miR-125b-5p delivered by adipose-derived stem cell exosomes alleviates hypertrophic scarring by suppressing Smad2.

Background: Hypertrophic scarring is the most serious and unmet challenge following burn and trauma injury and often leads to pain, itching and even loss of function. However, the demand for ideal scar prevention and treatment is difficult to satisfy. We aimed to discover the effects and mechanisms of adipose-derived stem cell (ADSC) exosomes in hypertrophic scarring. Methods: ADSC exosomes were isolated from the culture supernatant of ADSCs and identified by nanoparticle tracking analysis, transmission electron microscopy and western blotting. The effect of ADSC exosomes on wound healing and scar formation was detected by the wound model of BALB/c mice. We isolated myofibroblasts from hypertrophic scar tissue and detected the cell viability, proliferation and migration of myofibroblasts. In addition, collagen formation and fibrosis-related molecules were also detected. To further disclose the mechanism of ADSC exosomes on fibrosis in myofibroblasts, we detected the expression of Smad2 in hypertrophic scar tissue and normal skin and the regulatory mechanism of ADSC exosomes on Smad2. Injection of bleomycin was performed in male BALB/c mice to establish an in vivo fibrosis model while ADSC exosomes were administered to observe their protective effect. The tissue injury of mice was observed via hematoxylin and eosin and Masson staining and related testing. Results: In this study, we found that ADSC exosomes could not only speed up wound healing and improve healing quality but also prevent scar formation. ADSC exosomes inhibited expression of fibrosis-related molecules such as α-smooth muscle actin, collagen I (COL1) and COL3 and inhibited the transdifferentiation of myofibroblasts. In addition, we verified that Smad2 is highly expressed in both hypertrophic scar tissue and hypertrophic fibroblasts, while ADSC exosomes downregulated the expression of Smad2 in hypertrophic fibroblasts. Further regulatory mechanism analysis revealed that microRNA-125b-5p (miR-125b-5p) is highly expressed in ADSC exosomes and binds to the 3' untranslated region of Smad2, thus inhibiting its expression. In vivo experiments also revealed that ADSC exosomes could alleviate bleomycin-induced skin fibrosis and downregulate the expression of Smad2. Conclusions: We found that ADSC exosomes could alleviate hypertrophic scars via the suppression of Smad2 by the specific delivery of miR-125b-5p.

Imidazole functionalized photo-crosslinked aliphatic polycarbonate drug-eluting coatings on zinc alloys for osteogenesis, angiogenesis, and bacteriostasis in bone regeneration.

Zinc (Zn) alloys have demonstrated significant potential in healing critical-sized bone defects. However, the clinical application of Zn alloys implants is still hindered by challenges including excessive release of zinc ions (Zn2+), particularly in the early stage of implantation, and absence of bio-functions related to complex bone repair processes. Herein, a biodegradable aliphatic polycarbonate drug-eluting coating was fabricated on zinc-lithium (Zn-Li) alloys to inhibit Zn2+ release and enhance the osteogenesis, angiogenesis, and bacteriostasis of Zn alloys. Specifically, the photo-curable aliphatic polycarbonates were co-assembled with simvastatin and deposited onto Zn alloys to produce a drug-loaded coating, which was crosslinked by subsequent UV light irradiation. During the 60 days long-term immersion test, the coating showed distinguished stable drug release and Zn2+ release inhibition properties. Benefiting from the regulated release of Zn2+ and simvastatin, the coating facilitated the adhesion, proliferation, and differentiation of MC3T3-E1 cells, as well as the migration and tube formation of EA.hy926 cells. Astonishingly, the coating also showed remarkable antibacterial properties against both S. aureus and E. coli. The in vivo rabbit critical-size femur bone defects model demonstrated that the drug-eluting coating could efficiently promote new bone formation and the expression of platelet endothelial cell adhesion molecule-1 (CD31) and osteocalcin (OCN). The enhancement of osteogenesis, angiogenesis, and bacteriostasis is achieved by precisely controlling of the released Zn2+ at an appropriate level, as well as the stable release profile of simvastatin. This tailored aliphatic polycarbonate drug-eluting coating provides significant potential for clinical applications of Zn alloys implants.

TUBB, a robust biomarker with satisfying abilities in diagnosis, prognosis, and immune regulation via a comprehensive pan-cancer analysis.

