Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.

Miniaturized guided-mode resonance laser based on a one-dimensional finite heterostructure cavity.

Lasers based on the resonant nanostructures have attracted much attention due to their low threshold and compact dimensions. Guided-mode resonance (GMR) structures have been studied in lasing configurations because of their optical field enhancement and convenient free space excitation. However, the GMR inherently requires a larger footprint and is not suitable for high-density packaging. Here, we present numerical evidence of a miniaturized laser implemented in a one-dimensional finite heterostructure cavity (FHC). A GMR resonator and distributed Bragg reflectors are integrated to create the FHC, which enables the efficient coupling and localization of the electric field. Numerical findings indicate that the threshold is approximately 22.5 µJ/cm2, while the emission region is confined within a length of 5.4 µm. In addition, by adjusting the coupling strength, it is capable to achieve controllable lasing emission. The proposed structure provides a compact source for high-capacity optical communications, sensing, and quantum information processing.

G protein-coupled receptor kinase 2 as a novel therapeutic target for gland fibrosis of Sjögren's syndrome.

Sjogren's syndrome (SS) is a chronic, progressive autoimmune disorder characterized by gland fibrosis. We previously found a close correlation between gland fibrosis and the expression of G protein-coupled receptor kinase 2 (GRK2). In this study we explored the pathological and therapeutic significance of GRK2 in SS. Submandibular gland (SMG) antigen-induced SS mouse model was established in WT and GRK2+/- mice. We showed that the expression levels of GRK2 were significantly up-regulated in glandular tissue and positively correlated with fibrotic morphology in SS patients and mice. Hemizygous knockout of GRK2 significantly inhibited the gland fibrosis. In mouse salivary gland epithelial cells (SGECs), we demonstrated that GRK2 interacted with Smad2/3 to positively regulate the activation of TGF-ß-Smad signaling with a TGF-ß-GRK2 positive feedback loop contributing to gland fibrosis. Hemizygous knockout of GRK2 attenuated TGF-ß-induced collagen I production in SGECs in vitro and hindered gland fibrosis in murine SS though preventing Smad2/3 nuclear translocation. Around 28 days post immunization with SMG antigen, WT SS mice were treated with a specific GRK2 inhibitor paroxetine (Par, 5 mg·kg-1·d-1, i.g. for 19 days). We found that Par administration significantly attenuated gland fibrosis and alleviated the progression of SS in mice. We conclude that genetic knockdown or pharmacological inhibition of GRK2 significantly attenuates gland fibrosis and alleviates the progression of SS. GRK2 binds to Smad2/3 and positively regulates the activation of TGF-ß-Smad signaling. A TGF-ß-GRK2 positive feedback loop contributes to gland fibrosis. Our research points out that GRK2 could be a promising therapeutic target for treating SS.

Assessment of Endoscopy-Based Scoring Systems for Prognostication in Ulcerative Colitis: A Comparative Analysis.

BACKGROUND AND OBJECTIVE: Endoscopy-based scoring systems, including Mayo Endoscopic Score (MES), Modified Mayo Endoscopic Score (MMES), and Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) Score, have been introduced to evaluate UC prognosis. This study aims to compare their predictive capacity for clinical outcomes in UC patients. METHODS: Consecutive UC patients from a tertiary hospital were included. The primary outcome was acute severe ulcerative colitis (ASUC), and secondary outcomes were UC-related admission, medication treatment escalation, disease extension and surgery. Predictive performance was assessed using receiver operating characteristic (ROC) curves. RESULTS: Among 300 patients, 15.3% developed ASUC. Robust correlations were observed among the three scoring systems and were with elevated serum inflammatory markers. The DUBLIN score exhibited superior predictive ability for UC-related admission (AUC 0.751; 95%CI 0.698-0.799) and medication treatment escalation (AUC 0.735; 95% CI 0.681-0.784). No statistical differences were found among three scoring systems for predicting ASUC, disease extension, and surgery. Employing respective cut-offs of 2, 11.25, and 3, higher MES (HR = 3.859, 95% CI 1.636-9.107, p = 0.002), MMES (HR = 3.352, 95% CI 1.879-5.980, p < 0.001), and DUBLIN score (HR = 5.619, 95% CI 2.378-13.277, p < 0.001) were associated with an increased risk of developing ASUC. CONCLUSION: The DUBLIN score, assessing the overall inflammatory burden of the intestinal tract, outperforms the MMES in predicting admission and medication treatment escalation related to UC. Its integration into clinical practice has the potential to enhance risk stratification for patients with UC.

