The severity of intrahepatic cholestasis during pregnancy increases risks of adverse outcomes beyond stillbirth: evidence from 15,826 patients.

BACKGROUND: What kinds of fetal adverse outcomes beyond stillbirth directly correlate to the severity of intrahepatic cholestasis during pregnancy (ICP) remained tangled. Herein, we conducted a retrospective cohort study and a dose-response meta-analysis to speculate the association between the severity of ICP and its adverse outcomes. METHODS: We retrospectively collected a cohort of ICP patients from electronic records from Guangzhou Women and Children's Medical Center between Jan 1st, 2018, and Dec 31st, 2022. Also, we searched PubMed, Cochrane, Embase, Scopus, and Web of Science to extract prior studies for meta-analysis. The Kruskal-Wallis test, a one-way or two-way variants analysis (ANOVA), and multi-variant regression are utilized for cohort study. One stage model, restricted cubic spline analysis, and fixed-effect model are applied for dose-response meta-analysis. The data analysis was performed using the R programme. RESULTS: Our cohort included 1,289 pregnant individuals, including 385 mild ICP cases, 601 low moderate ICP cases, 282 high moderate ICP cases, and 21 severe ICP cases. The high moderate bile acid levels were correlated to preterm birth [RR = 2.14, 95%CI 1.27 to 3.62), P < 0.01], and preterm premature rupture of membranes [RR = 0.34, 95%CI 0.19 to 0.62), P < 0.01]. We added our cases to cases reported by other studies included in the meta-analysis. There were 15,826 patients included in dose-response meta-analysis. The severity of ICP was associated with increased risks of stillbirth, spontaneous preterm birth, iatrogenic preterm birth, preterm birth, admission to neonatal intensive care unit, and meconium-stained fluid (P < 0.05). CONCLUSIONS: Our study shows the correlation between the severity of ICP and the ascending risks of stillbirth, preterm birth, and meconium-stained fluid, providing new threshold TBA levels. PROSPERO REGISTRATION NUMBER: CRD42023472634.

Protective effects of nordalbergin against LPS-induced endotoxemia through inhibiting MAPK/NF-κB signaling pathway, NLRP3 inflammasome activation, and ROS production.

OBJECTIVE: Nordalbergin is a coumarin extracted from Dalbergia sissoo DC. To date, the biological effects of nordalbergin have not been well investigated. To investigate the anti-inflammatory responses and the anti-oxidant abilities of nordalbergin using lipopolysaccharide (LPS)-activated macrophages and LPS-induced sepsis mouse model. MATERIALS AND METHODS: Production of nitrite oxide (NO), prostaglandin E2 (PGE2), pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß), reactive oxygen species (ROS), tissue damage and serum inflammatory markers, and the activation of the NLRP3 inflammasome were examined. RESULTS: Our results indicated that nordalbergin reduced the production of NO and pro-inflammatory cytokines in vitro and ex vivo. Nordalbergin also suppressed iNOS and cyclooxygenase-2 expressions, decreased NF-κB activity, and attenuated MAPKs signaling pathway activation by decreasing JNK and p38 phosphorylation by LPS-activated J774A.1 macrophages. Notably, nordalbergin diminished NLRP3 inflammasome activation via repressing the maturation of IL-1ß and caspase-1 and suppressing ROS production by LPS/ATP- and LPS/nigericin-activated J774A.1 macrophages. Furthermore, nordalbergin exhibited protective effects against the infiltration of inflammatory cells and also inhibited the levels of organ damage markers (AST, ALT, BUN) by LPS-challenged mice. CONCLUSION: Nordalbergin possesses anti-inflammatory effects in macrophage-mediated innate immune responses, alleviates ROS production, decreases NLRP3 activation, and exhibits protective effects against LPS-induced tissue damage in mice.

GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver.

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1ß (IL-1ß)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells-rather than hepatocytes-mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

Conservation genomics of the critically endangered Chinese pangolin.

