CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions.

Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.

The emergence of economic rationality of GPT.

As large language models (LLMs) like GPT become increasingly prevalent, it is essential that we assess their capabilities beyond language processing. This paper examines the economic rationality of GPT by instructing it to make budgetary decisions in four domains: risk, time, social, and food preferences. We measure economic rationality by assessing the consistency of GPT's decisions with utility maximization in classic revealed preference theory. We find that GPT's decisions are largely rational in each domain and demonstrate higher rationality score than those of human subjects in a parallel experiment and in the literature. Moreover, the estimated preference parameters of GPT are slightly different from human subjects and exhibit a lower degree of heterogeneity. We also find that the rationality scores are robust to the degree of randomness and demographic settings such as age and gender but are sensitive to contexts based on the language frames of the choice situations. These results suggest the potential of LLMs to make good decisions and the need to further understand their capabilities, limitations, and underlying mechanisms.

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 .

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Chronic Viral Hepatitis B and C Outweigh MASLD in the Associated Risk of Cirrhosis and HCC.

BACKGROUND & AIMS: The impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the development of cirrhosis and hepatocellular carcinoma (HCC) by chronic hepatitis B (CHB) or C infection and antiviral treatment statuses is not well-known. METHODS: A total of 336,866 adults aged ≥30 years were prospectively enrolled in a health screening program between 1997-2013. MASLD was identified by abdominal ultrasonography and cardiometabolic profiles. Data linkage was performed using 3 nationwide databases-National Health Insurance, Cancer Registry, and Death Certification System-to obtain information on antiviral treatment, vital status, and newly diagnosed cirrhosis and HCC. Follow-up was conducted until December 31, 2019. RESULTS: In the total population, 122,669 (36.4%) had MASLD. Over a mean follow-up of 15 years, 5562 new cases of cirrhosis and 2273 new cases of HCC were diagnosed. Although MASLD significantly increased the cumulative risks of cirrhosis or HCC (P < .0001), the associated risk was more pronounced when comparing CHB or C infection with the presence of MASLD. Stratifying the participants based on their MASLD and CHB or C statuses, hazard ratios (HRadj) with 95% confidence intervals for HCC were 8.81 (7.83-9.92) for non-steatotic liver disease (SLD) with CHB or C, 1.52 (1.32-1.74) for MASLD without CHB or C, and 8.86 (7.76-10.12) for MASLD with CHB or C, compared with non-SLD without CHB or C (all P < .0001). Among CHB or C patients who received antivirals during follow-up, MASLD was associated with increased risks of cirrhosis and HCC, with HRadj of 1.23 (1.01-1.49) and 1.32 (1.05-1.65), respectively. CONCLUSIONS: These findings underscore the need to prioritize treatment of chronic viral hepatitis before addressing MASLD.

Long-term Risks of Cirrhosis and Hepatocellular Carcinoma Across Steatotic Liver Disease Subtypes.

INTRODUCTION: The prospective study aimed to investigate the long-term associated risks of cirrhosis and hepatocellular carcinoma (HCC) across various subtypes of steatotic liver disease (SLD). METHODS: We enrolled 332,175 adults who participated in a health screening program between 1997 and 2013. Participants were categorized into various subtypes, including metabolic dysfunction-associated SLD (MASLD), MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD), based on ultrasonography findings, alcohol consumption patterns, and cardiometabolic risk factors. We used computerized data linkage with nationwide registries from 1997 to 2019 to ascertain the incidence of cirrhosis and HCC. RESULTS: After a median follow-up of 16 years, 4,458 cases of cirrhosis and 1,392 cases of HCC occurred in the entire cohort, resulting in an incidence rate of 86.1 and 26.8 per 100,000 person-years, respectively. The ALD group exhibited the highest incidence rate for cirrhosis and HCC, followed by MetALD, MASLD, and non-SLD groups. The multivariate adjusted hazard ratios for HCC were 1.92 (95% confidence interval [CI] 1.51-2.44), 2.91 (95% CI 2.11-4.03), and 2.59 (95% CI 1.93-3.48) for MASLD, MetALD, and ALD, respectively, when compared with non-SLD without cardiometabolic risk factors. The pattern of the associated risk of cirrhosis was similar to that of HCC (all P value <0.001). The associated risk of cirrhosis for ALD increased to 4.74 (95% CI 4.08-5.52) when using non-SLD without cardiometabolic risk factors as a reference. DISCUSSION: This study highlights elevated risks of cirrhosis and HCC across various subtypes of SLD compared with non-SLD, emphasizing the importance of behavioral modifications for early prevention.