Association between dietary retinol intake and rheumatoid arthritis based on NHANES database.

OBJECTIVE: This study focused on the investigation of the correlation between dietary retinol intake and rheumatoid arthritis (RA) using the National Health and Nutrition Examination Survey (NHANES) database. METHODS: Data from five NHANES cycles from 2003 to 2012 were utilized for this study. Dietary retinol intake was considered as the independent variable, and RA was the dependent variable. A weighted logistic regression method was applied to construct the relational model of the two variables. Stratified analysis without adjusting for confounding factors and subgroup analysis with confounding factors adjusted were conducted to explore the association between dietary retinol intake and RA. The optimal intake of dietary retinol was determined by the restricted cubic splines (RCS) analysis. RESULTS: 22,971 samples were included in this study. The weighted logistic regression model was employed to construct the relational model of dietary retinol intake and RA (OR: 0.95, 95% CI: 0.91-0.99, p = 0.019). Stratified analysis displayed a great influence on the relational model exerted by the interaction between gender and retinol intake (p for interaction = 0.014). A significant association between retinol intake and RA was also indicated in the model adjusted for demographic characteristics (OR: 0.95, 95% CI: 0.90-1.00, p = 0.029). Subgroup analysis by gender showed that in the female population, unadjusted model (OR: 0.90, 95% CI: 0.84-0.96, p = 0.002), model adjusted for demographic characteristics only (OR: 0.89, 95% CI: 0.83-0.96, p = 0.002), and model adjusted for all confounding factors (OR: 0.91, 95% CI: 0.85-0.99, p = 0.019) indicated dietary retinol intake as a protective factor against RA. RCS analysis demonstrated that in the female population, regardless of the model used (Crude, Model I, and Model II), an intake of dietary retinol > 354.86 mcg was associated with RA disease reduction (OR < 1.0, p-non-linear < 0.05, p-overall < 0.05). CONCLUSION: Increased dietary retinol intake was associated with RA disease reduction, particularly in the female population. Women are recommended to increase their dietary retinol intake (> 354.86 mcg) to reduce the risk of RA.

The Minhang Pediatric Biobank cohort study: protocol overview and baseline characteristics.

BACKGROUND: Little has been done to establish biobanks for studying the environment and lifestyle risk factors for diseases among the school-age children. The Minhang Pediatric Biobank (MPB) cohort study aims to identify factors associated with health and diseases of school-aged children living in the urban or suburban area of Shanghai. METHODS: This population-based cohort study was started in all sub-districts/towns of Minhang district of Shanghai in 2014. First-grade students in elementary school were enrolled during the time of their routine physical examinations, with self-administered questionnaires completed by their primary caregivers. Additional information was extracted from multiple health information systems. Urine and saliva samples were collected during the baseline survey and follow-up visits. RESULTS: At the end of 2014 academic year, a total number of 8412 children and their parents were recruited, including 4339 boys and 4073 girls. All the participants completed the baseline survey and physical examination, and 7128 urine and 2767 saliva samples were collected. The five most prevalent childhood diseases in this population were dental caries, bronchitis, pneumonia, asthma and overweight/obese. CONCLUSIONS: The MPB cohort has been successfully established, serving as a useful platform for future research relating to the genetic, environmental and lifestyle risk factors for childhood diseases.

[Mechanism of Huangqin Qingre Chubi Capsules in improving rheumatoid arthritis based on METTL3-SFRP4/Wnt/ß-catenin pathway].