The Chinese pangolin (Manis pentadactyla, MP) has been extensively exploited and is now on the brink of extinction, but its population structure, evolutionary history, and adaptive potential are unclear. Here, we analyzed 94 genomes from three subspecies of the Chinese pangolin and identified three distinct genetic clusters (MPA, MPB, and MPC), with MPB further divided into MPB1 and MPB2 subpopulations. The divergence of these populations was driven by past climate change. For MPB2 and MPC, recent human activities have caused dramatic population decline and small population size as well as increased inbreeding, but not decrease in genomic variation and increase in genetic load probably due to strong gene flow; therefore, it is crucial to strengthen in situ habitat management for these two populations. By contrast, although human activities have a milder impact on MPA, it is at high risk of extinction due to long-term contraction and isolation, and genetic rescue is urgently needed. MPB1 exhibited a relatively healthy population status and can potentially serve as a source population. Overall, our findings provide novel insights into the conservation of the Chinese pangolin and biogeography of the mammals of eastern Asia.

The inhibitory activity of Flos Sophorae Immaturus extract and its major flavonoid components on pancreatic lipase.

Inhibition of pancreatic lipase (PL) is a strategy to prevent obesity. The inhibitory effects of Flos Sophorae Immaturus (FSI) extract and its main flavonoid components, rutin and quercetin, on PL were investigated. The contents of rutin and quercetin in FSI extract were 44.10 ± 1.33 % and 6.07 ± 1.62 %, respectively. The IC50 values of FSI extract, rutin and quercetin on PL were 322, 258 and 71 µg/mL, respectively. Rutin and quercetin inhibited PL in a reversible and noncompetitive manner. The combination of rutin and quercetin exhibited synergistic inhibitory effects at low concentration. The binding of rutin/quercetin with PL caused the fluorescence quenching of protein. Fluorescence titration showed the binding affinity of quercetin with PL protein was stronger than that of rutin. Circular dichroism analysis showed the binding changed the secondary structure of PL with an increase in random coil and a decrease in α-Helix and ß-Sheet. Molecular docking revealed that rutin and quercetin could interact with the amino acid residues around the catalytic site through multiple secondary interactions. In vivo studies showed that FSI extract can reduce fat absorption and promote fecal fat excretion through inhibition of PL activity, and the effects were mainly due to rutin and quercetin.

Orbital Hall diffraction and its application for vortex measurement.

We observe significant orbital angular momentum (OAM)-helicity-dependent centroid shifts in the Fraunhofer patterns for the far-field diffraction of optical vortex beams passing through a thin single wire, thus suggesting the orbital Hall effect (OHE) of light in diffraction. Based on the OHE with a thin cross wire, we further experimentally develop a compact and robust alignment-free method to measure the OAM states of light. These findings indicate that not only does the OHE of light offer insights into vortex diffraction with broken rotational symmetry, it may also provide a reliable and efficient way to simplify the vortex measurement for waves of different natures.

Combined Electrochemical Deposition and Photo-Reduction to Fabricate SERS-Active Silver Substrates: Characterization and Application for Malachite Green Detection in Aquaculture Water.

This research introduces a novel approach using silver (Ag) nanostructures generated through electrochemical deposition and photo-reduction of Ag on fluorine-doped tin oxide glass substrates (denoted as X-Ag-AgyFTO, where 'X' and 'y' represent the type of light source and number of deposited cycles, respectively) for surface-enhanced Raman spectroscopy (SERS). This study used malachite green (MG) as a Raman probe to evaluate the enhancement factors (EFs) in SERS-active substrates under varied fabrication conditions. For the substrates produced via electrochemical deposition, we determined a Raman EF of 6.15 × 104 for the Ag2FTO substrate. In photo-reduction, the impact of reductant concentration, light source, and light exposure duration were examined on X-Ag nanoparticle formation to achieve superior Raman EFs. Under optimal conditions (9.0 mM sodium citrate, 460 nm blue-LED at 10 W for 90 min), the combination of blue-LED-reduced Ag (B-Ag) and an Ag2FTO substrate (denoted as B-Ag-Ag2FTO) exhibited the best Raman EF of 2.79 × 105. This substrate enabled MG detection within a linear range of 0.1 to 1.0 µM (R2 = 0.98) and a detection limit of 0.02 µM. Additionally, the spiked recoveries in aquaculture water samples were between 90.0% and 110.0%, with relative standard deviations between 3.9% and 6.3%, indicating the substrate's potential for fungicide detection in aquaculture.

