Pig-to-human kidney xenotransplants using genetically modified minipigs.

This study develops an observational model to assess kidney function recovery and xenogeneic immune responses in kidney xenotransplants, focusing on gene editing and immunosuppression. Two brain-dead patients undergo single kidney xenotransplantation, with kidneys donated by minipigs genetically modified to include triple-gene knockouts (GGTA1, ß4GalNT2, CMAH) and human gene transfers (hCD55 or hCD55/hTBM). Renal xenograft functions are fully restored; however, immunosuppression without CD40-CD154 pathway blockade is ineffective in preventing acute rejection by day 12. This rejection manifests as both T cell-mediated rejection and antibody-mediated rejection (AMR), confirmed by natural killer (NK) cell and macrophage infiltration in sequential xenograft biopsies. Despite donor pigs being pathogen free before transplantation, xenografts and recipient organs test positive for porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) by the end of the observation period, indicating reactivation and contributing to significant immunopathological changes. This study underscores the critical need for extended clinical observation and comprehensive evaluation using deceased human models to advance xenograft success.

Inhibition of ADAM17 attenuates high glucose-induced angiogenesis and inflammation in endothelial cells partly through down-regulation of GRO-α/CXCR2 expression: implications in peritoneal dialysis.

BACKGROUND: Angiogenesis and inflammation are key events leading to peritoneal morphologic alteration and ultrafiltration failure in patients undergoing peritoneal dialysis (PD). The current study aims to explore the role of ADAM17 in the angiogenetic and inflammatory responses of endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured and treated with a high glucose-containing medium. In parallel experiments, the expression of ADAM17 in HUVECs was inhibited by SiRNA interference. The mRNA and protein expression of ADAM17, GRO-α and CXCR2 were assessed by qPCR and Western blotting, respectively. The concentrations of GRO-α, VEGF, IL-6 and TNF-α in the cellular supernatants were determined by ELISA. Tube formation and migration of HUVECs were evaluated by Matrigel and transwell migration apparatus. RESULTS: High glucose increased the expression of ADAM17, CXCR2 and GRO-α in cultured HUVECs. RNA silencing of ADAM17 abolished high glucose-mediated increase of GRO-α and CXCR2, which were accompanied by reduced secretion of VEGF, IL-6, TNF-α, as well as tube formation and cell migration in HUVECs. CONCLUSIONS: Inhibition of ADAM17 ameliorates high glucose-induced angiogenic and inflammatory responses in endothelial cells partly through down-regulation of GRO-α/CXCR2 expression.

Dual-energy Computed Tomography (DECT) predicts the efficacy of contrast medium extravasation and secondary cerebral hemorrhage after stent thrombectomy in acute ischemic cerebral infarction.

To prospective research the efficacy of dual-energy computed tomography (DECT) in predicting contrast medium extravasation and secondary cerebral hemorrhage after stent thrombectomy in acute ischemic cerebral infarction. Ninety-two patients with acute ischemic stroke who underwent intra-arterial thrombolysis in our hospital from December 2019 to January 2022 have opted as the study subjects. DECT was performed immediately after stent thrombectomy. Images were generated through the image workstation and routine diagnosis was performed 24 hours after the operation. To analyze the diagnostic value of To analyze the diagnostic value of DECT, and to explore the diagnostic status of lesions with hemorrhagic transformation or increased hemorrhage and their correlation with iodine concentration. (1) 68 situations were confirmed, 56 positive and 12 negative with detection rates of 10.71% for hemorrhage, 75.00% for contrast agent extravasation, and 14.29% for extravasation combined with hemorrhage; (2) DECT diagnosed 8 cases of postoperative bleeding and 44 cases of extravasation of contrast media and 4 cases of extravasation of contrast media with hemorrhage ; The accuracy of DECT in diagnosing postoperative hemorrhage was 96.43%. The accuracy of diagnosis of extravasation was 96.43%. (3) The mean iodine concentration of lesions with increased hemorrhage or hemorrhagic transformation was higher compared to those without; (4) There was a correlation between hemorrhagic transformation or increased hemorrhage and iodine concentration. Dual-energy CT (DECT) can accurately distinguish the extravasation of contrast agent and secondary cerebral hemorrhage, and can predict the increased bleeding and bleeding transformation, with good diagnostic value and good predictive efficacy.

hnRNPA1 promotes the metastasis and proliferation of gastric cancer cells through WISP2-guided Wnt/ß-catenin signaling pathway.

