Three new species of Cyanosporus (Polyporales, Basidiomycota) from China.

Cyanosporus is a cosmopolitan genus characterized by effused-reflexed to pileate basidiomata with a bluish tint and allantoid to cylindrical basidiospores which are negative to weakly positive in Melzer's reagent and Cotton Blue, causing a brown rot. Three new species of Cyanosporus, namely, C.linzhiensis, C.miscanthi and C.tabuliformis are described and illustrated. Phylogenies on Cyanosporus are reconstructed with seven loci DNA sequences including ITS, nLSU, nSSU, mtSSU, RPB1, RPB2 and TEF1 based on phylogenetic analyses combined with morphological examination. The description for the new species is given. The main morphological characteristics of all 38 accepted species in Cyanosporus are summarized.

Relationship between retinal volume changes and the prognosis of BRVO-ME treated with ranibizumab.

Background: This study aimed to evaluate the efficacy of ranibizumab for the treatment of macular edema secondary to branch retinal vein occlusion (BRVO-ME), changes in retinal volume and central retinal thickness (CRT) before and after therapy, and the connection between visual prognosis and changes in retinal volume. Methods: The 120 patients(121 eyes) of BRVO-ME were recruited from July 2020 to October 2022 at the Affiliated Hospital of Weifang Medical University. The clinical data of patients were retrospectively examined for changes in best-corrected visual acuity (BCVA), retinal volume, and CRT at 1 day, 1 week, 1 month, 3 months, 6 months and 1year after treatment. Findings: Visual acuity improved gradually and became steady approximately 1 months after treatment, whereas retinal volume decreased gradually in both the outer and full layers and stabilized around 6 month after treatment. The decline in retinal volume and CRT was more visible in the deeper layers than in the inner levels. A higher correlation was observed between retinal volume and BCVA than between CRT and BCVA. BCVA after one year of treatment had a high correlation with baseline outer retinal volume. Interpretation: Treatment of BRVO-ME with ranibizumab is highly effective, and the recovery of visual function was depends more on early treatment. The outer retina is the major site of edema. Changes in retinal volume may serve as a better predictor of visual prognosis than changes in CRT. Baseline ourter retinal volume is correlated with long-term visual prognosis.

Role of Curcuma longae Rhizoma in medical applications: research challenges and opportunities.

Curcuma longae Rhizoma, commonly known as turmeric, is extensively utilized not only in Traditional Chinese Medicine (TCM) but also across various traditional medicine systems worldwide. It is renowned for its effectiveness in removing blood stasis, promoting blood circulation, and relieving pain. The primary bioactive metabolites of Curcuma longae Rhizoma-curcumin, ß-elemene, curcumol, and curdione-have been extensively studied for their pharmacological benefits. These include anti-tumor properties, cardiovascular and cerebrovascular protection, immune regulation, liver protection, and their roles as analgesics, anti-inflammatories, antivirals, antibacterials, hypoglycemics, and antioxidants. This review critically examines the extensive body of research regarding the mechanisms of action of Curcuma longae Rhizoma, which engages multiple molecular targets and signaling pathways such as NF-κB, MAPKs, and PI3K/AKT. The core objective of this review is to assess how the main active metabolites of turmeric interact with these molecular systems to achieve therapeutic outcomes in various clinical settings. Furthermore, we discuss the challenges related to the bioavailability of these metabolites and explore potential methods to enhance their therapeutic effects. By doing so, this review aims to provide fresh insights into the optimization of Curcuma longae Rhizoma for broader clinical applications.

Esketamine vs. placebo combined with erector spinae plane block vs. intercostal nerve block on quality of recovery following thoracoscopic lung resection: A randomized controlled factorial trial.