Dome-type extracorporeal manual morcellation during laparoscopic uterine surgery: Two years' experience in a teaching hospital.

OBJECTIVE: This study aims to describe the dome-type manual morcellation technique, a modified form of C-type incision, its comparative advantages over existing morcellation methods, the perioperative outcomes of trainees with varying experience levels, and the variables influencing morcellation speed based on our two years of experience. METHODS: This retrospective cohort study included women who underwent laparoscopic myomectomy or hysterectomy using dome-type morcellation for tissue extraction at a tertiary teaching hospital between May 2020 and September 2022. Morcellation was performed by either a single surgeon or a trainee (resident). Basic patient characteristics, perioperative outcomes, and morcellation time and speed were compared between the surgeon and trainee group. Regression models were employed to analyze variables influencing morcellation speed. RESULTS: A total of 41 women were enrolled. Among them, 20 procedures were performed by a surgeon alone, while the remaining 21 procedures were completed by trainees under the surgeon's supervision. The median weight of the specimens was 378 g (range 91-1345 g), and the median time for morcellation was 10 min (range 1-55 min). The median morcellation speed of surgeon and trainees was 70.25 and 31.7 g/min, respectively. Trainees' level of experience was found to be associated with morcellation speed, particularly for soft specimens. Additionally, both incision size and specimen stiffness were significantly associated with morcellation speed. No morcellation-related complications or bag ruptures were observed. CONCLUSION: Dome-type manual morcellation is an intuitive, efficient and safe method for specimen removal and is easy to learn for beginners.

Biomimetic Integrated Nanozyme for Flare and Recurrence of Gouty Arthritis.

Flare and multiple recurrences pose significant challenges in gouty arthritis. Traditional treatments provide temporary relief from inflammation but fail to promptly alleviate patient pain or effectively prevent subsequent recurrences. It should also be noted that both anti-inflammation and metabolism of uric acid are necessary for gouty arthritis, calling for therapeutic systems to achieve these two goals simultaneously. In this study, we propose a biomimetic integrated nanozyme, HMPB-Pt@MM, comprising platinum nanozyme and hollow Prussian blue. It demonstrates anti-inflammatory properties by eliminating reactive oxygen species and reducing infiltration of inflammatory macrophages. Additionally, it rapidly targets inflamed ankles through the camouflage of macrophage membranes. Furthermore, HMPB-Pt@MM exhibits urate oxidase-like capabilities, continuously metabolizing locally elevated uric acid concentrations, ultimately inhibiting multiple recurrences of gouty arthritis. In summary, HMPB-Pt@MM integrates ROS clearance with uric acid metabolism, offering a promising platform for the treatment of gouty arthritis.

SpliceAPP: an interactive web server to predict splicing errors arising from human mutations.

BACKGROUND: Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequence variations within introns, particularly at branch sites. We have established a massively parallel splicing assay to assess the impact on splicing of 11,191 disease-relevant variants. Based on the experimental results, we then applied regression-based methods to identify factors determining splicing decisions and their respective weights. RESULTS: Our statistical modeling is highly sensitive, accurately annotating the splicing defects of near-exon intronic variants, outperforming state-of-the-art predictive tools. We have incorporated the algorithm and branchpoint information into a web-based tool, SpliceAPP, to provide an interactive application. This user-friendly website allows users to upload any genetic variants with genome coordinates (e.g., chr15 74,687,208 A G), and the tool will output predictions for splicing error scores and evaluate the impact on nearby splice sites. Additionally, users can query branch site information within the region of interest. CONCLUSIONS: In summary, SpliceAPP represents a pioneering approach to screening pathogenic intronic variants, contributing to the development of precision medicine. It also facilitates the annotation of splicing motifs. SpliceAPP is freely accessible using the link https://bc.imb.sinica.edu.tw/SpliceAPP . Source code can be downloaded at https://github.com/hsinnan75/SpliceAPP .

Selective therapeutic efficacy of tyrosine kinase inhibitor sorafenib on the restoration of methylglyoxal-induced peritoneal fibrosis.