The main cause of gastric cancer (GC)-related death is due to malignant cell unregulated distant metastasis and proliferation. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has been shown to play an important role in carcinogenesis and the development of metastasis in several tumors. However, its downstream regulatory mechanism in GC is not well defined. Our study aims to investigate the function and regulatory mechanism of hnRNPA1 in GC. We analyzed the differential expression of hnRNPA1 in gastric cancer and paired adjacent normal tissues in the TCGA database. Kaplan-Meier analysis was employed for survival assessment. The expressions of hnRNPA1 in GC cells were measured by qRT-PCR and Western blot. Transwell assay, CCK8 and colony formation assay were used to detect the effect of hnRNPA1 on the metastasis and proliferation ability of GC cells. Additionally, Western blotting was performed to examine the expression of proteins related to the Wnt/ß-catenin signaling pathway as well as epithelial-mesenchymal transition (EMT), while further investigations were carried out to explore potential regulatory mechanisms. The results showed that hnRNPA1 was highly expressed differentially in GC over normal gastric tissue. Knocking down hnRNPA1 inhibited the metastasis and proliferation of human gastric cancer cells. Overexpression of hnRNPA1 significantly enhanced the metastatic potential and proliferative capacity of human GC cells. Further mechanism exploration revealed that knocking down hnRNPA1 inhibited the Wnt/ß-catenin signaling pathway and WNT1 inducible signaling pathway protein-2 (WISP2), an activator of the Wnt/ß-catenin signaling pathway. Whereas overexpression of hnRNPA1 had the opposite effects. Our results demonstrated that hnRNPA1 promoted metastasis and proliferation of GC cells by activating Wnt/ß-catenin signaling pathway via WISP2. hnRNPA1 may serve as a potential biomarker and novel therapeutic targets for GC.

Detecting anomalous anatomic regions in spatial transcriptomics with STANDS.

Detection and Dissection of Anomalous Tissue Domains (DDATD) from multi-sample spatial transcriptomics (ST) data provides unprecedented opportunities to characterize anomalous tissue domains (ATDs), revealing both population-level and individual-specific pathogenic factors for understanding pathogenic heterogeneities behind diseases. However, no current methods can perform de novo DDATD from ST data, especially in the multi-sample context. Here, we introduce STANDS, an innovative framework based on Generative Adversarial Networks which integrates three core tasks in multi-sample DDATD: detecting, aligning, and subtyping ATDs. STANDS incorporates multimodal-learning, transfer-learning, and style-transfer techniques to effectively address major challenges in multi-sample DDATD, including complications caused by unalignable ATDs, under-utilization of multimodal information, and scarcity of normal ST datasets necessary for comparative analysis. Extensive benchmarks from diverse datasets demonstrate STAND's superiority in identifying both common and individual-specific ATDs and further dissecting them into biologically distinct subdomains. STANDS also provides clues to developing ATDs visually indistinguishable from surrounding normal tissues.

Ethical Implications of Mentor Influence on Career Choices in Dermatology.

Mentorship is a critical aspect of personal and professional development throughout anyone's life. Unlike many other fields, a medical career is a long multistep process that can begin in high school and continue throughout a physician's career. When considering competitive specialties such as dermatology, mentors are increasingly crucial in helping students successfully match to programs of their choice, but the variability and extent of mentorship can raise ethical concerns. We discuss the evolution of mentorship in dermatology and the potential ethical issues involved. We propose possible solutions to the ethical conflict between mentor and mentee.