Purpose: TUBB can encode a beta-tubulin protein. At present, the role of TUBB has not been ascertained in cancers. Hence, the importance of further systematic pan-cancer analyses is stressed to explore its value in the diagnosis, prognosis, and immune function of cancers. Methods: By collecting and handling integrative data from the TCGA, Firehose, UCSC Xena, cBioPortal, GEO, CPTAC, TIMER2.0, TISCH, CellMiner, GDSC, and CTRP databases, we explored the potential diagnostic and prognostic roles of TUBB in pan-cancers from multiple angles. Moreover, the GSEA analysis was conducted to excavate the biological functions of TUBB in pan-cancers. In addition, survival profiles were described, and the differential expressions of TUBB in different molecular subtypes were discussed. Also, we utilized the cMAP function to search drugs or micro-molecules that have an impact on TUBB expressions. Results: Based on the TCGA data, we found that TUBB was differentially expressed in a variety of tumors and showed an early-diagnostic value. Mutations, somatic copy number alterations, and DNA methylation would lead to its abnormal expression. TUBB expressions had relations with many clinical features. What's more, TUBB expressions were validated to be related to many metabolism-related, metastasis-related, and immune-related pathways. High TUBB expressions were proved to have a great impact on the prognosis of various types of cancers and would affect the sensitivity of some drugs. We also demonstrated that the expression of TUBB was significantly correlated to immunoregulator molecules and biomarkers of lymphocyte subpopulation infiltration. Conclusion: TUBB and its regulatory genes were systemically analyzed in this study, showing that TUBB had satisfying performances in disease diagnosing and prognosis predicting of multiple cancers. It could remodel the tumor microenvironment and play an integral role in guiding cancer therapies and forecasting responses to chemotherapy.

Mesoporous silica nanoparticles as a drug delivery mechanism.

Research in intelligent drug delivery systems within the field of biomedicine promises to enhance drug efficacy at disease sites and reduce associated side effects. Mesoporous silica nanoparticles (MSNs), characterized by their large specific surface area, appropriate pore size, and excellent biocompatibility, have garnered significant attention as one of the most effective carriers for drug delivery. The hydroxyl groups on their surface are active functional groups, facilitating easy functionalization. The installation of controllable molecular machines on the surface of mesoporous silica to construct nanovalves represents a crucial advancement in developing intelligent drug delivery systems (DDSs) and addressing the issue of premature drug release. In this review, we compile several notable and illustrative examples of MSNs and discuss their varied applications in DDSs. These applications span regulated and progressive drug release mechanisms. MSNs hold the potential to enhance drug solubility, improve drug stability, and mitigate drug toxicity, attributable to their ease of functionalization. Furthermore, intelligent hybrid nanomaterials are being developed, featuring programmable properties that react to a broad spectrum of stimuli, including light, pH, enzymes, and redox triggers, through the use of molecular and supramolecular switches.

Emerging contaminants: A One Health perspective.

Environmental pollution is escalating due to rapid global development that often prioritizes human needs over planetary health. Despite global efforts to mitigate legacy pollutants, the continuous introduction of new substances remains a major threat to both people and the planet. In response, global initiatives are focusing on risk assessment and regulation of emerging contaminants, as demonstrated by the ongoing efforts to establish the UN's Intergovernmental Science-Policy Panel on Chemicals, Waste, and Pollution Prevention. This review identifies the sources and impacts of emerging contaminants on planetary health, emphasizing the importance of adopting a One Health approach. Strategies for monitoring and addressing these pollutants are discussed, underscoring the need for robust and socially equitable environmental policies at both regional and international levels. Urgent actions are needed to transition toward sustainable pollution management practices to safeguard our planet for future generations.

Research progress in Alzheimer's disease and bone-brain axis.

Alzheimer's disease (AD) is the most common type of cognitive impairment. AD is closely related to orthopedic diseases, such as osteoporosis and osteoarthritis, in terms of epidemiology and pathogenesis. Brain and bone tissues can regulate each other in different manners through bone-brain axis. This article reviews the research progress of the relationship between AD and orthopedic diseases, bone-brain axis mechanisms of AD, and AD therapy by targeting bone-brain axis, in order to deepen the understanding of bone-brain communication, promote early diagnosis and explore new therapy for AD patients. Keywords.

Epidemiological characteristics of tuberculosis incidence and its macro-influence factors in Chinese mainland during 2014-2021.

