The effects of optimized microstructured surfaces on bond strength and durability of NPJ-printed zirconia.

OBJECTIVES: This study was to investigate the effects of optimized microstructured surfaces on bond strength and bond durability of the latest nanoparticle jetting (NPJ)-printed zirconia. METHODS: Zirconia microstructured surfaces with different geometries and void volume were analyzed through three-dimensional finite element analysis for surface micromorphology optimization. Zirconia disks and cylinders were additively manufactured by an NPJ 3D printer (N = 128). They were randomly divided into four groups based on surface micromorphology optimization and airborne-particle abrasion (APA) treatment before they were bonded using 10-methacryloloxydecyl dihydrogen phosphate (MDP) containing resin cement (Clearfil SA luting cement). The shear bond strengths (SBSs) were tested before and after 10,000 thermocycles and were analyzed by one-way ANOVA analysis. Failure modes were determined by optical microscopy. Zirconia surfaces were analyzed with X-ray diffraction, scanning electron microscopy, and three-dimensional interference microscopy. RESULTS: The optimized microstructured surface was characterized by circular microstructures with 60 % void volume, about 20 µm of depths, about 10 µm of undercuts, and consistent beam widths. The optimized microstructured surface combined with APA treatment and MDP-containing resin cement possessed the highest SBSs both before and after thermocycling aging (P＜0.05). The greater reductions of zirconia bond strengths occurred when the zirconia were not treated with APA (P＜0.05). SIGNIFICANCE: The optimized microstructured zirconia surface with circular microstructures and 60 % void volume fabricated by the latest NPJ printing technology could greatly enhance the zirconia bond strength and durability in combination with APA treatment and application of MDP-containing resin cement, which might be promising for adhesively bonded indirect restorations of NPJ-printed zirconia.

Suppression of overactivated immunity in the early stage is the key to improve the prognosis in severe burns.

Background: Severe burns can lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) due to inflammation-immunity dysregulation. This study aimed to identify key immune-related molecules and potential drugs for immune regulation in severe burn treatment. Method: Microarray datasets GSE77791 and GSE37069 were analyzed to identify immune-related differentially expressed genes (DEGs), enriched pathways and prognosis-related genes. The DGIdb database was used to identify potentially clinically relevant small molecular drugs for hub DEGs. Hub DEGs were validated by total RNA from clinical blood samples through qPCR. The efficacy of drug candidates was tested in a severe burn mouse model. Pathologic staining was used to observe organ damage. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the serum IL-1b, IL-6, TNF-a and MCP-1 contents. Activation of the NF-κB inflammatory pathway was detected by western blotting. Transcriptome sequencing was used to observe inflammatory-immune responses in the lung. Results: A total of 113 immune-related DEGs were identified, and the presence of immune overactivation was confirmed in severe burns. S100A8 was not only significantly upregulated and identified to be prognosis-related among the hub DEGs but also exhibited an increasing trend in clinical blood samples. Methotrexate, which targets S100A8, as predicted by the DGIdb, significantly reduces transcription level of S100A8 and inflammatory cytokine content in blood, organ damage (lungs, liver, spleen, and kidneys) and mortality in severely burned mice when combined with fluid resuscitation. The inflammatory-immune response was suppressed in the lungs. Conclusion: S100A8 with high transcription level in blood is a potential biomarker for poor severe burn prognosis. It suggested that methotrexate has a potential application in severe burn immunotherapy. Besides, it should be emphasized that fluid resuscitation is necessary for the function of methotrexate.

Inhibition of MAT2A Impairs Skeletal Muscle Repair Function.

The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A's critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. In vivo, inhibiting MAT2A activity aggravated BaCl2-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in Mat2a-knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53-Fas-mediated apoptosis.