BACKGROUND: Multimodal analgesic strategy is pivotal for enhanced recovery after surgery. The objective of this trial was to assess the effect of subanesthetic esketamine vs. placebo combined with erector spinae plane block (ESPB) vs. intercostal nerve block (ICNB) on postoperative recovery following thoracoscopic lung resection. MATERIALS AND METHODS: This randomized, controlled, 2×2 factorial trial was conducted at a university hospital in Suzhou, China. One hundred adult patients undergoing thoracoscopic lung surgery were randomized to one of four groups (esketamine-ESPB, esketamine-ICNB, placebo-ESPB, and placebo-ICNB) to receive i.v. esketamine 0.3 mg/kg or normal saline placebo combined with ESPB or ICNB using 0.375% ropivacaine 20 mL. All patients received flurbiprofen axetil and patient-controlled fentanyl. The primary outcome was quality of recovery (QoR) at 24 h postoperatively, assessed using the QoR-15 scale, with a minimal clinically important difference of 6.0. RESULTS: The median age was 57 years and 52% were female. No significant interaction effect was found between esketamine and regional blocks on QoR (P=0.215). The QoR-15 score at 24 h was 111.5±5.8 in the esketamine group vs. 105.4±4.5 in the placebo group (difference=6.1, 95% CI, 4.0-8.1; P<0.001); 109.7±6.2 in the ESPB group vs. 107.2±5.6 in the ICNB group (difference=2.5, 95% CI, 0.2-4.9; P=0.033; not statistically significant after Bonferroni correction). Additionally, esketamine resulted in higher QoR-15 scores at 48 h (difference=4.6) and hospital discharge (difference=1.6), while ESPB led to a higher QoR-15 score at 48 h (difference=3.0). CONCLUSIONS: For patients undergoing thoracoscopic lung resection, subanesthetic esketamine improved QoR after surgery, while ICNB can be used interchangeably with ESPB as a component of multimodal analgesia.

Nitrogen Vacancy Modulation of Tungsten Nitride Peroxidase-Mimetic Activity for Bacterial Infection Therapy.

Bacterial infections claim millions of lives every year, with the escalating menace of microbial antibiotic resistance compounding this global crisis. Nanozymes, poised as prospective substitutes for antibiotics, present a significant frontier in antibacterial therapy, yet their precise enzymatic origins remain elusive. With the continuous development of nanozymes, the applications of elemental N-modulated nanozymes have spanned multiple fields, including sensing and detection, infection therapy, cancer treatment, and pollutant degradation. The introduction of nitrogen into nanozymes not only broadens their application range but also holds significant importance for the design of catalysts in biomedical research. The synergistic interplay between W and N induces pivotal alterations in electronic configurations, endowing tungsten nitride (WN) with a peroxidase-like functionality. Furthermore, the introduction of N vacancies augments the nanozyme activity, thus amplifying the catalytic potential of WN nanostructures. Rigorous theoretical modeling and empirical validation corroborate the genesis of the enzyme activity. The meticulously engineered WN nanoflower architecture exhibits an exceptional ability in traversing bacterial surfaces, exerting potent bactericidal effects through direct physical interactions. Additionally, the topological intricacies of these nanostructures facilitate precise targeting of generated radicals on bacterial surfaces, culminating in exceptional bactericidal efficacy against both Gram-negative and Gram-positive bacterial strains along with notable inhibition of bacterial biofilm formation. Importantly, assessments using a skin infection model underscore the proficiency of WN nanoflowers in effectively clearing bacterial infections and fostering wound healing. This pioneering research illuminates the realm of pseudoenzyme activity and bacterial capture-killing strategies, promising a fertile ground for the development of innovative, high-performance artificial peroxidases.

Weakly supervised low-dose computed tomography denoising based on generative adversarial networks.