BACKGROUND: Tuberculosis (TB) remains a pressing public health issue, posing a significant threat to individuals' well-being and lives. This study delves into the TB incidence in Chinese mainland during 2014-2021, aiming to gain deeper insights into their epidemiological characteristics and explore macro-level factors to enhance control and prevention. METHODS: TB incidence data in Chinese mainland from 2014 to 2021 were sourced from the National Notifiable Disease Reporting System (NNDRS). A two-stage distributed lag nonlinear model (DLNM) was constructed to evaluate the lag and non-linearity of daily average temperature (℃, Atemp), average relative humidity (%, ARH), average wind speed (m/s, AWS), sunshine duration (h, SD) and precipitation (mm, PRE) on the TB incidence. A spatial panel data model was used to assess the impact of demographic, medical and health resource, and economic factors on TB incidence. RESULTS: A total of 6,587,439 TB cases were reported in Chinese mainland during 2014-2021, with an average annual incidence rate of 59.17/100,000. The TB incidence decreased from 67.05/100,000 in 2014 to 46.40/100,000 in 2021, notably declining from 2018 to 2021 (APC = -8.87%, 95% CI: -11.97, -6.85%). TB incidence rates were higher among males, farmers, and individuals aged 65 years and older. Spatiotemporal analysis revealed a significant cluster in Xinjiang, Qinghai, and Xizang from March 2017 to June 2019 (RR = 3.94, P < 0.001). From 2014 to 2021, the proportion of etiologically confirmed cases increased from 31.31% to 56.98%, and the time interval from TB onset to diagnosis shortened from 26 days (IQR: 10-56 days) to 19 days (IQR: 7-44 days). Specific meteorological conditions, including low temperature (< 16.69℃), high relative humidity (> 71.73%), low sunshine duration (< 6.18 h) increased the risk of TB incidence, while extreme low wind speed (< 2.79 m/s) decreased the risk. The spatial Durbin model showed positive associations between TB incidence rates and sex ratio (ß = 1.98), number of beds in medical and health institutions per 10,000 population (ß = 0.90), and total health expenses (ß = 0.55). There were negative associations between TB incidence rates and population (ß = -1.14), population density (ß = -0.19), urbanization rate (ß = -0.62), number of medical and health institutions (ß = -0.23), and number of health technicians per 10,000 population (ß = -0.70). CONCLUSIONS: Significant progress has been made in TB control and prevention in China, but challenges persist among some populations and areas. Varied relationships were observed between TB incidence and factors from meteorological, demographic, medical and health resource, and economic aspects. These findings underscore the importance of ongoing efforts to strengthen TB control and implement digital/intelligent surveillance for early risk detection and comprehensive interventions.

Promoting Oxygen Evolution Electrocatalysis by Coordination Engineering in Cobalt Phosphate.

Understanding the structure-activity correlation is an important prerequisite for the rational design of high-efficiency electrocatalysts at the atomic level. However, the effect of coordination environment on electrocatalytic oxygen evolution reaction (OER) remains enigmatic. In this work, the regulation of proton transfer involved in water oxidation by coordination engineering based on Co3(PO4)2 and CoHPO4 is reported. The HPO4 2- anion has intermediate pKa value between Co(II)-H2O and Co(III)-H2O to be served as an appealing proton-coupled electron transfer (PCET) induction group. From theoretical calculations, the pH-dependent OER properties, deuterium kinetic isotope effects, operando electrochemical impedance spectroscopy (EIS) and Raman studies, the CoHPO4 catalyst beneficially reduces the energy barrier of proton hopping and modulates the formation energy of high-valent Co species, thereby enhancing OER activity. This work demonstrates a promising strategy that involves tuning the local coordination environment to optimize PCET steps and electrocatalytic activities for electrochemical applications. In addition, the designed system offers a motif to understand the structure-efficiency relationship from those amino-acid residue with proton buffer ability in natural photosynthesis.

Continuous quality improvement project to reduce the downtime of medical linear accelerators: A case study at Zhejiang Cancer Hospital.