The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, ß-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and ß-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1ß, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P<0. 05). The paw retraction threshold and body weight mass index both significantly increased(P<0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P< 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3(P< 0. 05). At the same time, the m RNA and protein expressions of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P<0. 05). HQC could reduce the levels of IL-1ß, IL-6, and IL-8 to varying degrees(P<0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/ß-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.

Novel approach to soft tissue regeneration: in vitro study of compound hyaluronic acid and horizontal platelet-rich fibrin combination.

OBJECTIVE: This study aims to develop a compound biomaterial to achieve effective soft tissue regeneration. METHODOLOGY: Compound hyaluronic acid (CHA) and liquid horizontal-platelet-rich fibrin (H-PRF) were mixed at a ratio of 1:1 to form a CHA-PRF gel. Human gingival fibroblasts (HGFs) were used in this study. The effect of CHA, H-PRF, and the CHA-PRF gel on cell viability was evaluated by CCK-8 assays. Then, the effect of CHA, H-PRF, and the CHA-PRF gel on collagen formation and deposition was evaluated by qRT‒PCR and immunofluorescence analysis. Finally, qRT‒PCR, immunofluorescence analysis, Transwell assays, and scratch wound-healing assays were performed to determine how CHA, H-PRF, and the CHA-PRF gel affect the migration of HGFs. RESULTS: The combination of CHA and H-PRF shortened the coagulation time of liquid H-PRF. Compared to the pure CHA and H-PRF group, the CHA-PRF group exhibited the highest cell proliferation at all time points, as shown by the CCK-8 assay. Col1a and FAK were expressed at the highest levels in the CHA-PRF group, as shown by qRT‒PCR. CHA and PRF could stimulate collagen formation and HGF migration, as observed by fluorescence microscopy analysis of COL1 and F-actin and Transwell and scratch healing assays. CONCLUSION: The CHA-PRF group exhibited greater potential to promote soft tissue regeneration by inducing cell proliferation, collagen synthesis, and migration in HGFs than the pure CHA or H-PRF group. CHA-PRF can serve as a great candidate for use alone or in combination with autografts in periodontal or peri-implant soft tissue regeneration.

Polyethylene glycol-polyvinylidene fluoride/TiO2 nanocomposite polymer coatings with efficient antifouling strategies: Hydrophilized defensive surface and stable capacitive deionization.

Capacitive deionization (CDI) is flourishing as an energy-efficient and cost-effective water desalination method. However, challenges such as electrode degradation and fouling have hindered the practical deployment of CDI technology. To address these challenges, the key point of our strategy is applying a hydrophilic coating composed of polyethylene glycol (PEG)-functionalized nano-TiO2/polyvinylidene fluoride (PVDF) to the electrode interface (labeled as APPT electrode). The PEG/PVDF/TiO2 layer not only mitigates the co-ion depletion, but also imparts the activated carbon (AC) electrode hydrophilicity. As anticipated, the APPT electrode possessed an enhanced desalination capacity of 83.54 µmol g-1 and a low energy consumption of 17.99 Wh m-3 in 10 mM sodium chloride solution compared with the bare AC electrode. Notably, the APPT maintained about 93.19 % of its desalination capacity after 50 consecutive adsorption-desorption cycles in the presence of bovine serum albumin (BSA). During the trial, moreover, no obvious overall performance decline was noted in concentration reduction (Δc), water recovery (WR) and productivity (P) over 50 cycles. This strategy realizes energy-efficient, antifouling and stable brackish water desalination and has great promise for practical applications.

Spatiotemporal Synergism in Osteomyelitis Treatment with Photoactivated Core-Shell Zinc Oxide/Silver Sulfide Heterogeneous Nanoparticles.