A novel variant (p.A524P) in Spastin is responsible for a Chinese family with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) represents a group of monogenic neurodegenerative disorders characterized by high clinical and genetic heterogeneity. HSP is characterized by slowly progressing hypertonia of both lower extremities, spastic gait, and myasthenia. The most prevalent autosomal dominant form of HSP, known as spastic paraplegia 4 (SPG4), is attributed to variants in the spastin (SPAST) gene. METHODS AND RESULTS: Here, a Chinese family presenting with spasticity in both legs and a shuffling gait participated in our investigation. Whole exome sequencing of the proband was utilized to identify the genetic lesion in the family. Through data filtering, Sanger sequencing validation, and co-separation analysis, a novel variant (NM_014946.3: c.1669G > C:p.A557P) of SPAST was identified as the genetic lesion of this family. Furthermore, bioinformatic analysis revealed that this variant was deleterious and located in a highly evolutionarily conserved site. CONCLUSION: Our study confirmed the diagnosis of SPG4 in this family, contributing to genetic counseling for families affected by SPG4. Additionally, our study broadened the spectrum of SPAST variants and highlighted the importance of ATPases associated with various cellular activity domains of SPAST.

Development Status of Solar-Driven Interfacial Steam Generation Support Layer Based on Polymers and Biomaterials: A Review.

With the increasing shortage of water resources and the aggravation of water pollution, solar-driven interfacial steam generation (SISG) technology has garnered considerable attention because of its low energy consumption, simple operation, and environmental friendliness. The popular multi-layer SISG evaporator is composed of two basic structures: a photothermal layer and a support layer. Herein, the support layer underlies the photothermal layer and carries out thermal management, supports the photothermal layer, and transports water to the evaporation interface to improve the stability of the evaporator. While most research focuses on the photothermal layer, the support layer is typically viewed as a supporting object for the photothermal layer. This review focuses on the support layer, which is relatively neglected in evaporator development. It summarizes existing progress in the field of multi-layer interface evaporators, based on various polymers and biomaterials, along with their advantages and disadvantages. Specifically, mainly polymer-based support layers are reviewed, including polymer foams, gels, and their corresponding functional materials, while biomaterial support layers, including natural plants, carbonized biomaterials, and other innovation biomaterials are not. Additionally, the corresponding structure design strategies for the support layer were also involved. It was found that the selection and optimal design of the substrate also played an important role in the efficient operation of the whole steam generation system. Their evolution and refinement are vital for advancing the sustainability and effectiveness of interfacial evaporation technology. The corresponding potential future research direction and application prospects of support layer materials are carefully presented to enable effective responses to global water challenges.

Psychosocial Factors and Psychological Adjustment Among Adolescents and Young Adults: A Comparative Analysis of Occasional Drug Craving and Non-Craving.

OBJECTIVE: The rate of drug craving not only in Pakistan is escalating rapidly, but also from a wide range of cultures and geographically have been impacted by the drug problem. Recently, drug cravings among young Pakistani school and college students have significantly increased, particularly illegal substances like hashish, heroin, and ecstasy. METHODS: We recruited 338 students and gathered demographic and drug-craving data through a survey. To assess the study variables, we used the parental acceptance-rejection short version, peer pressure questionnaire, and adult personality assessment scale. RESULTS: The prevalence rate of occasional drug craving was 44.1% (tobacco, 39.9%; heroin, 1.8%; ice, 0.6%; and others), and 55.9% have never tried them. Initially, drug craving at the first onset at the age of 14 in friend gatherings (15.7%) in stressful situations (11.2%), high-income families, particularly in joint family systems with paternal rejection, peer enforcement, and maladjustment had a higher risk than affectionate parents and conventional peers. Stepwise binary logistic regression analysis disclosed that age, socioeconomic status, father affection, hostility, rejection, negligence, peer influences, and psychosocial adjustment, mother hostility were independently associated with occasional drug cravings. CONCLUSION: Findings suggested the high prevalence of occasional drug cravings in Pakistani students in the capital territory. Furthermore, the demographic and other social and clinical aspects could be linked. This study carried out theoretical significance in understanding the predictors of occasional drug craving and psychological adjustment, highlighting the peer and parent's roles and the educational institutions.

The influence of patellar morphology on clinical outcomes after unicompartmental knee arthroplasty.

