Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on cuproptosis-related genes through bioinformatics analysis and machine learning.

Background and aims: Cuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI). Methods: The datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes. Results: Seventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues. Conclusion: Our findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1ß-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

Physiology education in China: the current situation and changes over the past 3 decades.

OBJECTIVE: As an experimental biological science, physiology has been taught as an integral component of medical curricula for a long time in China. The teaching effectiveness of physiology courses will directly affect students' learning of other medical disciplines. The purpose of this study is to investigate the current situation and changes in physiology teaching over 30 years in Chinese medical schools. METHODS: National survey was conducted online on the platform SoJump via WeChat and the web. The head of the physiology department in medical school was asked to indicate the information of physiology education from three periods: 1991-2000, 2001-2010, and 2011-2020. The responses of 80 leaders of the Department of Physiology from mainland Chinese medical schools were included in the study for analysis. RESULTS: The survey showed that the class hours, both of theory and practice, had been decreased. During the past 20 years, the total number of physiology teachers, the number of physiology teachers who had been educated in medical schools, and the number of technicians had been reduced, whereas teachers with doctor's degrees had been increased. In addition to traditional didactic teaching, new teaching approaches, including problem-based learning/case-based learning/team-based learning, integrated curriculum and formative evaluation systems, had been employed, mostly for more than 5 years, in some medical schools. CONCLUSION: The present study has provided historical data regarding the current status of physiology education in China and that in the past thirty years by showing that physiology education in China has developed quickly,even it faces many challenges.

CYP3A Mediates an Unusual C(sp2)-C(sp3) Bond Cleavage via Ipso-Addition of Oxygen in Drug Metabolism.

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon-carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H2 18O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) site of N-protected pyridin-2-amines, and the other occurs by a pseudo-retro-aldol reaction after hydroxylation of a C(sp3) site. This is the first report of CYP3A-mediated C-C bond cleavage in drug metabolism via ipso-addition of oxygen mediated mechanism. CYP3A-mediated ipso-addition is also implicated in the regioselective C-C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A-catalyzed oxygen ipso-addition under environmentally friendly conditions may be attractive and inspire biomimetic or P450-engineering methods to address the challenging task of C-C bond cleavages.

Lymph node metastasis prediction and biological pathway associations underlying DCE-MRI deep learning radiomics in invasive breast cancer.

BACKGROUND: The relationship between the biological pathways related to deep learning radiomics (DLR) and lymph node metastasis (LNM) of breast cancer is still poorly understood. This study explored the value of DLR based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in LNM of invasive breast cancer. It also analyzed the biological significance of DLR phenotype based on genomics. METHODS: Two cohorts from the Cancer Imaging Archive project were used, one as the training cohort (TCGA-Breast, n = 88) and one as the validation cohort (Breast-MRI-NACT Pilot, n = 57). Radiomics and deep learning features were extracted from preoperative DCE-MRI. After dual selection by principal components analysis (PCA) and relief methods, radiomics and deep learning models for predicting LNM were constructed by the random forest (RF) method. A post-fusion strategy was used to construct the DLR nomograms (DLRNs) for predicting LNM. The performance of the models was evaluated using the receiver operating characteristic (ROC) curve and Delong test. In the training cohort, transcriptome data were downloaded from the UCSC Xena online database, and biological pathways related to the DLR phenotypes were identified. Finally, hub genes were identified to obtain DLR gene expression (RadDeepGene) scores. RESULTS: DLRNs were based on area under curve (AUC) evaluation (training cohort, AUC = 0.98; validation cohort, AUC = 0.87), which were higher than single radiomics models or GoogLeNet models. The Delong test (radiomics model, P = 0.04; GoogLeNet model, P = 0.01) also validated the above results in the training cohorts, but they were not statistically significant in the validation cohort. The GoogLeNet phenotypes were related to multiple classical tumor signaling pathways, characterizing the biological significance of immune response, signal transduction, and cell death. In all, 20 genes related to GoogLeNet phenotypes were identified, and the RadDeepGene score represented a high risk of LNM (odd ratio = 164.00, P < 0.001). CONCLUSIONS: DLRNs combining radiomics and deep learning features of DCE-MRI images improved the preoperative prediction of LNM in breast cancer, and the potential biological characteristics of DLRN were identified through genomics.

Ultra-high piezoelectric properties and ultra-high Curie temperature of Li/Ce-doped La2Ti2O7 ceramics.