Peritoneal fibrosis, a common complication observed in long-term peritoneal dialysis patients, can gradually lead to ultrafiltration failure and the development of encapsulating peritoneal sclerosis. Although mechanisms of peritoneal fibrosis have been proposed, effective therapeutic options are unsatisfactory. Recently, several tyrosine kinase inhibitors have proven to be anti-fibrosis in rodent models. To assess the potential therapeutic effects of tyrosine kinase inhibitors on peritoneal fibrosis in the larger animal model, a novel porcine model of peritoneal fibrosis induced by 40 mM methylglyoxal in 2.5 % dialysate was established, and two different doses (20 mg/kg and 30 mg/kg) of sorafenib were given orally to evaluate their therapeutic efficacy in this study. Our results showed that sorafenib effectively reduced adhesions between peritoneal organs and significantly diminished the thickening of both the parietal and visceral peritoneum. Angiogenesis, vascular endothelial growth factor A production, myofibroblast infiltration, and decreased endothelial glycocalyx resulting from dialysate and methylglyoxal stimulations were also alleviated with sorafenib. However, therapeutic efficacy in ameliorating loss of mesothelial cells, restoring decreased ultrafiltration volume, and improving elevated small solutes transport rates was limited. In conclusion, this study demonstrated that sorafenib could potentially be used for peritoneal fibrosis treatment, but applying sorafenib alone might not be sufficient to fully rescue methylglyoxal-induced peritoneal defects.

Full-Scale Aggregated MobileUNet: An Improved U-Net Architecture for SAR Oil Spill Detection.

Oil spills are a major threat to marine and coastal environments. Their unique radar backscatter intensity can be captured by synthetic aperture radar (SAR), resulting in dark regions in the images. However, many marine phenomena can lead to erroneous detections of oil spills. In addition, SAR images of the ocean include multiple targets, such as sea surface, land, ships, and oil spills and their look-alikes. The training of a multi-category classifier will encounter significant challenges due to the inherent class imbalance. Addressing this issue requires extracting target features more effectively. In this study, a lightweight U-Net-based model, Full-Scale Aggregated MobileUNet (FA-MobileUNet), was proposed to improve the detection performance for oil spills using SAR images. First, a lightweight MobileNetv3 model was used as the backbone of the U-Net encoder for feature extraction. Next, atrous spatial pyramid pooling (ASPP) and a convolutional block attention module (CBAM) were used to improve the capacity of the network to extract multi-scale features and to increase the speed of module calculation. Finally, full-scale features from the encoder were aggregated to enhance the network's competence in extracting features. The proposed modified network enhanced the extraction and integration of features at different scales to improve the accuracy of detecting diverse marine targets. The experimental results showed that the mean intersection over union (mIoU) of the proposed model reached more than 80% for the detection of five types of marine targets including sea surface, land, ships, and oil spills and their look-alikes. In addition, the IoU of the proposed model reached 75.85 and 72.67% for oil spill and look-alike detection, which was 18.94% and 25.55% higher than that of the original U-Net model, respectively. Compared with other segmentation models, the proposed network can more accurately classify the black regions in SAR images into oil spills and their look-alikes. Furthermore, the detection performance and computational efficiency of the proposed model were also validated against other semantic segmentation models.

Sulfur vacancy-rich bismuth sulfide nanowire derived from CAU-17 for radioactive iodine capture in complex environments: Performance and intrinsic mechanisms.

Effective capture and immobilization of volatile radioiodine from the off-gas of post-treatment plants is crucial for nuclear safety and public health, considering its long half-life, high toxicity, and environmental mobility. Herein, sulfur vacancy-rich Vs-Bi2S3@C nanocomposites were systematically synthesized via a one-step solvothermal vulcanization of CAU-17 precursor. Batch adsorption experiments demonstrated that the as-synthesized materials exhibited superior iodine adsorption capacity (1505.8 mg g-1 at 200 °C), fast equilibrium time (60 min), and high chemisorption ratio (91.7%), which might benefit from the nanowire structure and abundant sulfur vacancies of Bi2S3. Furthermore, Vs-Bi2S3@C composites exhibited excellent iodine capture performance in complex environments (high temperatures, high humidity and radiation exposure). Mechanistic investigations revealed that the I2 capture by fabricated materials primarily involved the chemical adsorption between Bi2S3 and I2 to form BiI3, and the interaction of I2 with electrons provided by sulfur vacancies to form polyiodide anions (I3-). The post-adsorbed iodine samples were successfully immobilized into commercial glass fractions in a stable form (BixOyI), exhibiting a normalized iodine leaching rate of 3.81 × 10-5 g m-2 d-1. Overall, our work offers a novel strategy for the design of adsorbent materials tailed for efficient capture and immobilization of volatile radioiodine.