Targeted protein quantitation in human body fluids by mass spectrometry.

Human body fluids (biofluids) contain various proteins, some of which reflect individuals' physiological conditions or predict diseases. Therefore, the analysis of biofluids can provide substantial information on novel biomarkers for clinical diagnosis and prognosis. In the past decades, mass spectrometry (MS)-based technologies have been developed as proteomic strategies not only for the identification of protein biomarkers but also for biomarker verification/validation in body fluids for clinical applications. The main advantage of targeted MS-based methodologies is the accurate and specific simultaneous quantitation of multiple biomarkers with high sensitivity. Here, we review MS-based methodologies that are currently used for the targeted quantitation of protein components in human body fluids, especially in plasma, urine, cerebrospinal fluid, and saliva. In addition, the currently used MS-based methodologies are summarized with a specific focus on applicable clinical sample types, MS configurations, and acquisition modes.

CD8 + T cell memory is sustained in mice by hepatic stellate cells.

BACKGROUND AND AIMS: Long-lasting immunological memory is the ultimate goal of vaccination. Homeostatic maintenance of memory CD8 + cytotoxic T cells (MemCD8TCs) is thought to be mediated by IL-15/IL-15R heterodimer (15HD)-expressing myeloid cells. Nonmyeloid hepatic stellate cells (HSCs) also express 15HD, but their role in maintaining MemCD8TC homeostasis is unknown. APPROACH AND RESULTS: We engineered a genetically engineered mouse in which IL-15R complementary DNA (cDNA) had been inserted in-frame with lecithin-retinol acyltransferase gene and bred onto an IL-15R-KO (15R-KO) genetic background (L15R) that expressed IL-15R in HSCs at normal levels, but not in other liver cells. Outside of the liver of L15R mice, IL-15R expression was found in a number of organs, but not in dendritic cells and macrophages. The low IL-15R expression in the bone marrow (BM) of L15R mice was eliminated by the reconstitution of lethally-irradiated L15R mice with 15R-KO BM to generate L15RC mice. Because MemCD8TC maintenance is mediated by 15HD, not empty IL-15R, 15HD content in L15R mice was determined and found for liver, lung, kidney, and heart. L15R and L15RC mice developed and maintained long-lasting, systemic antigen-specific MemCD8TCs that were efficacious against tumor growth and Listeria monocytogenes infection in an antigen-specific manner. Among the four organs with 15HD content, liver-associated MemCD8TCs were different from those found in the lung, kidney, and heart in two ways: (1) they were quantitatively the most numerous, and (2) they appeared uniquely in the form of clusters in a specialized structure, sinusoidal niches of the liver. CONCLUSIONS: The liver, the largest organ of the body, is endowed with the capability of effectuating long-lasting functional cytotoxic T cell memory.

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.

Functional characterization of stap2b in zebrafish vascular development.