Background: Low-dose computed tomography (LDCT) is a diagnostic imaging technique designed to minimize radiation exposure to the patient. However, this reduction in radiation may compromise computed tomography (CT) image quality, adversely impacting clinical diagnoses. Various advanced LDCT methods have emerged to mitigate this challenge, relying on well-matched LDCT and normal-dose CT (NDCT) image pairs for training. Nevertheless, these methods often face difficulties in distinguishing image details from nonuniformly distributed noise, limiting their denoising efficacy. Additionally, acquiring suitably paired datasets in the medical domain poses challenges, further constraining their applicability. Hence, the objective of this study was to develop an innovative denoising framework for LDCT images employing unpaired data. Methods: In this paper, we propose a LDCT denoising network (DNCNN) that alleviates the need for aligning LDCT and NDCT images. Our approach employs generative adversarial networks (GANs) to learn and model the noise present in LDCT images, establishing a mapping from the pseudo-LDCT to the actual NDCT domain without the need for paired CT images. Results: Within the domain of weakly supervised methods, our proposed model exhibited superior objective metrics on the simulated dataset when compared to CycleGAN and selective kernel-based cycle-consistent GAN (SKFCycleGAN): the peak signal-to-noise ratio (PSNR) was 43.9441, the structural similarity index measure (SSIM) was 0.9660, and the visual information fidelity (VIF) was 0.7707. In the clinical dataset, we conducted a visual effect analysis by observing various tissues through different observation windows. Our proposed method achieved a no-reference structural sharpness (NRSS) value of 0.6171, which was closest to that of the NDCT images (NRSS =0.6049), demonstrating its superiority over other denoising techniques in preserving details, maintaining structural integrity, and enhancing edge contrast. Conclusions: Through extensive experiments on both simulated and clinical datasets, we demonstrated the superior efficacy of our proposed method in terms of denoising quality and quantity. Our method exhibits superiority over both supervised techniques, including block-matching and 3D filtering (BM3D), residual encoder-decoder convolutional neural network (RED-CNN), and Wasserstein generative adversarial network-VGG (WGAN-VGG), and over weakly supervised approaches, including CycleGAN and SKFCycleGAN.

Prognostic nutritional index predicts lateral lymph node metastasis and recurrence free survival in papillary thyroid carcinoma.

BACKGROUND: Preoperative hematological parameters are predictors of pathological features and recurrence-free survival (RFS) in various malignancies. However, comprehensive studies of preoperative indicators associated with papillary thyroid carcinoma (PTC) are scarce. The present study investigated the association between preoperative indicators and RFS in patients with PTC. Accordingly, we explored the clinical impact of the prognostic nutritional index (PNI) on lymph node metastasis and RFS in patients with PTC. METHODS: A total of 619 PTC patients were retrospectively reviewed between Jan 2013 and Dec 2017. Laboratory values were measured and calculated. Receiver operating characteristic curves were generated to calculate the cutoff value. Univariate and multivariate analyses using the COX proportional hazard model were performed for RFS. The effects of PNI and age on RFS were investigated by the Kaplan-Meier method. Clinical characteristics and PNI were tested with the chi-square test. Univariate and multivariate logistic analyses were conducted to evaluate the predictive value of PNI for lymph node metastasis. RESULTS: In the multivariate Cox analysis, age, PNI and lymph node metastasis were independent prognostic indicators for RFS. The Kaplan-Meier method showed that the lower PNI group and age older than 55 years group displayed poor RFS. A low preoperative PNI was remarkably correlated with age, sex, extrathyroidal invasion, T stage, N stage and TNM stage. PNI was the only preoperative hematological indicator for lateral lymph node metastasis. CONCLUSIONS: Among the preoperative hematological indicators, PNI may serve as a promising and effective predictor for RFS and lateral lymph node metastasis in PTC patients.

Multi-omics pan-cancer analysis reveals the prognostic values and immunological functions of PPA2, with a spotlight on breast cancer.

Background: Recently, the role of inorganic pyrophosphatase 2 (PPA2) has been remaining merely superficial in many tumors. Hence, the aim was to analyze the potential functions of PPA2 in pan-cancer, focusing on its role in breast cancer. Methods: A systematic pan-cancer analysis conducted primarily utilizing various open databases such as TCGA and GTEx. We explored the clinical value of PPA2 as well as various biological functions, including expression levels and subcellular localization, multi-dimensional immune-correlation analysis, co-expression networks, and gene heterogeneity. In addition, we not only verified the function of PPA2 through cell experiments but also analyzed PPA2 at the single-cell level and its drug sensitivity. Results: PPA2 is abnormally expressed in various tumors, and it is mainly distributed in mitochondria. Furthermore, the indicators (OS, DSS, DFI, and PFI) of analysis hint that PPA2 exhibits significant prognostic value. At the same time, the genomic heterogeneity (including TMB, MSI, MATH, and NEO) of PPA2 in pan-cancer was analyzed. Across multiple tumors, the results showed a close correlation between PPA2 expression levels and different immune signatures (such as immune cell infiltration). All of these indicate that PPA2 could potentially be applied in the guidance of immunotherapy. We also have demonstrated that PPA2 promoted the process of breast cancer. Finally, some potential therapeutic agents (such as Fulvestrant) targeting the abnormal expression of PPA2 are revealed. Conclusion: In conclusion, the results demonstrated the great value of PPA2 in pan-cancer research, as well as its potential as a therapeutic target for breast tumors.