Hypogonadism among HIV-positive men who have sex with men in Taiwan: Prevalence and associated factors.

BACKGROUND: Male hypogonadism is not uncommon in people with HIV (PWH), with estimated prevalence ranging from 9% to 16%. Existing data are limited on the serum testosterone levels in PWH in Asian populations. METHODS: We enrolled HIV-positive men who have sex with men (MSM) and had been on stable antiretroviral therapy and MSM without HIV between February 2021 and November 2022. Serum free testosterone levels, sex hormone-binding globulins and other associated hormones were measured. Multiple linear regression analysis was performed to assess the association between serum free testosterone levels and clinical variables collected. RESULTS: A total of 447 MSM with HIV and 124 MSM without HIV were enrolled. Compared with MSM without HIV, MSM with HIV had a higher age (median, 41 versus 29.5 years) and prevalence of symptomatic hypogonadism (8.3% versus 1.6%). Among MSM who were aged <35 years, there were no significant differences in the serum free testosterone levels and prevalences of hypogonadism between the two groups. In multiple linear regression analysis, serum free testosterone level significantly decreased with advanced age (a decrease of 1.14 pg/mL per 1-year increase) and a higher body-mass index (BMI) (a decrease of 1.07 pg/mL per 1-kg/m2 increase), but was not associated with HIV serostatus. CONCLUSION: We found that MSM with HIV had a higher prevalence of symptomatic hypogonadism than MSM without HIV in Taiwan, which could be attributed to age difference. Serum free testosterone levels were negatively correlated with age and BMI, but did not show a significant correlation with HIV serostatus.

A combined nanotherapeutic approach targeting farnesoid X receptor, ferroptosis, and fibrosis for nonalcoholic steatohepatitis treatment.

Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist with favorable effects on fatty and glucose metabolism, has been considered the leading candidate drug for nonalcoholic steatohepatitis (NASH) treatment. However, its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback. Ferroptosis, a newly recognized form of cell death characterized by uncontrolled lipid peroxidation, is involved in the progression of NASH. Nitric oxide (NO) is a versatile biological molecule that can degrade extracellular matrix. In this study, we developed a PEGylated thiolated hollow mesoporous silica nanoparticles (MSN) loaded with OCA, as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol (ONL@MSN). Biochemical analyses, histology, multiplexed flow cytometry, bulk-tissue RNA sequencing, and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle (ONL@MSN) in a mouse NASH model. Compared with the OCA-loaded nanoparticles (O@MSN), ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis. ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis, inhibition of immune response/lipid peroxidation, and correction of microbiota dysbiosis. These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR, ferroptosis, and fibrosis.

N-ethyl-N-nitrosourea (ENU)-induced C-terminal truncation of Runx3 results in autoimmune colitis associated with Th17/Treg imbalance.