PURPOSE: To evaluate the influence of patellar morphology on functional outcomes and patellofemoral joint alignment after unicompartmental knee arthroplasty (UKA). METHODS: This study retrospectively analyzed the clinical and imaging data of 207 patients with osteoarthritis of the unicompartment of the knee who underwent UKA between September 2020 and April 2023. Patients were divided into three groups according to the Wiberg classification: group W1 (I, n = 47), group W2 (II, n = 117), and group W3 (III, n = 43). Knee function was assessed using the Hospital for Specialty Surgery (HSS) knee score and Feller patellar score, and the incidence of anterior knee pain after surgery was recorded and compared. Imaging parameters such as patellar tilt angle (PTA), lateral patellofemoral angle (LPA) and Insall-Salvati ratio (ISR) were measured to assess patellofemoral joint alignment. RESULTS: The HSS scores of the three groups were not statistically different; the postoperative Feller scores of the group W3 differed significantly from those of the other two groups. The incidence of early postoperative anterior knee pain was higher in the group W3 than in the other two groups. The difference between preoperative PTA, postoperative PTA and preoperative LPA in the group W3 and the other two groups was statistically significant. CONCLUSION: Patients with Wiberg III patellae exhibited worse patellar scores, as well as more anterior knee pain and patellar tilt postoperatively. This finding highlights the need for individualized treatment to the Wiberg III patella during UKA to enhance surgical outcomes.

Dynamic patterns of particulate matter concentration and size distribution in urban street canyons: insights into diurnal and short-term seasonal variations.

Time-varying characteristics of particulate matter (PM) pollution play a crucial role in shaping atmospheric dynamics, which impact the health and welfare of urban commuters. Previously published studies on the diurnal patterns of PMs are not consistent, especially in the context of field experiments in central China, and most field studies have only focused on particles with a single particle size. This study conducted regional-scale studies across 72 street canyon sets in Wuhan, China, investigated diurnal and seasonal PM concentration variations while also evaluating various PM size and the key driving factors. During summer (July, August, and September), evergreen tree-lined street canyons maintained a stable linear trend for smaller dp particulates (i.e., PM1, PM2.5, and PM4), while deciduous street canyons exhibited a bimodal distribution. In winter (January and February), fine particulates (i.e., PM1 and PM2.5) remained a linear trend in evergreen street canyons, while deciduous street canyons show a slightly wavy fluctuating pattern. Meanwhile, it exhibited quadrimodal-peak and triple-trough patterns in both PM7, PM10, and TSP concentrations. The lowest PM concentrations were observed between 14:00 and 16:00 for all particle sizes, with decreased summer pollution (7.81% lower in PM2.5, 53.47% lower in PM10, and 50.3% lower in TSP) noted in our seasonal analysis. Among the various meteorological factors, relative humidity (RH) was identified as the dominant influencing PM factor in both summer and winter. Results from this study will help us better understand field-based air pollutant dispersion processes within pedestrian spaces while laying the groundwork for future research into street PM experiments.

Sensitive detection of dipeptidyl peptidase based on DNA-peptide conjugates and double signal amplification of CHA and DNAzymes.

Dipeptidyl peptidase IV (DPPIV) is an enzyme belonging to the type II transmembrane serine protease family that has gained wide interest in the fields of hematology, immunology, and cancer biology. Moreover, DPPIV has emerged as a promising target for therapeutic intervention in type II diabetes. Due to its biological limitations, traditional strategies cannot meet the requirements of low abundance DPPIV analysis in complex environments. In this work, combining the high programmability of DNA and the chemical diversity of peptides, we designed DNA-peptide conjugates that can be specifically recognized, polypeptides as specific substrates for target DPPIV and DNA probes as primers for catalytic hairpin assembly (CHA), recycling a large amount of DNAzymes by triggering CHA amplification. The DNAzyme substrate modified with the FAM fluorescent group was immobilized on the surface of gold nanoparticles by S-Au chemical bonds to form a signal output probe. The DNAzymes enzyme cleaved the substrate of the signal outputs probe, yielding a double-amplified fluorescence signal. This method has a detection limit as low as 0.18 mU mL-1 and a linear range of 0-5 mU mL-1 in serum samples, showing high stability and good potential for practical applications.

The Innate Immune System and TRAIL-BCL-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females.

There is a significant sex-bias in lung cancer with males showing increased mortality compared to females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex-bias in humanized mice, with male patient-derived xenograft (PDX) lung tumors being more progressive and deadlier than female PDX lung tumors, we identified mouse tumor models of lung cancer with the same sex-bias. This sex-bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex-bias in growth and lethality required intact ovaries, functional innate natural killer (NK) cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anti-cancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-BCL-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the BCL-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer.

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). ß-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac ß-adrenoceptors (ßARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local ßAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different ßAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by ß1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced ß1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the ß1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with ß1AR were observed. Stimulating ß1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament ß1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Two-dimensional silk.