The demand for ultra-high-temperature piezoelectric sensors in industrial applications has witnessed a rapid upsurge. In this study, the piezoelectric properties of La2Ti2O7 (LTO) piezoelectric ceramics with a perovskite-like layered structure were enhanced by doping with Li/Ce ions. It was found that a remarkable 300% enhancement in the piezoelectric constant (d33) value was achieved in Li/Ce-doped LTO ceramics compared to their pristine counterparts, reaching 6.4 pC N-1 at room temperature with an ultra-high Curie temperature of 1408 °C. After annealing at 500 °C, the d33 value of the samples can be further improved to 7.4 pC N-1. Moreover, temperature-dependent resistivity measurements indicate that even at 1000 °C, the ceramics exhibit a high resistivity of 8.9 × 105 Ω cm. By combining X-ray diffraction, Raman spectra, transmission electron microscopy and piezoresponse force microscopy data, the enhanced piezoelectricity of the ceramics is attributed to local heterogeneity induced by Li/Ce doping. Our results unequivocally demonstrate the suitability of modified LTO ceramics for ultra-high-temperature piezoelectric applications.

General Anesthesia Exposure in Infancy and Childhood: A 10-year Bibliometric Analysis.

PURPOSE: Heated discussions have divided health care providers and policymakers on the risks versus benefits of general anesthesia in pediatric populations. We conducted this study to provide a comprehensive bibliometric analysis of general anesthesia in this specific population over the past decade. DESIGN: We summarized and quantitatively analyzed the studies related to general anesthesia in children and infants over the past decade. METHODS: Using the Web of Science Core Collection as the data source, we analyzed the literature using CiteSpace software, focusing on authors, countries, institutions, keywords, and references to identify hotspots and predict research trends. FINDINGS: A total of 2,364 publications on pediatric anesthesia were included in the analysis. The number of related publications and citations steadily increased from 2013 to 2022. The United States was the leading country in terms of output, and University of Toronto was the primary contributing institution. Co-citation analysis revealed that over the past decade research has mainly focused on the long-term adverse effects of general anesthesia on neurodevelopment and acute perioperative crisis events. Keyword analysis identified infant sedation and drug selection and compatibility as promising areas for development. In addition, improving the quality of perioperative anesthesia will be a major research focus in the future. CONCLUSIONS: Recent research in pediatric anesthesia has focused on mitigating the adverse effects of general anesthesia in infants and young children and studying the pharmacological compatibility of anesthetics. Our study results would assist researchers and clinicians in understanding the current research status and optimizing clinical practice in this field.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/-) male mice exhibited the core symptoms of autism. Rfwd2+/- male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/- female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/- male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.

Design and construction of a refrigerator-cooled adiabatic calorimeter for heat capacity measurement in liquid helium temperature region.

Heat capacity is a fundamental thermodynamic property of a substance. Although heat capacity values and related thermodynamic functions are available for many materials, low-temperature heat capacity measurements, especially for novel materials, can still provide valuable insights for research in physics, chemistry, thermodynamics, and other fields. Reliable low-temperature heat capacity data are typically measured using classical adiabatic calorimeters, which use liquid helium as the refrigerant to provide a cryogenic environment for heat capacity measurements. However, liquid helium is not only expensive but also not easy to obtain, which greatly limits the application of adiabatic calorimetry. In this work, an accurate adiabatic calorimeter equipped with a Gifford-MacMahon refrigerator was designed and constructed for measuring the heat capacity of condensed matter in the temperature range from 4 to 100 K. The Gifford-MacMahon refrigerator was utilized to provide a stable liquid helium-free cryogenic environment. A simple mechanical thermal switch assembly was designed to facilitate switching between the refrigeration mode and the adiabatic measurement mode of the calorimeter. Based on the measurement results of standard reference materials, the optimized repeatability and accuracy of heat capacity measurements were determined to be within 0.8% and 1.5%, respectively. The heat capacity of α-Fe2O3 nanoparticles was also investigated with this device. Furthermore, this adiabatic calorimeter only requires electricity to operate in the liquid helium temperature range, which may significantly advance the research on low-temperature heat capacity based on adiabatic calorimetry.

The origin of different bending stiffness between double-stranded RNA and DNA revealed by magnetic tweezers and simulations.