The genetic control and signaling pathways of vascular development are not comprehensively understood. Transcription factors Islet2 (Isl2) and nr2f1b are critical for vascular growth in zebrafish, and further transcriptome analysis has revealed potential targets regulated by isl2/nr2f1b. In this study, we focused on the potential activation gene signal-transducing adaptor protein 2b (stap2b) and revealed a novel role of stap2b in vascular development. stap2b mRNA was expressed in developing vessels, suggesting stap2b plays a role in vascularization. Knocking down stap2b expression by morpholino injection or Crispr-Cas9-generated stap2b mutants caused vascular defects, suggesting a role played by stap2b in controlling the patterning of intersegmental vessels (ISVs) and the caudal vein plexus (CVP). The vessel abnormalities associated with stap2b deficiency were found to be due to dysregulated cell migration and proliferation. The decreased expression of vascular-specific markers in stap2b morphants was consistent with the vascular defects observed. In contrast, overexpression of stap2b enhanced the growth of ISVs and reversed the vessel defects in stap2b morphants. These data suggest that stap2b is necessary and sufficient to promote vascular development. Finally, we examined the interaction between stap2b and multiple signaling. We showed that stap2b regulated ISV growth through the JAK-STAT pathway. Moreover, we found that stap2b was regulated by Notch signaling to control ISV growth, and stap2b interacted with bone morphogenetic protein signaling to contribute to CVP formation. Altogether, we demonstrated that stap2b acts downstream of the isl2/nr2f1b pathway to play a pivotal role in vascular development via interaction with multiple signaling pathways.

Role of sentinel lymph node evaluation during hysterectomy for preoperative pathology diagnosis of endometrial intraepithelial neoplasia in a community hospital setting.

OBJECTIVE: To determine the utility of sentinel lymph node (SLN) evaluation during hysterectomy for endometrial intraepithelial neoplasia (EIN) in a community hospital setting and identify descriptive trends among pathology reports from those diagnosed with endometrial cancer (EC). METHODS: We reviewed patients who underwent hysterectomy from January 2015 to July 2022 for a pathologically confirmed diagnosis of EIN obtained by endometrial biopsy (EMB) or dilation and curettage. Data was obtained via detailed chart review. Statistical testing was utilized for between-group comparisons and multivariate logistic regression modeling. RESULTS: Of the 177 patients with EIN who underwent hysterectomy during the study period, 105 (59.3%) had a final diagnosis of EC. At least stage IB disease was found in 29 of these patients who then underwent adjuvant therapy. Pathology report descriptors suspicious for cancer and initial specimen type obtained by EMB were independently and significantly associated with increased odds of EC diagnosis (aOR 8.192, p < 0.001;3.746, p < 0.001, respectively). Operative times were not increased by performance of SLN sampling while frozen specimen evaluation added an average of 28 min to procedure length. Short-term surgical outcomes were also similar between groups. CONCLUSION: Patients treated for EIN at community-based institutions might be more likely to upstage preoperative EIN diagnoses and have an increased risk of later stage disease than previous research suggests. Given no surgical time or short-term outcome differences, SLN evaluation should be more strongly considered in this practice setting, especially for patients diagnosed by EMB or with pathology reports indicating suspicion for EC.

Microbacterium abyssi sp. nov. and Microbacterium limosum sp. nov., two new species of the genus Microbacterium, isolated from deep-sea sediment samples.

Two Gram-positive, non-motile, short rod-shaped actinomycete strains, designated as A18JL241T and Y20T, were isolated from deep-sea sediment samples collected from the Southwest Indian Ocean and Western Pacific Ocean, respectively. Both of the isolates were able to grow within the temperature range of 5-40 °C, NaCl concentration range of 0-7  % (w/v) and at pH 6.0-12.0. The two most abundant cellular fatty acids of both strains were anteiso-C15  :  0 and anteiso-C17  :  0. The major polar lipid contents of the two strains were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and one unidentified glycolipid. These two strains shared common chemotaxonomic features comprising MK-10 and MK-12 as the respiratory quinones. The genomic DNA G+C contents of the two strains were 68.1 and 70.4  mol%, respectively. The 16S rRNA gene phylogeny showed that the novel strains formed two distinct sublines within the genus Microbacterium. Strain A18JL241T was most closely related to the type strain of Microbacterium tenebrionis KCTC 49593T (98.8 % sequence similarity), whereas strain Y20T formed a tight cluster with the type strain of Microbacterium schleiferi NBRC 15075T (99.0 %). The orthologous average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values with the type strains of related Microbacterium species were in the range of 74.1-89.1  % and 19.4-36.9  %, respectively, which were below the recognized thresholds of 95-96 % ANI and 70 % dDDH for species definition. Based on the results obtained here, it can be concluded that strains A18JL241T and Y20T represent two novel species of the genus Microbacterium, for which the names Microbacterium abyssi sp. nov. (type strain A18JL241T=JCM 33956T=MCCC 1A16622T) and Microbacterium limosum sp. nov. (type strain Y20T=JCM 33960T=MCCC 1A16747T) are proposed.