Osteomyelitis is primarily caused by bacterial infections, and treatment requires precise sequential therapy, including antibacterial therapy in the early stages and bone defect reconstruction in later stages. We aimed to synthesize core-shell-structured zinc oxide/silver sulfide heterogeneous nanoparticles (ZnO/Ag2S NPs) using wet chemical methods. Using density functional theory and ultraviolet photoelectron spectroscopy, we showed that the optimized band structure endowed ZnO/Ag2S NPs with photodynamic properties under near-infrared (NIR) irradiation. Moreover, ZnO/Ag2S NPs exhibited a distinguished and stable photothermal performance within the same wavelength range. With single-wavelength irradiation, ZnO/Ag2S NPs achieved a bifunctional antibacterial effect during the acute stage of osteomyelitis. Antibacterial action was confirmed through colony-forming unit (CFU) counting assays, scanning electronic microscopy (SEM) observations, live-dead staining, growth curves, and quantitative real-time polymerase chain reaction (qPCR) assays. The Ag2S coating on the NPs realized the sustained release of zinc ions, thereby controlling the zinc ion concentration. Alkaline phosphatase (ALP) staining, alizarin red S (ARS) staining, and qPCR assays confirmed that the ZnO/Ag2S NPs exhibited good osteogenic effects in vitro. These effects were verified in an in vivo mouse femur model during chronic stages using micro-computed tomography (micro-CT) and histological analysis. This study provides a novel biocompatible core-shell nanomaterial for the two-phase treatment of osteomyelitis, contributing to versatile nanotherapies for infections and inflammation.

Interaction between Per- and Polyfluorinated Substances (PFAS) and Acetaminophen in Disease Exacerbation-Focusing on Autism and the Gut-Liver-Brain Axis.

This review presents a new perspective on the exacerbation of autism spectrum disorder (ASD) by per- and polyfluoroalkyl substances (PFAS) through the gut-liver-brain axis. We have summarized evidence reported on the involvement of the gut microbiome and liver inflammation that led to the onset and exacerbation of ASD symptoms. As PFAS are toxicants that particularly target liver, this review has comprehensively explored the possible interaction between PFAS and acetaminophen, another liver toxicant, as the chemicals of interest for future toxicology research. Our hypothesis is that, at acute dosages, acetaminophen has the ability to aggravate the impaired conditions of the PFAS-exposed liver, which would further exacerbate neurological symptoms such as lack of social communication and interest, and repetitive behaviors using mechanisms related to the gut-liver-brain axis. This review discusses their potential interactions in terms of the gut-liver-brain axis and signaling pathways that may contribute to neurological diseases.

Validation of disease severity index for predicting complicated disease in Crohn's disease: A comparison study with Lémann index.

BACKGROUND: Disease Severity Index (DSI) provides comprehensive assessment of bowel damage (BD). AIMS: To evaluate DSI in patients with Crohn's disease (CD) at high risk of disease progression, compared to Lémann Index (LI). METHODS: Patients with CD in our center were reviewed consecutively between 2017 and 2019. DSI, LI, and complicated CD course were analyzed. RESULTS: The median LI and DSI of included 300 patients were 1.63 (IQR 1.25-3.13) and 42 (IQR 32-51), respectively. 152 patients (50.7%) experienced a complicated disease course (median 5.1 months; IQR 1.1-20.2). DSI (AUC 0.66; 95% CI 0.60-0.72) better predicted a complicated course of CD over LI (AUC 0.56; 95% CI 0.50-0.63; P = 0.007). The cumulative probability of complicated CD course in severe patients was higher than those with 'mild CD' (P < 0.001). The Cox analysis identified DSI>43 (HR 2.18; 95% CI 1.54-3.09; P < 0.001), B2/3 vs. B1 (HR 2.80; 95% CI 1.99-3.94; P < 0.001), and a higher level of CRP (HR 1.01; 95% CI 1.00-1.02; P = 0.005) as independent prognostic factors for complicated CD. However, LI was not associated with complicated CD (P = 0.164). CONCLUSIONS: Higher DSI was associated with complicated disease outcomes. DSI might play a better role than LI in identifying patients at high risks of disease progression.