Transcranial direct current stimulation enhances the protective effect of isoflurane preconditioning on cerebral ischemia/reperfusion injury: A new mechanism associated with the nuclear protein Akirin2.

AIMS: Ischemic stroke is a major cause of disability and mortality worldwide. Transcranial direct current stimulation (tDCS) and isoflurane (ISO) preconditioning exhibit neuroprotective properties. However, it remains unclear whether tDCS enhances the protective effect of ISO preconditioning on ischemic stroke, and the underlying mechanisms are yet to be clarified. METHOD: A model of middle cerebral artery occlusion (MCAO), a rat ischemia-reperfusion (I/R) injury model, and an in vitro oxygen-glucose deprivation/re-oxygenation (O/R) model of ischemic injury were developed. ISO preconditioning and tDCS were administered daily for 7 days before MCAO modeling. Triphenyltetrazolium chloride staining, modified neurological severity score, and hanging-wire test were conducted to assess infarct volume and neurological outcomes. Untargeted metabolomic experiments, adeno-associated virus, lentiviral vectors, and small interfering RNA techniques were used to explore the underlying mechanisms. RESULTS: tDCS/DCS enhanced the protective effects of ISO pretreatment on I/R injury-induced brain damage. This was evidenced by reduced infarct volume and improved neurological outcomes in rats with MCAO, as well as decreased cortical neuronal death after O/R injury. Untargeted metabolomic experiments identified oxidative phosphorylation (OXPHOS) as a critical pathological process for ISO-mediated neuroprotection from I/R injury. The combination of tDCS/DCS with ISO preconditioning significantly inhibited I/R injury-induced OXPHOS. Mechanistically, Akirin2, a small nuclear protein that regulates cell proliferation and differentiation, was found to decrease in the cortex of rats with MCAO and in cortical primary neurons subjected to O/R injury. Akirin2 functions upstream of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). tDCS/DCS was able to further upregulate Akirin2 levels and activate the Akirin2/PTEN signaling pathway in vivo and in vitro, compared with ISO pretreatment alone, thereby contributing to the improvement of cerebral I/R injury. CONCLUSION: tDCS treatment enhances the neuroprotective effects of ISO preconditioning on ischemic stroke by inhibiting oxidative stress and activating Akirin2-PTEN signaling pathway, highlighting potential of combination therapy in ischemic stroke.

Thiazolidine Deprotection Using an Organic Solvent Extractable Aldehyde Scavenger for One-Pot Four-Segment Ligation.

We report a simple and convenient N-terminal thiazolidine (Thz) deprotection strategy and its application in one-pot multisegment ligation. In this strategy, O-benzylhydroxylamine (O-BHA) is used to efficiently and rapidly convert Thz into N-terminal cysteine. O-BHA can be easily separated from the ligation buffer by organic solvent extraction, avoiding the degradation of the peptide thioester by O-BHA. The utility of the O-BHA-based one-pot ligation strategy has been demonstrated in the assembly of CC chemokine ligand-2.

Ethics of Dynamic and Differential Pricing for Cosmetic Procedures.

Patient demand for procedures has increased in the evolving landscape of cosmetic dermatology. This has been fueled, in part, by social media and the growing normalization of cosmetic enhancements; however, this has led some patients to have potentially unrealistic expectations, placing undue pressure on dermatologists to meet these often unrealizable demands. This pressure is further exacerbated by patients who are seen as difficult, demanding, and time-consuming and who may require extensive counseling. Physicians may adopt dynamic or differential pricing strategies to offset the additional time and effort these patients require. We discuss the ethical concerns surrounding these pricing strategies in the cosmetic sphere, highlight the importance of transparency in pricing, and offer suggestions to promote clarity and fairness in cosmetic dermatology practices.

SRP54 of black carp negatively regulates MDA5-mediated antiviral innate immunity.