Objective: To analyse and continually improve existing issues in the quality improvement process of medical linear accelerators (LINACs) and enhance the quality control management of LINACs. Methods: Data were collected from eight LINACs (sourced from three manufacturers) at Zhejiang Cancer Hospital using Excel diaries between January 2019 and December 2020. The data description and analysis were performed using the analytic hierarchy process, SPSSAU and Excel software, and mean-time-to-repair (MTTR)/mean-time-between-failure (MTBF) metrics. Continuous quality improvement was executed using the quality control circle (QCC) quality management method. Results: After quality improvement, the risk frequency of 'LINAC down' events decreased by 43.63% and downtime was reduced by 40.45%. The weight of downtime risk improved by 73.69%. The MTTR recovery value increased by 31.90%, and MTBF reliability increased by 2.97 h. The simulation results demonstrated that the proposed quality improvement measures could effectively decrease the frequency and duration of downtimes, consequently extending the normal operational time of LINACs. Conclusion: Transitioning from instant repair to preventative maintenance can enhance the operational efficiency of equipment and yield economic benefits for hospitals. The QCC method and the event risk evaluation model are effective in reducing the downtime of LINACs and improving their quality control management.

Accuracy of the OMRON HEM-7361T blood pressure monitor in the differentiation between atrial fibrillation and sinus rhythm.

OBJECTIVE: We investigated the accuracy of the OMRON HEM-7361T automated oscillometric blood pressure (BP) monitor in the differentiation between atrial fibrillation and sinus rhythm. METHODS: An approximately equal number of patients with persistent atrial fibrillation and individuals with sinus rhythm were recruited from outpatients and inpatients of Ruijin Hospital, Shanghai, China. BP was measured three times consecutively with a 30-s interval with the OMRON HEM-7361T automatic electronic BP monitor for atrial fibrillation detection. A hand-held single lead electrocardiogram device was used for simultaneous electrocardiogram recordings. RESULTS: The device accurately identified atrial fibrillation in 100 (99.0%) of the 101 patients, with only 1 patient incorrectly classified as non-atrial fibrillation. The device correctly identified 99 (95.2%) of the 104 participants with sinus rhythm as non-atrial fibrillation, with five participants incorrectly classified as atrial fibrillation. The device had a positive predictive value of 95.2%, negative predictive value of 99.0%, and overall accuracy of 97.1%. Among the six misclassified participants, one with atrial fibrillation had a heart rate of 65 beats/min, and four of the five participants with sinus rhythm had cardiac arrhythmias (atrial or ventricular premature beat in one participants, sinus tachycardia in one participant, and both arrhythmias in one participant). CONCLUSION: The OMRON HEM-7361T BP monitor is accurate in the differentiation between atrial fibrillation and sinus rhythm. Whether the device is sufficiently accurate in the differentiation between atrial fibrillation and other cardiac arrhythmias remains under investigation.

Improved Preservation of Mouse Intestinal Tissue Using a Formalin/Acetic Acid Fixative and Quantitative Histological Analysis Using QuPath.

The architecture and morphology of the intestinal tissue from mice or other small animals are difficult to preserve for histological and molecular analysis due to the fragile nature of this tissue. The intestinal mucosa consists of villi and crypts lined with epithelial cells. In between the epithelial folds extends the lamina propria, a loose connective tissue that contains blood and lymph vessels, fibroblasts, and immune cells. Underneath the mucosa are two layers of contractile smooth muscle and nerves. The tissue experiences significant changes during fixation, which can impair the reliability of histologic analysis. Poor-quality histologic sections are not suitable for quantitative image-based tissue analysis. This article offers a new fixative composed of neutral buffered formalin (NBF) and acetic acid, called FA. This fixative significantly improved the histology of mouse intestinal tissue compared to traditional NBF and enabled precise, reproducible histologic molecular analyses using QuPath software. Algorithmic training of QuPath allows for automated segmentation of intestinal compartments, which can be further interrogated for cellular composition and disease-related changes. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Improved preservation of mouse intestinal tissue using a formalin/acetic acid fixative Support Protocol: Quantitative tissue analysis using QuPath.

Optimization of machine tool settings for Spirac hypoid gears by controlling symmetry of contact paths.

A novel optimization method to control the symmetry of contact paths on the concave and convex tooth surfaces of the gear then improves the meshing quality was proposed. By modifying the angular setting of the head cutter when cutting the pinion, the direction angles of the two contact paths are equated to estimate their symmetry. The relation between the direction angles is formulated precisely, the influence of the angular setting on the contact paths is investigated, and the equations for obtaining the values of the machine tool settings are derived. The proposed method is applied to a numerical example of a Spirac hypoid gear pair, and the results reveal that the contact paths on the concave and convex tooth surfaces are approximately symmetrical and the transmission errors of both sides are comparable.