Nanomedicines targeting activated immune cells and effector cells for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and inflammatory cellular infiltration. Functional cells in the RA microenvironment (RAM) are composed of activated immune cells and effector cells. Activated immune cells, including macrophages, neutrophils, and T cells, can induce RA. Effector cells, including synoviocytes, osteoclasts, and chondrocytes, receiving inflammatory stimuli, exacerbate RA. These functional cells, often associated with the upregulation of surface-specific receptor proteins and significant homing effects, can secrete pro-inflammatory factors and interfere with each other, thereby jointly promoting the progression of RA. Recently, some nanomedicines have alleviated RA by targeting and modulating functional cells with ligand modifications, while other nanoparticles whose surfaces are camouflaged by membranes or extracellular vesicles (EVs) of these functional cells target and attack the lesion site for RA treatment. When ligand-modified nanomaterials target specific functional cells to treat RA, the functional cells are subjected to attack, much like the intended targets. When functional cell membranes or EVs are modified onto nanomaterials to deliver drugs for RA treatment, functional cells become the attackers, similar to arrows. This study summarized how diversified functional cells serve as targets or arrows by engineered nanoparticles to treat RA. Moreover, the key challenges in preparing nanomaterials and their stability, long-term efficacy, safety, and future clinical patient compliance have been discussed here.

Association between short-term ozone exposure and allergic conjunctivitis in China: A multi-city case-crossover study.

Short-term exposure to ozone has been linked to multiple allergic diseases, but the relationship between ozone exposure and allergic conjunctivitis (AC) remains unclear. This study aimed to investigate the association between short-term exposure to ozone and the risk of AC. We conducted a time-stratified case-crossover study across five Chinese cities from 2014 to 2022. Daily outpatient visit records for AC were identified in five hospitals using either the diagnosis name or ICD-10 code H10.1. Data on air pollution and meteorological conditions were also collected. We first examined the city-specific association between short-term ozone exposure and AC using conditional logistic regression. A random-effects meta-analysis was then conducted to obtain overall estimates. During the study period, 130,093 outpatient visits for AC occurred, with 58.8% (76,482) being male and 41.2% (53,611) female. A one-standard-deviation (SD) increase in ozone was associated with an 8.3% increase (95% CI: 3.8%, 13.0%) in AC outpatient visits. Similar positive associations were observed when adjusting for other pollutants (PM2.5, CO, SO2 and NO2) in two-pollutant and multi-pollutant models. Furthermore, the positive association remained consistent when using mixed-effects regression models or further adjusting for meteorological conditions. In addition, no effect modification of the AC-ozone association by sex, age and season was apparent. This study provides evidence supporting a positive association between short-term ozone exposure and AC risk in China. This highlights the potential value of mitigating ozone pollution to reduce the risk of ocular surface disorders.

The disparity of platelet factor 4 and platelets in individuals of different ages.

The aging process profoundly impacts the systemic milieu, with specific blood-borne factors playing critical roles in its regulation. Platelet Factor 4 (PF4), released by platelets, has emerged as a novel blood-borne factor that contributes to the rejuvenation of aging brains in rodents. However, the age-related disparity in PF4 levels in humans remains poorly understood. To explore the relationship between PF4 and the natural aging process in humans, we collected peripheral blood (PB) samples from young (23.40 ± 2.13 years, n = 15) and elderly (75.23 ± 4.19 years, n = 13) individuals, along with cord blood (CB) samples (n = 15). ELISA analysis revealed higher PF4 levels in platelet-rich plasma lysate from young PB compared with that from elderly PB. Consistent with this, qPCR results demonstrated the highest PF4 expression in young PB among the three groups. In addition, FACS analysis showed increased expression of CXCR3 in mononuclear cells of young PB, indicating a greater responsiveness to PF4. Finally, our RNA-sequencing analysis corroborated platelets as a sensitive element during the natural aging process, and indicated platelets play a pivotal role in antioxidant response during aging, as evidenced by significant enrichment of several age-related pathways. These findings reveal that, alongside PF4 levels, platelets undergo substantial alterations during aging. Taken together, our data identified age-related disparities in platelets and PF4-related elements during natural aging and underscored the potential of targeting platelet modulation as an intervention in the aging process.

A ROS-responsive loaded desferoxamine (DFO) hydrogel system for traumatic brain injury therapy.