Signal Recognition Particle 54 kDa (SRP54) is a subunit of the signal recognition particle (SRP), a cytoplasmic ribonucleoprotein complex guiding the transportation of newly synthesized proteins from polyribosomes to endoplasmic reticulum. In mammals, it has been reported to regulate the RLR signaling pathway negatively by impairing the association between MAVS and MDA5/RIG-I. However, the role of SRP54 in teleost antiviral innate immune response remains obscure. In this study, the SRP54 homolog of black carp (bcSRP54) has been cloned, and its function in antiviral innate immunity has been elucidated. The CDS of bcSRP54 gene consists of 1515 nucleotides and encodes 504 amino acids. Immunofluorescence (IF) showed that bcSRP54 was mainly distributed in the cytoplasm. Overexpressed bcSRP54 significantly reduced bcMDA5-mediated transcription of interferon (IFN) promoter in reporter assay. Co-expression of bcSRP54 and bcMDA5 significantly suppressed bcMDA5-mediated IFN signaling and antiviral activity, while bcSRP54 knockdown increased the antiviral ability of host cells. In addition, the results of the immunofluorescence staining demonstrated the subcellular overlapping between bcSRP54 and bcMDA5, and the co-immunoprecipitation (co-IP) experiment identified their association. Furthermore, the over-expression of bcSRP54 did not influence the protein expression and ubiquitination modification level of bcMDA5, however, hindered the binding of bcMDA5 to bcMAVS. In summary, our results conclude that bcSRP54 targets bcMDA5 and inhibits the interaction between bcMDA5 and bcMAVS, thereby negatively regulating antiviral innate immunity, which provides insight into how teleost SRP54 regulates IFN signaling.

Self-reported Infection Status, Knowledge and Associated Factors of Monkeypox Among Men Who Have Sex with Men in Jiaxing, China.

BACKGROUND: As of September 2023, more than 1,000 cases of monkeypox (mpox) have been reported in China. Based on the available evidence, men who have sex with men (MSM) are at high risk for mpox infection. This study aimed to analyses the self-reported infection status, knowledge, attitude and influencing factors of monkeypox among MSM in Jiaxing City, China. METHODS: A web-based cross-sectional survey was conducted in September 2023 to gather data on participants' socio-demographic profiles, mpox-related knowledge, sexual behavior characteristics, and other potentially related information to mpox knowledge. Multivariate regression modeling was employed to analyze the factors influencing the level of mpox-related knowledge. RESULTS: A total of 562 MSM were recruited; 4.3% self-reported being HIV-positive, 83.3% of respondents had heard of mpox, and 2.3% of them reported having suspected symptoms. 89.7% of respondents were willing to be vaccinated against mpox, but only 24.8% had a high level of knowledge about mpox. The main factors influencing knowledge of mpox were education level, household registration, homosexual anal intercourse in the past 6 months, and taking the HIV pre-exposure prophylaxis (PrEP). CONCLUSIONS: Knowledge of mpox among MSM living in the Jiaxing area needs to be enhanced, but willingness to get vaccinated is high. Educational level, household location, sexual behavior and PrEP use have important effects on knowledge of mpox. Individuals exhibiting symptoms indicative of suspected mpox had a diminutive consultation frequency, and it is imperative to augment screening efforts for mpox symptoms within specific demographic groups to prevent the underreporting of mpox cases.

cypress: an R/Bioconductor package for cell-type-specific differential expression analysis power assessment.

SUMMARY: Recent methodology advances in computational signal deconvolution have enabled bulk transcriptome data analysis at a finer cell-type level. Through deconvolution, identifying cell-type-specific differentially expressed (csDE) genes is drawing increasing attention in clinical applications. However, researchers still face a number of difficulties in adopting csDE genes detection methods in practice, especially in their experimental design. Here we present cypress, the first experimental design and statistical power analysis tool in csDE genes identification. This tool can reliably model purified cell-type-specific (CTS) profiles, cell-type compositions, biological and technical variations, offering a high-fidelity simulator for bulk RNA-seq convolution and deconvolution. cypress conducts simulation and evaluates the impact of multiple influencing factors, by various statistical metrics, to help researchers optimize experimental design and conduct power analysis. AVAILABILITY AND IMPLEMENTATION: cypress is an open-source R/Bioconductor package at https://bioconductor.org/packages/cypress/.