Suppression of HSV-1 infection and viral reactivation by CRISPR-Cas9 gene editing in 2D and 3D culture models.

Although our understanding of herpes simplex virus type 1 (HSV-1) biology has been considerably enhanced, developing therapeutic strategies to eliminate HSV-1 in latently infected individuals remains a public health concern. Current antiviral drugs used for the treatment of HSV-1 complications are not specific and do not address latent infection. We recently developed a CRISPR-Cas9-based gene editing platform to specifically target the HSV-1 genome. In this study, we further used 2D Vero cell culture and 3D human induced pluripotent stem cell-derived cerebral organoid (CO) models to assess the effectiveness of our editing constructs targeting viral ICP0 or ICP27 genes. We found that targeting the ICP0 or ICP27 genes with AAV2-CRISPR-Cas9 vectors in Vero cells drastically suppressed HSV-1 replication. In addition, we productively infected COs with HSV-1, characterized the viral replication kinetics, and established a viral latency model. Finally, we discovered that ICP0- or ICP27-targeting AAV2-CRISPR-Cas9 vector significantly reduced viral rebound in the COs that were latently infected with HSV-1. In summary, our results suggest that CRISPR-Cas9 gene editing of HSV-1 is an efficient therapeutic approach to eliminate the latent viral reservoir and treat HSV-1-associated complications.

Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.

BACKGROUND: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. METHODS: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. RESULTS: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. CONCLUSIONS: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.

Electrochemical Acid-Base Transport Limitation Principle for Low Electroactive Analyte Sensing in Wastewater Monitoring.

Electrochemical sensing (ES) is crucial for improving data acquisition in wastewater treatment, but obtaining the signal for a low electroactive analyte is challenging. Here, we propose an electrochemical acid-base transport limitation (eABTL) principle for inertness-based sensing, offering a new insight into generating ES signals from an interfacial transport process rather than electron transfer. This principle enables potential ES application for various weak acids and bases (WABs) without reactions themselves. We established an eABTLP method for detecting orthophosphate in solutions as a proof of concept, demonstrating commendable accuracy and precision, and a wide detection range from 10 µM to over 300 mM. Endogenous interferences were identified using 23 weak acids, indicating no significant endogenous interfering factors in typical wastewaters. Of them, volatile fatty acids are the main interference, but their effect can be eliminated by adjusting pH above 6.0. Exogenous factors like anions, cations, ion strength, temperature, organic load, and dissolved oxygen were examined, and most of their effects can be ignored by maintaining consistent analytical procedures between calibration curve and sample. Furthermore, measurement of wastewater samples confirmed the applicability toward domestic wastewater and demonstrated its wide applicability when combined with digestion pretreatment. Given the merits of inertness-based sensing, the eABTL-based methods have the potential to be a crucial part of ES techniques for environmental and industrial monitoring.

Development and evaluation of a rapid diagnostic method for Sporothrix globosa in Asia using quantitative real-time PCR.

BACKGROUND: Sporotrichosis is a chronic granulomatous infection of the skin and subcutaneous tissue that can affect any organ through lymphatic spread. The prevalence of sporotrichosis infections is increasing and its treatment is challenging as there are no unified and standard diagnostic techniques or antifungal medications. Controlling further spread requires a rapid diagnosis. Assessment of clinical symptoms, histological analysis, serological testing, and pathogen culture are all necessary for the diagnosis of sporotrichosis. However, these procedures are unable to identify the species. The development of safe, reliable, and species-specific diagnostic techniques is essential. OBJECTIVE: To establish and evaluate a new quantitative real-time PCR assay for the rapid diagnosis of sporotrichosis and to identify relevant species. METHODS: Polymorphisms in calmodulin (CAL) gene sequences and the internal transcribed spacer (ITS) were used in a quantitative real-time PCR assay to identify S. globosa, S. schenckii, and non-target species. RESULTS: The quantitative real-time PCR assay had 100% sensitivity and specificity. The limit of detection was 6 fg/µl. Thirty-four clinical specimens were verified to be infected with S. globosa with a 100% positive detection rate. CONCLUSIONS: The quantitative PCR technique developed in this study is a quick, accurate, and targeted method of identifying S. globosa based on polymorphisms in CAL sequences and ITS. It can be used for a prompt clinical diagnosis to identify S. globosa in clinical specimens from patients with sporotrichosis.