Traumatic brain injury (TBI) produces excess iron, and increased iron accumulation in the brain leads to lipid peroxidation and reactive oxygen species (ROSs), which can exacerbate secondary damage and lead to disability and death. Therefore, inhibition of iron overload and oxidative stress has a significant role in the treatment of TBI. Functionalized hydrogels with iron overload inhibiting ability and of oxidative stress inhibiting ability will greatly contribute to the repair of TBI. Herein, an injectable, post-traumatic microenvironment-responsive, ROS-responsive hydrogel encapsulated with deferrioxamine mesylate (DFO) was developed. The hydrogel is rapidly formed via dynamic covalent bonding between phenylboronic acid grafted hyaluronic acid (HA-PBA) and polyvinyl alcohol (PVA), and phenylboronate bonds are used to respond to and reduce ROS levels in damaged brain tissue to promote neuronal recovery. The release of DFO from HA-PBA/PVA hydrogels in response to ROS further promotes neuronal regeneration and recovery by relieving iron overload and thus eradicating ROS. In the Feeney model of Sprague Dawley rats, HA-PBA/PVA/DFO hydrogel treatment significantly improved the behavior of TBI rats and reduced the area of brain contusion in rats. In addition, HA-PBA/PVA/DFO hydrogel significantly reduced iron overload to reduce ROS and could effectively promote post-traumatic neuronal recovery. Its effects were also explored, and notably, HA-PBA/PVA/DFO hydrogel can reduce iron overload as well as ROS, thus protecting neurons from death. Thus, this injectable, biocompatible and ROS-responsive drug-loaded hydrogel has great potential for the treatment of TBI. This work suggests a novel method for the treatment of secondary brain injury by inhibiting iron overload and the oxidative stress response after TBI.

Developing a Machine-Learning Prediction Model for Infliximab Response in Crohn's Disease: Integrating Clinical Characteristics and Longitudinal Laboratory Trends.

BACKGROUND: Achieving long-term clinical remission in Crohn's disease (CD) with antitumor necrosis factor α (anti-TNF-α) agents remains challenging. AIMS: This study aims to establish a prediction model based on patients' clinical characteristics using a machine-learning approach to predict the long-term efficacy of infliximab (IFX). METHODS: Three cohorts comprising 746 patients with CD were included from 3 inflammatory bowel disease (IBD) centers between June 2013 and January 2022. Clinical records were collected from baseline, 14-, 30-, and 52-week post-IFX treatment. Three machine-learning approaches were employed to develop predictive models based on 23 baseline predictors. The SHapley Additive exPlanations (SHAP) algorithm was used to dissect underlying predictors, and latent class mixed model (LCMM) was applied for trajectory analysis of the longitudinal change of blood routine tests along with long-term IFX therapy. RESULTS: The XGBoost model exhibited the best discrimination between long-term responders and nonresponders. In the internal training and testing set, the model achieved an AUC of 0.91 (95% CI, 0.86-0.95) and 0.71 (95% CI, 0.66-0.87), respectively. Moreover, it achieved a moderate predictive performance in the independent external cohort, with an AUC of 0.68 (95% CI, 0.59-0.77). The SHAP algorithm revealed disease-relevant laboratory measurements, notably hemoglobin (HB), white blood cells (WBC), erythrocyte sedimentation rate (ESR), albumin (ALB), and platelets (PLT), alongside age at diagnosis and the Montreal classification, as the most influential predictors. Furthermore, 2 distinct patient clusters based on dynamic laboratory tests were identified for monitoring the long-term remission. CONCLUSIONS: The established prediction model demonstrated remarkable discriminatory power in distinguishing long-term responders from nonresponders to IFX therapy. The identification of distinct patient clusters further emphasizes the need for tailored therapeutic approaches in CD management.

The study developed a machine-learning model using clinical data to predict long-term efficacy of IFX in Crohn's disease. The XGBoost model demonstrated strong discriminatory power, revealing influential predictors and distinct patient clusters, emphasizing the importance of tailored therapeutic approaches in CD management.

Membranous aplasia cutis congenita: A rare case report highlighting clinical presentation, genetic insights, and the need for comprehensive evaluation.