The subtle differences in the chemical structures of double-stranded (ds) RNA and DNA lead to significant variations in their biological roles and medical implications, largely due to their distinct biophysical properties, such as bending stiffness. Although it is well known that A-form dsRNA is stiffer than B-form dsDNA under physiological salt conditions, the underlying cause of this difference remains unclear. In this study, we employ high-precision magnetic-tweezer experiments along with molecular dynamics simulations and reveal that the relative bending stiffness between dsRNA and dsDNA is primarily determined by the structure- and salt-concentration-dependent ion distribution around their helical structures. At near-physiological salt conditions, dsRNA shows a sparser ion distribution surrounding its phosphate groups compared to dsDNA, causing its greater stiffness. However, at very high monovalent salt concentrations, phosphate groups in both dsRNA and dsDNA become fully neutralized by excess ions, resulting in a similar intrinsic bending persistence length of approximately 39 nm. This similarity in intrinsic bending stiffness of dsRNA and dsDNA is coupled to the analogous fluctuations in their total groove widths and further coupled to the similar fluctuation of base-pair inclination, despite their distinct A-form and B-form helical structures.

Functional oral status and oral health-related quality of life in community-dwelling older adults in Singapore.

OBJECTIVES: The objectives were to investigate the association between oral functional status (defined by the number of functional teeth and functional occluding units [FOUs]) on oral health-related quality of life (OHRQoL). It also aimed to determine if dentures could compensate for the loss of FOUs in terms of OHRQoL in community-dwelling older adults in Singapore. METHODS: Community-dwelling older adults, aged 60 years and above, were recruited from a community-based oral health functional screening programme from 1 May 2018 to 31 December 2019. During the screening, an Oral Health Impact Profile-14 (OHIP-14) questionnaire and oral examination were administered. Statistical analysis was performed using the chi-square test, univariate logistic regression and multivariate predictive modelling. RESULTS: Data from 1037 participants were analysed (52% female; mean age 71.5 (SD 7.15)). The mean OHIP-14 score was 4.5 ± 7.2. The OHIP-14 scores were significantly associated with the number of functional teeth and the number of FOUs (p < .001). Having at least 20 functional teeth or 10 FOUs was associated with a significantly lower OHIP-14 score. Those with no FOUs had higher OHIP-14 scores compared to those with at least 10 FOUs, even in the presence of a satisfactory denture. CONCLUSION: Maintaining at least 20 functional teeth or 10 FOUs was associated with better OHRQoL among community-dwelling older adults in Singapore. Dentures may have limited compensatory ability in terms of replacing natural functional occlusal units and maintaining OHRQoL.

Timing of Caffeine Ingestion Does Not Improve Three-Point Shooting Accuracy in College Basketball Players.

This study investigated the effects of the timing of caffeine (3 mg/kg body mass) ingestion on three-point shooting accuracy and other performance parameters during a basketball exercise simulation test (BEST). Eighteen college basketball players (mean ± SD: age = 24.4 ± 1.5 years, height = 181.7 ± 9.5 cm, body mass = 80.9 ± 13.2 kg) underwent one familiarization trial and three main conditions in a randomized order: (a) placebo (maltodextrin) and placebo, (b) caffeine and placebo, and (c) placebo and caffeine. Participants ingested either the placebo or caffeine pill 75 and 15 min before performing four quarters of the BEST and a three-point shooting protocol. During each quarter, participants completed 16 rounds of the BEST and ten three-point shots. Vertical jump height, 6 m sprint timing, BEST completion timing, three-point shooting accuracy, heart rate, rate of perceived exertion, blood glucose, blood lactate, and psychological measures pertaining to performance were measured. The BEST completion timing differed among conditions (placebo and placebo = 26.4 ± 2.0 s, caffeine and placebo = 25.8 ± 2.0 s, placebo and caffeine = 25.9 ± 2.1 s; p = .031) but not three-point shooting accuracy (placebo and placebo = 12.33 ± 4.10; caffeine and placebo = 12.61 ± 2.81; placebo and caffeine = 11.67 ± 3.77; p = .648), vertical jump height, or sprint times. Manipulating ingestion timing of caffeine did not improve three-point shooting accuracy, vertical jump height, or 6 m sprint timings, but caffeine can improve performance times during simulated basketball exercise irrespective of ingestion timing.

Self-Efficacy in Patients With Hypertension and Their Perceived Usage of Patient Portals.