Clinical follow-up investigation on thickness changes in the peripapillary retinal nerve fibre layer of patients with Leber hereditary optic neuropathy.

BACKGROUND: To investigate the peripapillary retinal nerve fibre layer (RNFL) thickness changes and analyse factors associated with visual recovery of G11778A Leber hereditary optic neuropathy (LHON) patients. METHODS: Patients diagnosed with G11778A LHON between July 2017 and December 2020 in Tongji hospital were included in this follow-up study. Patients were grouped according to disease duration. Variations in the RNFL thickness in each quadrant at different disease stages were characterised using optical coherence tomography. According to the absence or presence of significant visual acuity improvements, LHON patients of disease duration ≥ 6 months were divided into two groups. A bivariate logistic regression model was constructed to analyse the potential factors associated with spontaneous visual recovery. RESULTS: This study included 56 G11778A LHON patients (112 eyes) and 25 healthy controls (50 eyes), with a mean follow-up of 5.25 ± 1.42 months. All quadrants and mean RNFL thicknesses of LHON patients first increased and then decreased, except for the temporal RNFL. As the disease progressed, RNFL thinning slowed; however, gradual RNFL thinning occurred. Logistic regression revealed that baseline best corrected visual acuity was related to spontaneous visual recovery of LHON patients with disease duration ≥ 6 months. CONCLUSION: The pattern of RNFL involvement could be helpful in the differential diagnosis of LHON and other optic neuropathies. LHON patients with better vision are more likely to experience some degree of spontaneous visual acuity recovery after the subacute phase.

Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as potent reversal agents against ABCB1-mediated multidrug resistance.

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 µM (IC50 = 27.00 nM, RF = 247.40) and 10 µM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

Molecular characterization of a novel mitovirus from the plant-pathogenic fungus Nigrospora oryzae.

Here, we characterized a novel mitovirus from the fungus Nigrospora oryzae, which was named "Nigrospora oryzae mitovirus 3" (NoMV3). The NoMV3 genome is 2,492 nt in length with a G + C content of 33%, containing a single large open reading frame (ORF) using the fungal mitochondrial genetic code. The ORF encodes an RNA-dependent RNA polymerase (RdRp) of 775 amino acids with a molecular mass of 88.75 kDa. BLASTp analysis revealed that the RdRp of NoMV3 had 68.6%, 50.6%, and 48.6% sequence identity to those of Nigrospora oryzae mitovirus 2, Suillus luteus mitovirus 6, and Fusarium proliferatum mitovirus 3, respectively, which belong to the genus Unuamitovirus within the family Mitoviridae. Phylogenetic analysis based on amino acid sequences supported the classification of NoMV3 as a member of a new species in the genus Unuamitovirus within the family Mitoviridae.

Enhanced the energy conversion of corn stalk via co-production of photo-fermentation biohydrogen and bioethanol.

Hydrogen-ethanol co-production can significantly improve the energy conversion efficiency of corn stalk (CS). In this study, with CS as the raw material, the co-production characteristics of one-step and two-step photo-fermentation hydrogen production (PFHP) and ethanol production were investigated. In addition, the gas and liquid characteristics of the experiment were analyzed. The kinetics of hydrogen-ethanol co-production was calculated, and the economics of hydrogen and ethanol were analyzed. Results of the experiments indicated that the two-step hydrogen-ethanol co-production had the best hydrogen production performance when the concentration of CS was 25 g/L. The total hydrogen production was 350.08 mL, and the hydrogen yield was 70.02 mL/g, which was 2.45 times higher than that of the one-step method. The efficiency of hydrogen-ethanol co-production was 17.79 %, which was 2.76 times more efficient than hydrogen compared to fermentation with hydrogen. The result provides technical reference for the high-quality utilization of CS.

The Chrysosplenium sinicum genome provides insights into adaptive evolution of shade plants.