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.

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.

The association of preconceptional folic acid supplementation with gestational age and preterm birth risk in twin pregnancies: a prospective cohort study in China.

PURPOSE: This study aims to explore the association of maternal preconceptional folic acid (FA) supplementation with gestational age and preterm birth in twin pregnancies, and whether the association varies by chorionicity or conception mode. METHODS: From November 2018 to December 2021, the information of FA supplementation and pregnancy outcomes were collected in twin pregnant women. The linear regression models and the logistic regression were used to test the association of preconceptional FA supplementation with gestational age at delivery and preterm birth and premature rupture of membranes (PROM). RESULTS: A total of 416 twin pregnancies were included. Compared with no use in twins, maternal preconceptional FA use was associated with a 0.385-week longer gestational age (95% CI 0.019-0.751) and lower risk of preterm birth < 36 weeks (adjusted OR 0.519; 95% CI 0.301-0.895) and PROM (adjusted OR 0.426; 95% CI 0.215-0.845). The protective effect on preterm birth < 36 weeks and PROM is similar whether taking FA supplements alone or multivitamins. However, the associations varied by chorionicity and conception mode of twins or compliance with supplementation. The positive associations between preconceptional FA use and gestational age only remained significant among twins via assisted reproductive technology or dichorionic diamniotic twins. Significant protective effects on preterm birth < 36 weeks and PROM were only found among women who took FA at least 4 times a week before conception. CONCLUSION: Maternal preconceptional FA supplementation was associated with longer gestation duration and lower risk of preterm birth < 36 weeks and PROM in twin pregnancies. To improve the success of their pregnancies, reproductive women should start taking FA supplements well before conception and with good compliance.

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.

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.

First Report of Kiwifruit Root Rot Caused by Globisporangium spinosum in China.