INTRODUCTION: Self-efficacy in individuals optimizes their hypertension management. Electronic patient portals are being increasingly used to support chronic disease management, as they raise the health literacy of patients and enable them in self-management. However, the association between the use of patient portals and self-efficacy in hypertension management remains unclear. The study aimed to determine the association between self-efficacy among patients with hypertension who are managed in primary care and their demographic characteristics and usage patterns of patient portals. METHOD: A cross-sectional survey was conducted at a public primary care clinic in urban Singapore. Multi-ethnic adult patients with hypertension were invited to participate in a self-administered electronic questionnaire. Chi-square test was performed for bivariate analysis; adjusted logistic regression models were used for factors with P value <.1. RESULTS: A total of 310 patients (66.8% Chinese, 55.5% males, mean age of 63.1 years) completed the survey. Patient portal users had higher self-efficacy scores than non-users (mean score=63 vs 60, maximum = 80, P = .011). The factors associated with increased patient portal access included younger age <65 years (absolute odds ratio [AOR] = 2.634, 95%CI = 1.432-4.847; P = .002), monthly income >$5000 (AOR = 2.324, 95%CI = 1.104-4.892; P = .026), and post-secondary education level (AOR = 3.128, 95%CI = 1.675-5.839; P < .001). Most patients (93.1%) used the portal to check medical appointments but only1.3% of them used it to record home blood pressure measurements (HBPM). CONCLUSIONS: Patient portal usage was associated with higher self-efficacy scores in patients with hypertension. These users were younger, more educated, and earned more than the non-users, but only 1.3% of them used it for HBPM documentation.

Triglyceride glucose-body mass index as a novel predictor of slow coronary flow phenomenon in patients with ischemia and nonobstructive coronary arteries (INOCA).

BACKGROUND: The triglyceride glucose-body mass index (TyG-BMI index) has been suggested as a novel predictor of insulin resistance. However, its predictive value for slow coronary flow phenomenon (SCFP) in patients with ischemia and nonobstructive coronary arteries (INOCA) remains unclear. METHODS: We consecutively recruited 1625 patients with INOCA from February 2019 to February 2023 and divided them into two groups based on thrombolysis in myocardial infarction (TIMI) frame counts (TFCs): the SCFP group (n = 79) and the control group. A 1:2 age-matched case-control study was then performed. The TyG-BMI index was calculated as ln [plasma triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI. RESULTS: TyG-BMI index in the SCFP group (218.3 ± 25.2 vs 201.0 ± 26.5, P < .001) was significantly higher than in the normal controls. TyG-BMI index also increased with the number of coronary arteries involved in the SCFP. Multivariate logistic regression analysis showed that TyG-BMI, BMI, and TG were independent predictors for SCFP. Receiver operating characteristic (ROC) curve analysis showed that when the TyG-BMI index was above 206.7, the sensitivity and specificity were 88.6% and 68.5%, respectively, with an AUC of 0.809 (95% CI: 0.756-0.863, P = .027). Combined BMI with TG, the TyG-BMI index had a better predictive value for SCFP than BMI and TG (P < .001). CONCLUSION: The TyG-BMI index was an independent predictor for SCFP in INOCA patients, and it had a better predictive value than BMI and TG.

GPS-Free Wireless Precise Positioning System for Automatic Flying and Landing Application of Shipborne Unmanned Aerial Vehicle.

This research is dedicated to developing an automatic landing system for shipborne unmanned aerial vehicles (UAVs) based on wireless precise positioning technology. The application scenario is practical for specific challenging and complex environmental conditions, such as the Global Positioning System (GPS) being disabled during wartime. The primary objective is to establish a precise and real-time dynamic wireless positioning system, ensuring that the UAV can autonomously land on the shipborne platform without relying on GPS. This work addresses several key aspects, including the implementation of an ultra-wideband (UWB) circuit module with a specific antenna design and RF front-end chip to enhance wireless signal reception. These modules play a crucial role in achieving accurate positioning, mitigating the limitations caused by GPS inaccuracy, thereby enhancing the overall performance and reception range of the system. Additionally, the study develops a wireless positioning algorithm to validate the effectiveness of automatic landing on the shipborne platform. The platform's wave vibration is considered to provide a realistic landing system for shipborne UAVs. The UWB modules are practically installed on the shipborne platform, and the UAV and the autonomous three-body vessel are tested simultaneously in the outdoor open water space to verify the functionality, precision, and adaptability of the proposed UAV landing system. Results demonstrate that the UAV can autonomously fly from 200 m, approach, and automatically land on the moving shipborne platform without relying on GPS.

Recovery of kidney function after acute kidney disease-a multi-cohort analysis.