Controlling the Orientation-Dependent Second Harmonic Generation in Hybrid Germanium Perovskite Crystals.

Manipulating the crystal orientation plays a crucial role in the conversion efficiency during second harmonic generation (SHG). Here, we provide a new strategy in controlling the surface-dependent anisotropic SHG with the precise design of (101) and (20) MAGeI3 facets. Based on the SHG measurement, the (101) MAGeI3 single crystal exhibits larger SHG (1.3 × (20) MAGeI3). Kelvin probe force microscopy imaging shows a smaller work function for the (101) MAGeI3 compared with the (20), which indirectly demonstrates the stronger intrinsic polarization on the (101) surface. X-ray photoelectron spectroscopy confirms the band bending within the (101) facet. Temperature-dependent steady-state and time-resolved photoluminescence spectroscopy show shorter lifetime and wider emission band in the (101) MAGeI3 single crystal, revealing the higher defect states. Additionally, powder X-ray diffraction patterns show the (101) MAGeI3 possesses larger in-plane polar units [GeI3]- density, which could directly enhance the spontaneous polarization in the (101) facet. Density functional theory (DFT) calculation further demonstrates the higher intrinsic polarization in the (101) facet compared with the (20) facet, and the larger built-in electric field in the (101) facet facilitates surface vacancy defect accumulation. Our work provides a new angle in tuning and optimizing hybrid perovskite-based nonlinear optical materials.

The relationship between physical activity and Internet addiction among adolescents in western China: a chain mediating model of anxiety and inhibitory control.

This study aims to investigate the mediating effect of anxiety and inhibitory control in the relationship between physical activity and Internet addiction (IA) among adolescents. A total of 951 adolescents from western China completed a self-report survey assessing physical activity, anxiety, inhibitory control, and IA. Descriptive analysis, correlation analysis, and mediation analysis were conducted using SPSS software and the Process plug-in. Controlling for age, gender, and only child status, the findings revealed a negative association between physical activity and anxiety, inhibitory control, and IA. Moreover, anxiety were positively correlated with inhibitory control and IA. Additionally, anxiety exhibited a positive association with inhibitory control. Notably, physical activity directly and negatively predicted IA in adolescents, while also indirectly predicting it through anxiety and inhibitory control. This study contributes to a deeper understanding of the mechanisms that underlie the complex effects of physical activity on IA among adolescents.

Improving Thermal Stability of High-Efficiency Methylammonium-Free Perovskite Solar Cells via Chloride Additive Engineering.

Tin dioxide (SnO2), in perovskite solar cells (PSCs), stands out as the material most suited to the electron transport layer (ETL), yielding advantages with regard to ease of preparation, high mobility, and favorable energy level alignment. Nonetheless, there is a chance that energy losses from defects in the SnO2 and interface will result in a reduction in the Voc. Consequently, optimizing the interfaces within solar cell devices is a key to augmenting both the efficiency and the stability of PSCs. Herein this present study, we introduced butylammonium chloride (BACl) into the SnO2 ETL. The resulting optimized SnO2 film mitigated interface defect density, thereby improving charge extraction. The robust bonding capability of negatively charged Cl- ions facilitated their binding with noncoordinated Sn4+ ions, effectively passivating defects associated with oxygen vacancies and enhancing charge transport within the SnO2 ETL. Concurrently, doped BA+ and Cl- diffused into the perovskite lattice, fostering perovskite grain growth and reducing the defects in perovskite. In comparison to the control device, the Voc saw a 70 mV increase, achieving a champion efficiency of 22.86%. Additionally, following 1000 h of ambient storage, the unencapsulated device based on SnO2 preburied with BACl retained around 90% of its initial photovoltaic conversion efficiency.

Pseudomonas aeruginosa two-component system LadS/PA0034 regulates macrophage phagocytosis via fimbrial protein cupA1.