Selective autophagy receptor p62/SQSTM1 inhibits TBK1-IRF7 innate immune pathway in triploid hybrid fish.

The production of type I interferon is tightly regulated to prevent excessive immune activation. However, the role of selective autophagy receptor SQSTM1 in this regulation in teleost remains unknown. In this study, we cloned the triploid fish SQSTM1 (3nSQSTM1), which comprises 1371 nucleotides, encoding 457 amino acids. qRT-PCR data revealed that the transcript levels of SQSTM1 in triploid fish were increased both in vivo and in vitro following spring viraemia of carp virus (SVCV) infection. Immunofluorescence analysis confirmed that 3nSQSTM1 was mainly distributed in the cytoplasm. Luciferase reporter assay results showed that 3nSQSTM1 significantly blocked the activation of interferon promoters induced by 3nMDA5, 3nMAVS, 3nTBK1, and 3nIRF7. Co-immunoprecipitation assays further confirmed that 3nSQSTM1 could interact with both 3nTBK1 and 3nIRF7. Moreover, upon co-transfection, 3nSQSTM1 significantly inhibited the antiviral activity mediated by TBK1 and IRF7. Mechanistically, 3nSQSTM1 decreased the TBK1 phosphorylation and its interaction with 3nIRF7, thereby suppressing the subsequent antiviral response. Notably, we discovered that 3nSQSTM1 also interacted with SVCV N and P proteins, and these viral proteins may exploit 3nSQSTM1 to further limit the host's antiviral innate immune responses. In conclusion, our study demonstrates that 3nSQSTM1 plays a pivotal role in negatively regulating the interferon signaling pathway by targeting 3nTBK1 and 3nIRF7.

Enhancing Zn2+/H+ Joint Charge Storage in MnO2: Concurrently Tailoring Mn's Local Electron Density and O's p-Band Center.

Enhancing proton storage in the zinc-ion battery cathode material of MnO2 holds promise in promoting its electrochemical performance by mitigating the intense Coulombic interaction between divalent zinc ions and the host structure. However, challenges persist in addressing the structural instability caused by Jahn-Teller effects and accurately modulating H+ intercalation in MnO2. Herein, the doping of high-electronegativity Sb with fully occupied d-orbital in MnO2 is reported. The Sb doping strategy engenders the formation of Mn-O-Sb path in the structure with a strong dipole polarization field, which facilitates the delocalization of eg orbital electron in Mn and thus mitigates the Jahn-Teller effects. Simultaneously, adjusting the level of Sb doping in MnO2 leads to modulation of the p-band center of O, optimizing its interaction with hydrogen and thereby enhancing proton storage. Consequently, MnO2 doped with 6% Sb exhibits commendable performance in both rate capability and cycling endurance, delivering 113 mAh g-1 at 2 A g-1 after 2000 cycles. This investigation underscores the crucial role of electronic structural engineering in elevating the electrochemical performance of cathode materials for zinc-ion batteries.

Acetyl-CoA Carboxylase Proteolysis-Targeting Chimeras: Conceptual Design and Application as Insecticides.