Despite the promise of silk-based devices, the inherent disorder of native silk limits performance. Here, we report highly ordered two-dimensional silk fibroin (SF) films grown epitaxially on van der Waals (vdW) substrates. Using atomic force microscopy, nano-Fourier transform infrared spectroscopy, and molecular dynamics, we show that the films consist of lamellae of SF molecules that exhibit the same secondary structure as the nanocrystallites of native silk. Increasing the SF concentration results in multilayers that grow either by direct assembly of SF molecules into the lamellae or, at high concentrations, along a two-step pathway beginning with a disordered monolayer that then crystallizes. Scanning Kelvin probe measurements show that these films substantially alter the surface potential; thus, they provide a platform for silk-based electronics on vdW solids.

Age-Disturbed Vascular Extracellular Matrix Links to Abdominal Aortic Aneurysms.

Abdominal aortic aneurysm (AAA) is a common but life-threatening vascular condition in men at an advanced age. However, the underlying mechanisms of age-increased incidence and mortality of AAA remain elusive. Here, we performed RNA sequencing (RNA-seq) of mouse aortas from males (young: 3-month, n = 4 vs old: 23-month, n = 4) and integrated with the data sets of human aortas (young: 20-39, n = 47 vs old: 60-79 years, n = 92) from GTEx project and the data set (GSE183464) for AAA to search for age-shifted aortic aneurysm genes, their relevant biological processes, and signaling pathways. Angiotensin II-induced AAA in mice was used to verify the critical findings. We found 1 001 genes transcriptionally changed with ages in both mouse and human. Most age-increased genes were enriched intracellularly and the relevant biological processes included mitochondrial function and translational controls, whereas the age-decreased genes were largely localized in extracellular regions and cell periphery and the involved biological processes were associated with extracellular matrix (ECM). Fifty-one were known genes for AAA and found dominantly in extracellular region. The common age-shifted vascular genes and known aortic aneurysm genes had shared functional influences on ECM organization, apoptosis, and angiogenesis. Aorta with angiotensin II-induced AAA exhibited similar phenotypic changes in ECM to that in old mice. Together, we present a conserved transcriptional signature for aortic aging and provide evidence that mitochondrial dysfunction and the imbalanced ribosomal homeostasis act likely as driven-forces for aortic aging and age-disturbed ECM is the substrate for developing AAA.

The combination of apatinib and antigen-specific DC-induced T cells exert antitumor effects by potently improving the immune microenvironment of osteosarcoma.

Objective: Osteosarcoma (OS) is the most common primary bone sarcoma with a high propensity for local invasion and metastasis. Although the antitumor effect of apatinib has been well confirmed in advanced OS, the synergistic effect of apatinib and immunotherapies has not yet been elucidated. Methods: In this study, we established tumour-bearing mice and observed tumour size with low and high doses of apatinib treatments. The expression of 17 cytokines, including vascular endothelial growth factor (VEGF), was detected by protein microarray analysis. Moreover, we designed apatinib and antigen-specific dendritic cell (DC)-T combination treatment for tumour-bearing mice. Tumour growth was detected by statistical analysis of tumour size and microvessel density (MVD) counting, the protein expression of VEGF by western blotting, the cytokines interleukin 6 (IL-6), IL-17 and interferon-gamma (IFN-γ) by enzyme-linked immunosorbent assay (ELISA), and the numbers of myeloid-derived suppressor cells (MDSCs) and tumour-infiltration macrophages (TAMs) by flow cytometry. Results: The results showed that apatinib efficiently suppressed tumour growth, and high-dose apatinib achieved a stronger effect. The same was true for DC-T immunotherapy. However, their combination treatment revealed a better oncolytic effect. Meanwhile, apatinib or DC-T treatment inhibited the expression of VEGF and the proangiogenic mediators IL-6 and IL-17 but increased IFN-γ production. Combination therapy further reduced/increased these effects. In addition, the combination treatment reduced MDSC but enhanced TAM-M1 ratios in the OS microenvironment. These findings indicated that apatinib and antigen-specific DC-T combination therapy was more efficient in oncolysis by regulating pro-/anti-angiogenic inducers and improving the immune state in the OS microenvironment. Conclusion: This study proved that it was feasible to employ immunotherapy with therapeutic agents in OS treatment, which may provide a new approach in addition to the combination of surgery with chemotherapy in tumour treatment.