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory intestinal disease that affects people around the world. The primary cause of IBD is an imbalance in the host immune response to intestinal flora. Several human genes, including IL10, STAT3, IRGM, ATG16L1, NOD2 and RUNX3, are associated with inappropriate immune responses in IBD. It has been reported that homozygous Runx3-knockout (ko) mice spontaneously develop colitis. However, the high mortality rate in these mice within the first two weeks makes it challenging to study the role of Runx3 in colitis. To address this issue, a spontaneous colitis (SC) mouse model carrying a C-terminal truncated form of Runx3 with Tyr319stop point mutation has been generated. After weaning, SC mice developed spontaneous diarrhea and exhibited prominent enlargement of the colon, accompanied by severe inflammatory cell infiltration. Results of immunofluorescence staining showed massive CD4+ T cell infiltration in the inflammatory colon of SC mice. Colonic IL-17A mRNA expression and serum IL-17A level were increased in SC mice. CD4+ T cells from SC mice produced stronger IL-17A than those from wildtype mice in Th17-skewing conditions in vitro. In addition, the percentages of Foxp3+ Treg cells as well as the RORγt+Foxp3+ Treg subset, known for its role in suppressing Th17 response in the gut, were notably lower in colon lamina propria of SC mice than those in WT mice. Furthermore, transfer of total CD4+ T cells from SC mice, but not from wildtype mice, into Rag1-ko host mice resulted in severe autoimmune colitis. In conclusion, the C-terminal truncated Runx3 caused autoimmune colitis associated with Th17/Treg imbalance. The SC mouse model is a feasible approach to investigate the effect of immune response on spontaneous colitis.

Hyperthermia/glutathione-triggered ferritin nanoparticles amplify the ferroptosis for synergistic tumor therapy.

Breast cancer is the most diagnosed malignancy in women globally, and drug resistance is among the major obstacles to effective breast cancer treatment. Emerging evidence indicates that photothermal therapy and ferroptosis are both promising therapeutic techniques for the treatment of drug-resistant breast tumors. In this study, we proposed a thermal/ferroptosis/magnetic resonance imaging (MRI) triple functional nanoparticle (I@P-ss-FRT) in which ferritin, an iron storage material with excellent cellular uptake capacity, was attached via disulfide bonds onto polydopamine coated iron oxide nanoparticle (I@P) as photothermal transduction agent and MRI probe. I@P-ss-FRT converted the near-infrared light (NIR) into localized heat which accelerated the release of ferrous ions from ferritin accomplished by glutathione reduction and subsequently induced ferroptosis. The drug-resistant cancer cell lines exhibited a more significant uptake of I@P-ss-FRT and sensitivity to PTT/ferroptosis compared with normal cancer cell lines. In vivo, I@P-ss-FRT plus NIR displayed the best tumor-killing potential with inhibitory rate of 83.46 %, along with a decline in GSH/GPX-4 content and an increase in lipid peroxides generation at tumor sites. Therefore, I@P-ss-FRT can be applied to combat drug-resistant breast cancer.

Assessing the response of marine fish communities to climate change and fishing.

Globally, marine fish communities are being altered by climate change and human disturbances. We examined data on global marine fish communities to assess changes in community-weighted mean temperature affinity (i.e., mean temperatures within geographic ranges), maximum length, and trophic levels, which, respectively, represent the physiological, morphological, and trophic characteristics of marine fish communities. Then, we explored the influence of climate change and fishing on these characteristics because of their long-term role in shaping fish communities, especially their interactive effects. We employed spatial linear mixed models to investigate their impacts on community-weighted mean trait values and on abundance of different fish lengths and trophic groups. Globally, we observed an initial increasing trend in the temperature affinity of marine fish communities, whereas the weighted mean length and trophic levels of fish communities showed a declining trend. However, these shift trends were not significant, likely due to the large variation in midlatitude communities. Fishing pressure increased fish communities' temperature affinity in regions experiencing climate warming. Furthermore, climate warming was associated with an increase in weighted mean length and trophic levels of fish communities. Low climate baseline temperature appeared to mitigate the effect of climate warming on temperature affinity and trophic levels. The effect of climate warming on the relative abundance of different trophic classes and size classes both exhibited a nonlinear pattern. The small and relatively large fish species may benefit from climate warming, whereas the medium and largest size groups may be disadvantaged. Our results highlight the urgency of establishing stepping-stone marine protected areas to facilitate the migration of fishes to habitats in a warming ocean. Moreover, reducing human disturbance is crucial to mitigate rapid tropicalization, particularly in vulnerable temperate regions.

