- or embedding Na+ in the cavities results in larger micelles and a larger deviation from the spherical shape. Two typical configurations of fullerene surfactant micelles, quadrilateral plane and tetrahedral structure, are presented. The dipole moments of the fullerene molecules are also calculated, and the results show that the embedded negatively charged Cl- leads to a decrease in the polarity of the pure fullerene molecules, while the embedded positively charged Na+ leads to an increase.

Microemulsions based on Acer truncatum seed oil and its fatty acids: fabrication, rheological property, and stability.

AIMS: To construct the microemulsion delivery system (ME) loading ATSO and NA and study their physicochemical characteristics to enhance their stability and water solubility. METHODS: By plotting ternary phase diagrams, the composition and proportions of the MEs were determined. The physicochemical characteristics and stability of MEs were evaluated by mean diameter, polydispersity index (PDI), pH, electrical conductivity, transmission electron microscopy (TEM), rheological behaviour measurement, and phase inversion temperature (PIT). RESULTS: The MEs was composed with EL-40 as a surfactant and specifically with the addition of ethanol as a cosurfactant in NA-loaded ME. The mean diameters of ATSO-loaded ME and NA-loaded ME were 39.65 ± 0.24 nm and 32.90 ± 2.65 nm, and PDI were 0.49 ± 0.01 and 0.28 ± 0.14, respectively. The TEM confirmed the spherical and smooth morphology of MEs. The rheological results indicated that MEs are dilatant fluids with the advantages of low viscosity, high fluidity, and tolerance to temperature fluctuations. The mean diameter and PDI of MEs showed no significant change after storage at 25 °C for 28 days and centrifugation. CONCLUSION: The prepared microemulsions could expand the application prospects of ATSO and NA products in cosmetics, medicine, foods and other fields.