Simultaneous detection of breast cancer biomarkers HER2 and miRNA-21 based on duplex-specific nuclease signal amplification.

The detection of a single biomarker is prone to false negative or false positive results. Simultaneous analysis of two biomarkers can greatly improve the accuracy of diagnosis. In this work, we designed a new method for coinstantaneous detection of two breast cancer biomarkers miRNA-21 and HER2 using the properties of duplex-specific nuclease (DSN). Cy5-labeled DNA1 and FAM-labeled DNA2 are used as signal probes to distinguish the two signals. When the sample contains the targets HER2 and miRNA-21, HER2 binds to the HER2 aptamer on the double-stranded DNA2, while miRNA-21 binds to the complementary DNA1. Then, DSN enzyme is added to cut the DNA probes adsorbed on the HER2 aptamer and miRNA-21, releasing the fluorescent groups, which can be readsorbed to the empty sites, thus repeating the cutting of the probes and producing an exponential signal amplification with two distinct fluorescent signals. The detection limits of miRNA-21 and HER2 are 1.12 pM and 0.36 ng mL-1, respectively, with linear ranges of 5 pM to 50 pM and 1 ng mL-1 to 15 ng mL-1. The method was validated in real biological samples, providing a new approach for synchronous analysis of important markers in breast cancer.

ADSCs encapsulated in Gelatin methacrylate substrate promotes the repair of peripheral nerve injury by SIRT6/PGC-1α pathway.

Peripheral nerve injury is a prevalent disease but the spontaneous recovery of nerve function is protracted and incomplete. Given the damaging of stem cells and fragile of intra-neural structures in the course of stem cell transplantation, our study tried to investigate whether encapsulating adipose derived mesenchymal stem cells (ADSCs) with GelMA could achieve better repair in peripheral nerve injury. PC-12 cells were cultured on the surface of GelMA encapsulating ADSCs and 3D co-culture system was constructed. CCK-8, Real-Time PCR, ELISA, Immunofluorescent Assay and Western Blot were used to evaluate the functionality of this system. Ultimately, nerve conduit containing the 3D co-culture system was linked between the two ends of an injured nerve. ADSCs encapsulated in 5% GeIMA had a better activity than 10% GeIMA. Furthermore, the viability of PC-12 cells was also better in this 3D co-culture system than in co-culture system with ADSCs without GeIMA. The expression of SIRT6 and PGC-1α in PC-12 cells were prominently promoted, and the entry to nuclear of PGC-1α was more obvious in this 3D co-culture system. After silencing of SIRT6, the protein expression level of PGC-1α was inhibited, and the activity of PC-12 cells was significantly reduced, suggesting that ADSCs encapsulated in GelMA upregulated the expression of SIRT6 to induce the level of PGC-1α protein, thereby achieving an impact on the activity of PC-12 cells. In vivo, nerve conduit containing the 3D co-culture system significantly promoted the repair of damaged peripheral nerves. In conclusion, our study demonstrated that 5% GelMA enhanced ADSCs activity, thereby promoting the activity of nerve cells and repair of damaged peripheral nerves by SIRT6/PGC-1α pathway.

Neurophysiological markers of disease severity and cognitive dysfunction in major depressive disorder: A TMS-EEG study.

Background: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) is a powerful technique to study the neuropathology and biomarkers of major depressive disorder (MDD). This study investigated cortical activity and its relationship with clinical symptoms and cognitive dysfunction in MDD patients by indexing TMS-EEG biomarkers in the dorsolateral prefrontal cortex (DLPFC). Methods: 133 patients with MDD and 76 healthy individuals participated in this study. Single-pulse TMS was performed on the left DLPFC to obtain TMS-evoked potential (TEP) indices. TMS-EEG waveforms and components were determined by global mean field amplitude. We used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to measure participants' cognitive function. Results: Patients with MDD had a lower excitatory P180 index compared to healthy controls, and P180 amplitude was negatively correlated with the severity of depressive and anxiety symptoms in patients with MDD. In the MDD group, P30 amplitude was negatively associated with RBANS Visuospatial/ Constructional index and total score. Conclusions: TMS-EEG findings suggest that abnormal cortical excitation and inhibition induced by TMS on the DLPFC are associated with the severity of clinical symptoms and cognitive dysfunction in patients with MDD. P180 and P30 have the potential to serve as neurophysiological biomarkers of clinical symptoms and cognitive dysfunction in MDD patients, respectively.