Kiwifruit is widely cultivated for its high vitamin C content and nutritional value. In January 2022, root rot symptoms were found in about 30% of Actinidia chinensis cv. Jinyan plants grafted on A. deliciosa rootstocks in an orchard located in Sanming (26.32°N, 117.23°E), Fujian Province of China. The affected plants appeared stunted, with brown and decaying roots, some of which were covered with white hyphae. To isolate the pathogen, the surfaces of typical symptomatic roots were sterilized for 30 s using 75% ethanol, followed by four rinses in sterile water, placing on potato dextrose agar (PDA), and incubating away from light at 25°C for 7 days. 16 Globisporangium-like isolates were obtained through hyphal tip isolation, displaying a milky-white appearance with irregular protuberances on the surface, and yellow-white backs with radial fold lines. The isolates were then cultured on corn meal agar for 5 days at 25°C in dark for morphological characteristics. Under microscope, the hyphae appeared as long strips without septa and 4.1 to 8.2 µm wide (average 6.7 µm), containing irregularly sized spherical droplets. Both terminal and intercalary hyphae swellings were observed; these appeared either spherical or subspherical, with some having projections. Their dimensions were 12.3 to 27.6 µm (average 17.3 µm). The oospores were mostly spherical, either plerotic or aplerotic, 11.8 to 22.3 µm wide (average 18.9 µm), with occasional projections. The antheridia were rod-shaped and curved, with one end attached to the oogonia. Amplification of the sequences of internal transcribed spacer (ITS) regions and cytochrome c oxidase subunit I (COI) were conducted using the primers ITS1/ITS4 (White et al. 1990) and OomCoxI-Levlo/OomCoxI-Levup (Robideau et al. 2011), respectively. The sequencing results revealed identical ITS and COI sequences in all 16 isolates. BLASTn analysis of the 969-bp ITS sequence ON202808 showed 99.38-99.59% similarity (965/971bp, 967/971bp) with the KJ162353 and AY598701 sequences from Globisporangium spinosum isolates, while the 700-bp COI sequence ON075783 showed 100% and 99.41% identity (680/680bp, 676/680bp) with the GenBank sequences HQ708835 and HQ708832, respectively, from G. spinosum. Phylogenetic analysis also showed that the obtained isolate (termed MA16) clustered with isolates from G. spinosum on the same evolutionary branch. For pathogenicity testing, four-month-old healthy Jinyan (A. chinensis) plants grown in sterilized media were transferred to sterile petri dishes covered with wet filter paper, and their roots were inoculated with a 5-mm-wide disk of MA16 when cultivated on PDA medium for 5 days. Miliang-1 (A. deliciosa) and Hongyang (A. chinensis) plants were treated similarly. The control groups each included three plants that were inoculated with non-colonized PDA. The plants were kept at 25 °C with a 12-/12-h light/dark cycle for 10 days when the inoculated plants exhibited root rot symptoms similar to those seen in the field, together with rotting and browning of the leaves. The control plants appeared healthy with no symptoms. After re-isolated from infected tissues, the pathogen was verified to be G. spinosum according to its ITS sequence, thus fulfilling the Koch's postulates. Recently, Pythium spinosum has been classified as G. spinosum according to whole-genome sequencing and phylogenomic analysis (Nguyen et al. 2022). Based on the morphological features and pathogenicity results, MA16 was identified as G. spinosum (van der Plaats-Niterink 1981; Huo et al. 2023). This report appears to be the first description of kiwifruit root rots caused by G. spinosum in China, and its identification will assist the development of strategies to counteract the disease.

G-quadruplex DNA-based colorimetric biosensor for the ultrasensitive visual detection of strontium ions using MnO2 nanorods as oxidase mimetics.

Strontium-90 (90Sr) is a major radioactive component that has attracted great attention, but its detection remains challenging since there are no specific energy rays indicative of its presence. Herein, a biosensor that is capable of rapidly detecting Sr2+ ions is demonstrated. Simple colorimetric method for sensitive detection of Sr2+ with the help of single-stranded DNA was developed by preparing MnO2 nanorods as oxidase mimic catalysis 3,3',5,5'-tetramethylbenzidine (TMB). Under weakly acidic conditions, MnO2 exhibited a strong oxidase-mimicking activity to oxidize colorless TMB into blue oxidation products (oxTMB) with discernible absorbance signals. Nevertheless, the introduction of a guanine-rich DNA aptamer inhibited MnO2-mediated TMB oxidation and reduced oxTMB formation, resulting in blue fading and diminished absorbance. Upon the addition of strontium ions to the system, the aptamers formed a stable G-quadruplex structure with strontium ions, thereby restoring the oxidase-mimicking activity of MnO2. Under the best experimental conditions, the absorbance exhibits a linear relationship with the Sr2+ concentration within the range 0.01-200 µM, with a limit of detection of 0.0028 µM. When the concentration of Sr2+ from 10-8 to 10-6 mol L-1, a distinct color change gradient could be observed in paper-based sensor. We successfully applied this approach to determine Sr2+ in natural water samples, obtaining recoveries ranging from 97.6 to 103% with a relative standard deviation of less than 5%. By providing technical solutions for detection, our work contributed to the effective monitoring of transportation of radioactive Sr in the environment.