Novel approaches for pest control are essential to ensure a sufficient food supply for the growing global population. The development of new insecticides must meet rigorous regulatory requirements for safety and address the resistance issues of existing insecticides. Proteolysis-targeting chimeras (PROTACs), originally developed for human diseases, show promise in agriculture. They offer innovative insecticides tailored to overcome resistance, opening avenues for agricultural applications. In this study, we developed small-molecule degraders by incorporating pomalidomide as an E3 ligand. These degraders were linked to a ligand (spirotetratmat enol) targeting the ACC protein through a flexible chain, aiming to achieve the efficient control of insects. Compounds 9a-9d were designed, synthesized, and evaluated for biological activities and mechanisms. Among them, 9b exhibited superior potency against Aphis craccivora (LC50 = 107.8 µg mL-1) compared to others and effectively degraded ACC proteins through the ubiquitin-proteasome system. These findings highlight the potential of utilizing PROTAC-based approaches in the development of insecticides for efficient pest control.

Predicting tumor invasion depth in gastric cancer: developing and validating multivariate models incorporating preoperative IVIM-DWI parameters and MRI morphological characteristics.

INTRODUCTION: Accurate assessment of the depth of tumor invasion in gastric cancer (GC) is vital for the selection of suitable patients for neoadjuvant chemotherapy (NAC). Current problem is that preoperative differentiation between T1-2 and T3-4 stage cases in GC is always highly challenging for radiologists. METHODS: A total of 129 GC patients were divided into training (91 cases) and validation (38 cases) cohorts. Pathology from surgical specimens categorized patients into T1-2 and T3-4 stages. IVIM-DWI and MRI morphological characteristics were evaluated, and a multimodal nomogram was developed. The MRI morphological model, IVIM-DWI model, and combined model were constructed using logistic regression. Their effectiveness was assessed using receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC). RESULTS: The combined nomogram, integrating preoperative IVIM-DWI parameters (D value) and MRI morphological characteristics (maximum tumor thickness, extra-serosal invasion), achieved the highest area under the curve (AUC) values of 0.901 and 0.883 in the training and validation cohorts, respectively. No significant difference was observed between the AUCs of the IVIM-DWI and MRI morphological models in either cohort (training: 0.796 vs. 0.835, p = 0.593; validation: 0.794 vs. 0.766, p = 0.79). CONCLUSION: The multimodal nomogram, combining IVIM-DWI parameters and MRI morphological characteristics, emerges as a promising tool for assessing tumor invasion depth in GC, potentially guiding the selection of suitable candidates for neoadjuvant chemotherapy (NAC) treatment.

Association Between Prenatal Exposure to Per- and Poly-Fluoroalkyl Substances From Electronic Waste Disassembly Areas and Steroid Hormones in Human Milk Samples.

Per- and poly-fluoroalkyl substances (PFAS), which are long-lasting environmental contaminants that are released into the environment during the e-waste disassembly process, pose a threat to human health. Human milk is a complex and dynamic mixture of endogenous and exogenous substances, including steroid hormones and PFAS. Therefore, in this study, we aimed to investigate the association between PFAS and steroid hormones in human milk from women living close to an e-waste disassembly area. In 2021, we collected milk samples from 150 mothers within 4 weeks of delivery and analyzed them via liquid chromatography-tandem mass spectrometry to determine the levels of 21 perfluorinated compounds and five steroid hormones (estrone, estriol, testosterone, progesterone, and androstenedione [A-dione]). We also performed multiple linear regression analysis to clarify the association between maternal PFAS exposure and steroid hormone concentrations. Our results indicated that PFOA and PFOS were positively associated with estrone (ß, 0.23; 95% CI, 0.08-0.39) and A-dione (ß, 0.186; 95% CI, 0.016-0.357) concentrations in human milk, respectively. Further, the average estimated daily intake of PFOA and PFOS were 36.5 ng/kg bw/day (range, 0.52-291.7 ng/kg bw/day) and 5.21 ng/kg bw/day (range, 0.26-32.3 ng/kg bw/day), respectively. Of concern, the PFAS intake of breastfeeding infants in the study area was higher than the recommended threshold. These findings suggested that prenatal exposure to PFAS from the e-waste disassembly process can influence steroid hormones levels in human milk. Increased efforts to mitigate mother and infant exposure to environmental pollutants are also required.