Molecular mechanisms of Buqing granule for the treatment of diabetic retinopathy: Network pharmacology analysis and experimental validation.

BACKGROUND: Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Its blindness rate is high; therefore, finding a reasonable and safe treatment plan to prevent and control DR is crucial. Currently, there are abundant and diverse research results on the treatment of DR by Chinese medicine Traditional Chinese medicine compounds are potentially advantageous for DR prevention and treatment because of its safe and effective therapeutic effects. AIM: To investigate the effects of Buqing granule (BQKL) on DR and its mechanism from a systemic perspective and at the molecular level by combining network pharmacology and in vivo experiments. METHODS: This study collected information on the drug targets of BQKL and the therapeutic targets of DR for intersecting target gene analysis and protein-protein interactions (PPI), identified various biological pathways related to DR treatment by BQKL through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and preliminarily validated the screened core targets by molecular docking. Furthermore, we constructed a diabetic rat model with a high-fat and high-sugar diet and intraperitoneal streptozotocin injection, and administered the appropriate drugs for 12 weeks after the model was successfully induced. Body mass and fasting blood glucose and lipid levels were measured, and pathological changes in retinal tissue were detected by hematoxylin and eosin staining. ELISA was used to detect the oxidative stress index expression in serum and retinal tissue, and immunohistochemistry, real-time quantitative reverse transcription PCR, and western blotting were used to verify the changes in the expression of core targets. RESULTS: Six potential therapeutic targets of BQKL for DR treatment, including Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3, were screened using PPI. Enrichment analysis indicated that the MAPK signaling pathway might be the core target pathway of BQKL in DR treatment. Molecular docking prediction indicated that BQKL stably bound to these core targets. In vivo experiments have shown that compared with those in the Control group, rats in the Model group had statistically significant (P < 0.05) severe retinal histopathological damage; elevated blood glucose, lipid, and malondialdehyde (MDA) levels; increased Caspase-3, c-Jun, and TP53 protein expression; and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, ganglion cell number, AKT1, MAPK1, and MAPK3 protein expression. Compared with the Model group, BQKL group had reduced histopathological retinal damage and the expression of blood glucose and lipids, MDA level, Caspase-3, c-Jun and TP53 proteins were reduced, while the expression of SOD, GSH-Px level, the number of ganglion cells, AKT1, MAPK1, and MAPK3 proteins were elevated. These differences were statistically significant (P < 0.05). CONCLUSION: BQKL can delay DR onset and progression by attenuating oxidative stress and inflammatory responses and regulating Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3 proteins in the MAPK signaling pathway mediates these alterations.

How to safeguard the continuous renal replacement therapy circuit: a narrative review.

The high prevalence of acute kidney injury (AKI) in ICU patients emphasizes the need to understand factors influencing continuous renal replacement therapy (CRRT) circuit lifespan for optimal outcomes. This review examines key pharmacological interventions-citrate (especially in regional citrate anticoagulation), unfractionated heparin (UFH), low molecular weight heparin (LMWH), and nafamostat mesylate (NM)-and their effects on filter longevity. Citrate shows efficacy with lower bleeding risks, while UFH remains cost-effective, particularly in COVID-19 cases. LMWH is effective but associated with higher bleeding risks. NM is promising for high-bleeding risk scenarios. The review advocates for non-tunneled, non-cuffed temporary catheters, especially bedside-inserted ones, and discusses the advantages of surface-modified dual-lumen catheters. Material composition, such as polysulfone membranes, impacts filter lifespan. The choice of treatment modality, such as Continuous Veno-Venous Hemodialysis (CVVHD) or Continuous Veno-Venous Hemofiltration with Dialysis (CVVHDF), along with the management of effluent volume, blood flow rates, and downtime, are critical in prolonging filter longevity in CRRT. Patient-specific conditions, particularly the type of underlying disease, and the implementation of early mobilization strategies during CRRT are identified as influential factors that can extend the lifespan of CRRT filters. In conclusion, this review offers insights into factors influencing CRRT circuit longevity, supporting evidence-based practices and suggesting further multicenter studies to guide ICU clinical decisions.