Chrysosplenium sinicum, a traditional Tibetan medicinal plant, can successfully thrive in low-light environments for long periods of time. To investigate the adaptive evolution of shade plants in low-light environments, we generated a chromosome-scale genome assembly (~320 Mb) for C. sinicum by combining PacBio sequencing and Hi-C technologies. Based on our results, gene families related to photosynthesis and cell respiration greatly expanded and evolved in C. sinicum genome due to intracellular DNA transfer from organelle genome to nuclear genome. Under positive selective pressure, adaptive evolution of light-harvesting complex II (LHCII) component protein CsLhcb1s resulted in the expansion of threonine residues at the phosphorylation site of STN7 kinase, potentially establishing a crucial genomic foundation for enhancing C. sinicum's adaptability in low-light environments. Through transcriptome and metabolome analysis, we identified chrysosplenol and chrysosplenoside as predominant flavonoid metabolites of C. sinicum and predicted their synthesis pathways. In addition, analysis of alternative splicing (AS) revealed that AS events help regulate state transition and flavonoid biosynthesis. The present study provides new insights into the genomes of shade plants exposed to low-light conditions and adaptive evolution of these genomes; in addition, the results improve our current knowledge on the biosynthetic and regulatory processes of chrysosplenol and chrysosplenoside.

Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling.

DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFß-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.

Baseline Performance of Ultrasound-Based Strategies in Breast Cancer Screening Among Chinese Women.

RATIONALE AND OBJECTIVE: There is a notable absence of robust evidence on the efficacy of ultrasound-based breast cancer screening strategies, particularly in populations with a high prevalence of dense breasts. Our study addresses this gap by evaluating the effectiveness of such strategies in Chinese women, thereby enriching the evidence base for identifying the most efficacious screening approaches for women with dense breast tissue. METHODS: Conducted from October 2018 to August 2022 in Central China, this prospective cohort study enrolled 8996 women aged 35-64 years, divided into two age groups (35-44 and 45-64 years). Participants were screened for breast cancer using hand-held ultrasound (HHUS) and automated breast ultrasound system (ABUS), with the older age group also receiving full-field digital mammography (FFDM). The Breast Imaging Reporting and Data System (BI-RADS) was employed for image interpretation, with abnormal results indicated by BI-RADS 4/5, necessitating a biopsy; BI-RADS 3 required follow-up within 6-12 months by primary screening strategies; and BI-RADS 1/2 were classified as negative. RESULTS: Among the screened women, 29 cases of breast cancer were identified, with 4 (1.3‰) in the 35-44 years age group and 25 (4.2‰) in the 45-64 years age group. In the younger age group, HHUS and ABUS performed equally well, with no significant difference in their AUC values (0.8678 vs. 0.8679, P > 0.05). For the older age group, ABUS as a standalone strategy (AUC 0.9935) and both supplemental screening methods (HHUS with FFDM, AUC 0.9920; ABUS with FFDM, AUC 0.9928) outperformed FFDM alone (AUC 0.8983, P < 0.05). However, there was no significant difference between HHUS alone and FFDM alone (AUC 0.9529 vs. 0.8983, P > 0.05). CONCLUSION: The findings indicate that both HHUS and ABUS exhibit strong performance as independent breast cancer screening strategies, with ABUS demonstrating superior potential. However, the integration of FFDM with these ultrasound techniques did not confer a substantial improvement in the overall effectiveness of the screening process.

Wrapping stem cells with wireless electrical nanopatches for traumatic brain injury therapy.

Electrical stimulation holds promise for enhancing neuronal differentiation of neural stem cells to treat traumatic brain injury. However, once the stem cells leave the stimulating material and migrate post transplantation, electrical stimulation on them is diminished. Here, we wrap the stem cells with wireless electrical nanopatches, the conductive graphene nanosheets. Under electromagnetic induction, electrical stimulation can thus be applied in-situ to individual nanopatch-wrapped stem cells on demand, stimulating their neuronal differentiation through a MAPK/ERK signaling pathway. Consequently, 41% of the nanopatch-wrapped stem cells differentiate into functional neurons in 5 days, as opposed to only 16.3% of the unwrapped ones. The brain injury male mice implanted with the nanopatch-wrapped stem cells and exposed to a rotating magnetic field 30 min/day exhibit significant recovery of brain tissues, behaviors, and cognitions, within 28 days. This study opens up an avenue to individualized electrical stimulation of transplanted stem cells for treating neurodegenerative diseases.