Introduction: Membranous aplasia cutis congenita (MACC) is the most common clinical subtype of aplasia cutis congenita (ACC). It is typified by a localized skin lesion devoid of hair and features a membranous surface. While most MACC individuals do not present with concurrent abnormalities, it can sometimes co-occur with additional physical anomalies and various malformation syndromes. Moreover, the underlying causes of MACC remain elusive. Case presentation: We describe a case of a 6-month-old female infant diagnosed with MACC. The patient presented with a midline skin lesion on the occipital scalp, characterized by a glistening surface and a hair collar sign. Dermoscopic examination revealed specific features, including translucency, telangiectasia, and hypertrichosis. The infant had a history of patent foramen ovale, and further examination uncovered an asymptomatic ventricular septal defect. Whole exome sequencing revealed 20 gene variants relevant to the clinical phenotype of the patient, suggesting a possible association with MACC. Conclusion: MACC is a rare and underreported condition, primarily diagnosed based on its distinctive clinical features. It is imperative to emphasize the significance of thorough evaluations in MACC patients, encompassing developmental, cardiac, neurological, and genetic assessments to facilitate early detection and the exclusion of potentially life-threatening comorbidities. Importantly, genetic characterization, as demonstrated in this case, contributes to our understanding of MACC's etiology and highlights the need for further research in this field.

Characterization of Salmonella Phage P1-CTX and the Potential Mechanism Underlying the Acquisition of the blaCTX-M-27 Gene.

The P1 phage has garnered attention as a carrier of antibiotic resistance genes (ARGs) in Enterobacteriaceae. However, the transferability of ARGs by P1-like phages carrying ARGs, in addition to the mechanism underlying ARG acquisition, remain largely unknown. In this study, we elucidated the biological characteristics, the induction and transmission abilities, and the acquisition mechanism of the blaCTX-M-27 gene in the P1 phage. The P1-CTX phage exhibited distinct lytic plaques and possessed a complete head and tail structure. Additionally, the P1-CTX phage was induced successfully under various conditions, including UV exposure, heat treatment at 42 °C, and subinhibitory concentrations (sub-MICs) of antibiotics. Moreover, the P1-CTX phage could mobilize the blaCTX-M-27 gene into three strains of Escherichia coli (E. coli) and the following seven different serotypes of Salmonella: Rissen, Derby, Kentucky, Typhimurium, Cerro, Senftenberg, and Muenster. The mechanism underlying ARG acquisition by the P1-CTX phage involved Tn1721 transposition-mediated movement of blaCTX-M-27 into the ref and mat genes within its genome. To our knowledge, this is the first report documenting the dynamic processes of ARG acquisition by a phage. Furthermore, this study enriches the research on the mechanism underlying the phage acquisition of drug resistance genes and provides a basis for determining the risk of drug resistance during phage transmission.

Photoresponsive Nanoarchitectonics Based on Copper-Porphyrins for Near-Infrared-Enhanced Bacterial Treatment.

Antibiotic resistance is one of the biggest challenges that causes incurable diseases and endangers public health. Metal-porphyrin-modified nanoarchitectonics can enhance the bacterial affinity and destruction of cell walls. Herein, a new photoresponsive nanoarchitectonics (BPGa@COF-Cu) was synthesized by doping Ga(III) on the surface of black phosphorus (BP) and subsequently loaded into a Cu(II)-based covalent-organic framework (COF-Cu). The COF-Cu was induced by the coupling reaction of terephthalic chloride with amino-substituted porphyrin derivatives (THPP), followed by the coordination of the Cu(II) ion. The material BPGa@COF-Cu is a nanoball, and the mean radius is ca. 250 nm. The photochemical properties of BPGa@COF-Cu show that it efficiently catalyzes H2O2 into ·OH. BPGa@COF-Cu can also produce both singlet oxygen and heat upon 808 nm irradiation. Further, BPGa@COF-Cu was employed to inhibit bacteria, and the results showed that it can destroy the membrane of bacteria. The MIC (minimal inhibition concentration) of BPGa@COF-Cu against E. coli was 1 µg/mL. All the data suggest that BPGa@COF-Cu is a multiple nanoarchitectonics for bacterial treatment.