BACKGROUND: There are no consensus definitions for evaluating kidney function recovery after acute kidney injury (AKI) and acute kidney disease (AKD), nor is it clear how recovery varies across populations and clinical subsets. We present a federated analysis of four population-based cohorts from Canada, Denmark and Scotland, 2011-18. METHODS: We identified incident AKD defined by serum creatinine changes within 48 h, 7 days and 90 days based on KDIGO AKI and AKD criteria. Separately, we applied changes up to 365 days to address widely used e-alert implementations that extend beyond the KDIGO AKI and AKD timeframes. Kidney recovery was based on resolution of AKD and a subsequent creatinine measurement below 1.2× baseline. We evaluated transitions between non-recovery, recovery and death up to 1 year; within age, sex and comorbidity subgroups; between subset AKD definitions; and across cohorts. RESULTS: There were 464 868 incident cases, median age 67-75 years. At 1 year, results were consistent across cohorts, with pooled mortalities for creatinine changes within 48 h, 7 days, 90 days and 365 days (and 95% confidence interval) of 40% (34%-45%), 40% (34%-46%), 37% (31%-42%) and 22% (16%-29%) respectively, and non-recovery of kidney function of 19% (15%-23%), 30% (24%-35%), 25% (21%-29%) and 37% (30%-43%), respectively. Recovery by 14 and 90 days was frequently not sustained at 1 year. Older males and those with heart failure or cancer were more likely to die than to experience sustained non-recovery, whereas the converse was true for younger females and those with diabetes. CONCLUSION: Consistently across multiple cohorts, based on 1-year mortality and non-recovery, KDIGO AKD (up to 90 days) is at least prognostically similar to KDIGO AKI (7 days), and covers more people. Outcomes associated with AKD vary by age, sex and comorbidities such that older males are more likely to die, and younger females are less likely to recover.

Exploiting the Carboxylate-Binding Pocket of ß-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library.

ß-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important ß-lactam class of antibiotics. The OXA-48 and NDM-1 ß-lactamases cause resistance to the last-resort ß-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel ß-lactamase inhibitors. We exploited the ß-lactamase enzyme-substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all ß-lactamases. A library of 106 compounds, each containing a carboxylic acid or a tetrazole as an enzyme recognition element, was designed, constructed, and used to identify OXA-48 and NDM-1 inhibitors with micromolar to nanomolar potency. Further optimization led to NDM-1 inhibitors with increased potencies and biological activities. This work demonstrates that the carboxylate-binding pocket-targeting DECL, designed based on substrate binding information, aids in inhibitor identification and led to the discovery of novel non-ß-lactam pharmacophores for the development of ß-lactamase inhibitors for enzymes of different structural and mechanistic classes.

Erratum: CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain: Erratum.

[This corrects the article DOI: 10.7150/thno.44364.].

Multifunctional AuPt Nanoparticles for Synergistic Photothermal and Radiation Therapy.

Background: Photothermal therapy (PTT) has gained considerable interest as an emerging modality for cancer treatment in recent years. Radiation therapy (RT) has been widely used in the clinic as a traditional treatment method. However, RT and PTT treatments are limited by side effects and penetration depth, respectively. In addition, hypoxia within the tumor can lead to increased resistance to treatment. Methods: We synthesized multiple sizes of AuPt by modulating the reaction conditions. The smallest size of AuPt was selected and modified with folic acid (FA) for PTT and RT synergy therapy. Various methods including transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FITR) are used to determine the structure and composition of AuPt-FA (AF). In addition, we researched the photothermal properties of AF with IR cameras and infrared lasers. Flow cytometry, colony formation assays, CCK8, and fluorescent staining for probing the treatment effect in vitro. Also, we explored the targeting of AF by TEM and In Vivo Imaging Systems (IVIS). In vivo experiments, we record changes in tumor volume and weight as well as staining of tumor sections (ROS, Ki67, and hematoxylin and eosin). Results: The AuPt with particle size of 16 nm endows it with remarkably high photothermal conversion efficiency (46.84%) and catalase activity compared to other sizes of AuPt (30 nm and 100 nm). AF alleviates hypoxia in the tumor microenvironment, leading to the production of more reactive oxygen species (ROS) during the treatment. In addition, the therapeutic effect was significantly enhanced by combining RT and PTT, with an apoptosis rate of 81.1% in vitro and an in vivo tumor volume reduction rate of 94.0% in vivo. Conclusion: These results demonstrate that AF potentiates the synergistic effect of PTT and RT and has the potential for clinical translation.