Análisis de la respuesta de las comunidades de peces marinos ante el cambio climático y la pesca Resumen Las comunidades de peces marinos sufren alteraciones en todo el mundo causadas por el cambio climático y las perturbaciones humanas. Analizamos los datos sobre las comunidades de peces marinos de todo el mundo para valorar los cambios en la afinidad térmica media (es decir, la temperatura media dentro de las distribuciones geográficas), la longitud máxima y los niveles tróficos, todos con ponderación comunitaria, los cuales representan respectivamente las características fisiológicas, morfológicas y tróficas de las comunidades de peces marinos. Después exploramos la influencia del cambio climático y la pesca sobre estos rasgos, ya que desempeñan un papel a largo plazo en la formación de las comunidades de peces, especialmente sus efectos interactivos. Empleamos modelos espaciales lineales mixtos para investigar el impacto del cambio climático y la pesca sobre los valores promedio de los rasgos con ponderación comunitaria y sobre la abundancia de las diferentes longitudes de peces y grupos tróficos. Observamos una tendencia inicial en incremento en la afinidad térmica de las comunidades de peces marinos en todo el mundo, mientras que el promedio con ponderación comunitaria de la longitud y el nivel trófico mostró una tendencia en declinación. Sin embargo, estos cambios en las tendencias no fueron significativas, probablemente debido a la gran variación de las comunidades de latitud media. La presión de pesca incrementó la afinidad térmica de las comunidades de peces en las regiones que experimentan el calentamiento climático. Además, este calentamiento estuvo asociado con un incremento en el promedio con ponderación comunitaria de la longitud y el nivel trófico de las comunidades. La temperatura de referencia climática baja pareció mitigar el efecto del calentamiento climático sobre la afinidad térmica y los niveles tróficos. El efecto del calentamiento sobre la abundancia relativa de las diferentes clases tróficas y el tamaño de las clases exhibió un patrón no lineal. Las especies de peces pequeños y relativamente grandes podrían beneficiarse con el calentamiento climático, mientras que los grupos de mayor tamaño y tamaño mediano estarían en desventaja. Nuestros resultados resaltan la urgencia por establecer áreas marinas protegidas que faciliten la migración de peces hacia hábitats en un océano cada vez más caliente. Además, es crucial reducir la perturbación humana para mitigar la rápida tropicalización, particularmente en las regiones templadas vulnerables.

Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIM: This study estimated the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long-term impacts of MASLD on all-cause and cardiometabolic-specific mortality were evaluated. METHODS: We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self-reported medication use and clinical seromarkers. All-cause and cardiometabolic-specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020. RESULTS: The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (Pfor trend < 0.001). After follow-up, patients with MASLD had a 9%-29% higher risk of all-cause, cardiovascular-related, or diabetes-related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate-adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05-1.25) and 1.10 (1.03-1.17), respectively, and those for diabetes deaths were 1.42 (1.05-1.93) and 1.24 (0.98-1.57), respectively, compared with those in the non-MASLD group (Pfor trend < 0.001). DISCUSSION: Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all-cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications.

Foldable paper-based photoelectrochemical biosensor based on etching reaction of CoOOH nanosheets-coated laser-induced PbS/CdS/graphene for sensitive detection of ampicillin.

Timely and rapid detection of antibiotic residues in the environment is conducive to safeguarding human health and promoting an ecological virtuous cycle. A foldable paper-based photoelectrochemical (PEC) sensor was successfully developed for the detection of ampicillin (AMP) based on glutathione/zirconium dioxide hollow nanorods/aptamer (GSH@ZrO2 HS@apt) modified cellulose paper as a reactive zone with laser direct-writing lead sulfide/cadmium sulfide/graphene (PbS/CdS/LIG) as photoelectrode and cobalt hydroxide (CoOOH) as a photoresist material. Initially, AMP was introduced into the paper-based reaction zone as a biogate aptamer, which specifically recognized the target and then left the ZrO2 HS surface, releasing glutathione (GSH) encapsulated inside. Subsequently, the introduction of GSH into the reaction region and etching of CoOOH nanosheets to expose the PbS/CdS/LIG photosensitive material increased photocurrent. Under optimal conditions, the paper-based PEC biosensor showed a linear response to AMP in the range of 5.0 - 2 × 104 pM with a detection limit of 1.36 pM (S/N = 3). In addition, the constructed PEC sensing platform has excellent selectivity, high stability and favorable reproducibility, and can be used to assess AMP residue levels in various real water samples (milk, tap water, river water), indicating its promising application in environmental antibiotic detection.