Pseudomonas aeruginosa is one of the most common nosocomial pathogens worldwide, known for its virulence, drug resistance, and elaborate sensor-response network. The primary challenge encountered by pathogens during the initial stages of infection is the immune clearance arising from the host. The resident macrophages of barrier organs serve as the frontline defense against these pathogens. Central to our understanding is the mechanism by which bacteria modify their behavior to circumvent macrophage-mediated clearance, ensuring their persistence and colonization. To successfully evade macrophage-mediated phagocytosis, bacteria must possess an adaptive response mechanism. Two-component systems provide bacteria the agility to navigate diverse environmental challenges, translating external stimuli into cellular adaptive responses. Here, we report that the well-documented histidine kinase, LadS, coupled to a cognate two-component response regulator, PA0034, governs the expression of a vital adhesin called chaperone-usher pathway pilus cupA. The LadS/PA0034 system is susceptible to interference from the reactive oxygen species likely to be produced by macrophages and further lead to a poor adhesive phenotype with scantily cupA pilus, impairing the phagocytosis efficiency of macrophages during acute infection. This dynamic underscores the intriguing interplay: as macrophages deploy reactive oxygen species to combat bacterial invasion, the bacteria recalibrate their exterior to elude these defenses. IMPORTANCE: The notoriety of Pseudomonas aeruginosa is underscored by its virulence, drug resistance, and elaborate sensor-response network. Yet, the mechanisms by which P. aeruginosa maneuvers to escape phagocytosis during acute infections remain elusive. This study pinpoints a two-component response regulator, PA0034, coupled with the histidine kinase LadS, and responds to macrophage-derived reactive oxygen species. The macrophage-derived reactive oxygen species can impair the LadS/PA0034 system, resulting in reduced expression of cupA pilus in the exterior of P. aeruginosa. Since the cupA pilus is an important adhesin of P. aeruginosa, its deficiency reduces bacterial adhesion and changes their behavior to adopt a planktonic lifestyle, subsequently inhibiting the phagocytosis of macrophages by interfering with bacterial adhesion. Briefly, reactive oxygen species may act as environmental cues for the LadS/PA0034 system. Upon recognition, P. aeruginosa may transition to a poorly adhesive state, efficiently avoiding engulfment by macrophages.

Biodegradation of ochratoxin A by Brevundimonas diminuta HAU429: Characterized performance, toxicity evaluation and functional enzymes.

Ochratoxin A (OTA) is a notorious mycotoxin commonly contaminating food products worldwide. In this study, an OTA-degrading strain Brevundimonas diminuta HAU429 was isolated by using hippuryl-L-phenylalanine as the sole carbon source. The biodegradation of OTA by strain HAU429 was a synergistic effect of intracellular and extracellular enzymes, which transformed OTA into ochratoxin α (OTα) through peptide bond cleavage. Cytotoxicity tests and cell metabolomics confirmed that the transformation of OTA into OTα resulted in the detoxification of its hepatotoxicity since OTA but not OTα disturbed redox homeostasis and induced oxidative damage to hepatocytes. Genome mining identified nine OTA hydrolase candidates in strain HAU429. They were heterologously expressed in Escherichia coli, and three novel amidohydrolase BT6, BT7 and BT9 were found to display OTA-hydrolyzing activity. BT6, BT7 and BT9 showed less than 45 % sequence identity with previously identified OTA-degrading amidohydrolases. BT6 and BT7 shared 60.9 % amino acid sequence identity, and exhibited much higher activity towards OTA than BT9. BT6 and BT7 could completely degrade 1 µg mL-1 of OTA within 1 h and 50 min, while BT9 hydrolyzed 100 % of OTA in the reaction mixture by 12 h. BT6 was the most thermostable retaining 38 % of activity after incubation at 70 °C for 10 min, while BT7 displayed the highest tolerance to ethanal remaining 76 % of activity in the presence of 6 % ethanol. This study could provide new insights towards microbial OTA degradation and promote the development of enzyme-catalyzed OTA detoxification during food processing.

Therapeutic efficacy of a K5-specific phage and depolymerase against Klebsiella pneumoniae in a mouse model of infection.

Klebsiella pneumoniae has become one of the most intractable gram-negative pathogens infecting humans and animals due to its severe antibiotic resistance. Bacteriophages and protein products derived from them are receiving increasing amounts of attention as potential alternatives to antibiotics. In this study, we isolated and investigated the characteristics of a new lytic phage, P1011, which lyses K5 K. pneumoniae specifically among 26 serotypes. The K5-specific capsular polysaccharide-degrading depolymerase dep1011 was identified and expressed. By establishing murine infection models using bovine strain B16 (capable of supporting phage proliferation) and human strain KP181 (incapable of sustaining phage expansion), we explored the safety and efficacy of phage and dep1011 treatments against K5 K. pneumoniae. Phage P1011 resulted in a 60% survival rate of the mice challenged with K. pneumoniae supporting phage multiplication, concurrently lowering the bacterial burden in their blood, liver, and lungs. Unexpectedly, even when confronted with bacteria impervious to phage multiplication, phage therapy markedly decreased the number of viable organisms. The protective efficacy of the depolymerase was significantly better than that of the phage. The depolymerase achieved 100% survival in both treatment groups regardless of phage propagation compatibility. These findings indicated that P1011 and dep1011 might be used as potential antibacterial agents to control K5 K. pneumoniae infection.

A rapid and simple non-radioactive assay for measuring uptake by solute carrier transporters.

Introduction: Solute carrier (SLC) transport proteins play a crucial role in maintaining cellular nutrient and metabolite homeostasis and are implicated in various human diseases, making them potential targets for therapeutic interventions. However, the study of SLCs has been limited due to the lack of suitable tools, particularly cell-based substrate uptake assays, necessary for understanding their biological functions and for drug discovery purposes. Methods: In this study, a cell-based uptake assay was developed using a stable isotope-labeled compound as the substrate for SLCs, with detection facilitated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay aimed to address the limitations of existing assays, such as reliance on hazardous radiolabeled substrates and limited availability of fluorescent biosensors. Results: The developed assay was successfully applied to detect substrate uptakes by two specific SLCs: L-type amino acid transporter 1 (LAT1) and sodium taurocholate co-transporting polypeptide (NTCP). Importantly, the assay demonstrated comparable results to the radioactive method, indicating its reliability and accuracy. Furthermore, the assay was utilized to screen for novel inhibitors of NTCP, leading to the identification of a potential NTCP inhibitor compound. Discussion: The findings highlight the utility of the developed cell-based uptake assay as a rapid, simple, and environmentally friendly tool for investigating SLCs' biological roles and for drug discovery purposes. This assay offers a safer alternative to traditional methods and has the potential to contribute significantly to advancing our understanding of SLC function and identifying therapeutic agents targeting SLC-mediated pathways.

A nomogram based on neuron-specific enolase and substantia nigra hyperechogenicity for identifying cognitive impairment in Parkinson's disease.

Background: One in four individuals with Parkinson's disease (PD) experience cognitive impairment (CI). However, few practical models integrating clinical and neuroimaging biomarkers have been developed to address CI in PD. This study aimed to evaluate the correlation between circulating neuron-specific enolase (NSE) levels, substantia nigra hyperechogenicity (SNH), and cognitive function in PD and to develop a nomogram based on clinical and neuroimaging biomarkers for predicting CI in patients with PD. Methods: A total of 385 patients with PD who underwent transcranial sonography (TCS) from January 2021 to December 2022 at Beijing Tiantan Hospital, Capital Medical University, were recruited as the training cohort. For validation, 165 patients with PD treated from January 2023 to December 2023 were enrolled. Data for SNH, plasma NSE, and other clinical measures were collected, and cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Logistic regression analysis was employed to select potential risk factors and establish a nomogram. The receiver operating characteristic curve and calibration curve were generated to evaluate the performance of the nomogram. Results: Patients with PD exhibiting CI displayed advanced age, elevated Unified PD Rating Scale-III (UPDRS-III) score, an increased percentage of SNH, higher levels of plasma NSE and homocysteine (Hcy), a larger SNH area, and lower education levels compared to PD patients without CI. Gender [odds ratio (OR) =0.561, 95% confidence interval (CI): 0.330-0.954, P=0.03], age (OR =1.039; 95% CI: 1.011-1.066; P=0.005), education level (OR =0.892; 95% CI: 0.842-0.954; P<0.001), UPDRS-III scores (OR =1.026; 95% CI: 1.009-1.043; P=0.003), plasma NSE concentration (OR =1.562; 95% CI: 1.374-1.776; P<0.001), and SNH (OR =0.545; 95% CI: 0.330-0.902; P=0.02) were independent predictors of CI in patients with PD. A nomogram developed using these six factors yielded a moderate discrimination performance with an area under the curve (AUC) of 0.823 (95% CI 0.781-0.864; P<0.001). The calibration curve demonstrated acceptable agreement between predicted outcomes and actual values. Validation further confirmed the reliability of the nomogram, with an AUC of 0.864 (95% CI: 0.805-0.922; P<0.001). Conclusions: The level of NSE in plasma and the SNH assessed by TCS are associated with CI in patients with PD. The proposed nomogram has the potential to facilitate the detection of cognitive decline in individuals with PD.