Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

Impact of heavy metals exposure on herpes simplex virus type I infection: A population-based cross-sectional study.

This study aims to investigate the significant relationship between serum heavy metals (lead [Pb], cadmium [Cd], mercury [Hg]) and the risk of herpes simplex virus type 1 (HSV-1) infection. Data were derived from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States from 2007 to 2016. This nationally representative survey, conducted by the National Center for Health Statistics, assessed the health status of participants through interviews, physical examinations, and laboratory tests. After excluding participants lacking serum Pb, Cd, and Hg data, as well as those missing HSV-1 testing data and pregnant women, the analysis included 13 772 participants, among whom 3363 were adolescents. A survey-weighted multivariate logistic regression model was used to evaluate the association between heavy metal exposure and the risk of HSV-1 infection, and to explore the dose-response relationship between them. In adults and adolescents, serum concentrations of Pb and Cd were higher in those infected with HSV-1 than in those not infected. However, an increase in serum Hg concentration was observed only in infected adolescents. After adjusting for potential confounders, elevated serum Pb and Cd concentrations in adults were associated with an increased risk of HSV-1 infection. Higher serum Pb and Cd concentrations were associated with an increased risk of HSV-2 infection, irrespective of HSV-1 infection status. In adults, serum concentrations of Pb and Hg showed an approximately linear relationship with HSV-1 infection risk (p for nonlinearity > 0.05), whereas the dose-response relationship between serum Cd concentration and HSV-1 infection was nonlinear (p for nonlinearity = 0.004). In adolescents, serum concentrations of heavy metals (Pb, Cd, Hg) showed an approximately linear relationship with HSV-1 infection (p for nonlinearity > 0.05). Furthermore, the study examined the relationship between serum heavy metal levels and the risk of HSV-1 infection across different genders, races, income levels, weight statuses, and immune statuses. In conclusion, there is a significant association between serum heavy metal concentrations and HSV-1 infection, which warrants further investigation into the causal relationship between them.

Bicyclol mitigates lipopolysaccharide-induced acute lung injury through myeloid differentiation factor 88 inhibition.

Acute lung injury (ALI) remains a significant clinical challenge due to the absence of effective treatment alternatives. This study presents a new method that employs a screening platform focusing on MyD88 affinity, anti-inflammatory properties, and toxicity. This platform was used to evaluate a 300-compound library known for its anti-inflammatory potential. Among the screened compounds, Bicyclol emerged as a standout, exhibiting MyD88 binding and a significant reduction in LPS-stimulated pro-inflammatory factors production in mouse primary peritoneal macrophages. By targeting MyD88, Bicyclol disrupts the MyD88/TLR4 complex and MyD88 polymer formation, thereby mitigating the MAPKs and NF-κB signaling pathways. In vivo experiments further confirmed Bicyclol's efficacy, demonstrating alleviated ALI symptoms, decreased inflammatory cytokines level, and reduced inflammatory cells presence in lung tissues. These findings were associated with a decrease in mortality in LPS-challenged mice. Overall, Bicyclol represents a promising treatment option for ALI by specifically targeting MyD88 and limiting inflammatory responses.

Detection of uridine diphosphate glucuronosyltransferase 1A1 for pancreatic cancer imaging and treatment via a "turn-on" fluorescent probe.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is expressed ubiquitously in cancer cells and can metabolize exogenous substances. Studies show higher UGT1A1 levels in pancreatic cancer cells than normal cells. Therefore, we need a method to monitor the activity level of UGT1A1 in pancreatic cancer cells and in vivo. Here, we report a fluorescent probe, BCy-panc, for UGT1A1 imaging in cells and in vivo. Compared with other molecular probes, this probe is readily prepared, with high selectivity and sensitivity for the detection of UGT1A1. Our results show that BCy-panc rapidly detects UGT1A1 in pancreatic cancer. In addition, there is an urgent need for evidence to clarify the relationship between UGT1A1 and pancreatic cancer development. The present investigation found that the increase of UGT1A1 by chrysin was effective in inducing apoptosis in pancreatic cancer cells. These results indicate that the synergistic effect of chrysin and cisplatin at the cellular level is superior to that of cisplatin alone. The UGT1A1 level may be a biomarker for early diagnosis of cancer. Meanwhile, UGT1A1 plays a crucial role in pancreatic cancer, and the combination of chrysin and cisplatin may provide effective ideas for pancreatic cancer treatment.

SMARCB1 (INI1) Deficient Tumours of the Uterine Cervix: Report of Two Cases, Including One Associated With an NTRK Fusion.

Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings.

Inflammation Is More Sensitive than Cell Proliferation in Response to Rapamycin Treatment in Polycystic Kidney Disease.

INTRODUCTION: It has been reported that rapamycin inhibited inflammation in renal interstitial diseases. We therefore hypothesized that rapamycin could attenuate inflammation in polycystic kidney disease (PKD). METHODS: Han:SPRD rats were treated with rapamycin by daily gavage from 4 weeks to 12 weeks of age at the dosage of 0.5 mg/kg/day (low dose) or 1 mg/kg/day (high dose). WT9-12 human PKD cells were treated with various concentrations of rapamycin. RESULTS: Two-kidney/total body weight ratio and cystic index in Cy/+ kidneys were significantly reduced with the treatment of low-dose rapamycin and further reduced by the treatment with high-dose rapamycin. However, the renal function of Cy/+ rats was equally improved by the treatment with either low-dose or high-dose rapamycin. The renal cell proliferation was significantly decreased in Cy/+ kidneys with the treatment of low-dose rapamycin and was further decreased with the treatment of high-dose rapamycin as examined by Ki67 staining. The phosphorylation of S6K in cystic kidneys was decreased by low-dose rapamycin and further decreased by high-dose rapamycin. Both low-dose and high-dose rapamycin treatment decreased macrophage infiltration and the expression of complement factor B (CFB), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) to a similar level. The expression of CFB, MCP-1, and TNF-α and phosphorylation of S6K were inhibited in WT9-12 cells treated with 10 nm rapamycin at 24 h and 48 h, respectively. Moreover, the phosphorylation of Akt was not increased by 1 nm and 10 nm of rapamycin and enhanced by 1 µm rapamycin treatment. Interestingly, WT9-12 cell proliferation could be inhibited by 1 µm rapamycin. CONCLUSION: Low dose of rapamycin could inhibit inflammation and protect renal function in PKD. Inflammation is more sensitive than cell proliferation in response to rapamycin treatment in PKD.

Association between dietary magnesium intake and all-cause mortality among patients with diabetic retinopathy: a retrospective cohort study of the NHANES 1999-2018.

This study aimed to investigate the association between dietary magnesium intake and all-cause mortality among diabetic retinopathy (DR) patients. In this retrospective cohort study, data of 1,034 DR patients were extracted from the National Health and Nutrition Examination Survey (NHANES) (1999-2018). Dietary magnesium data were obtained from two 24-hour dietary recall interviews, and categorized into quartiles. Potential confounders were selected using weighted univariate Cox regression models. Weighted univariate and multivariate Cox regression models were used to explore the association between dietary magnesium intake and all-cause mortality in DR patients. The results were presented with hazard ratios (HRs) and 95% confidence intervals (CIs). Associations were further explored for subgroups related to age, gender, cardiovascular disease, and chronic kidney disease. Our study included 1,034 DR patients, of whom 438 (42.36%) died. The mean age of all patients was 63.26 (0.51) years old, with a median follow-up time of 75.00 months. Higher magnesium intake was associated with lower all-cause mortality risk (HR=0.58, 95% CI: 0.38-0.88) in DR patients. The association remained for those aged <65 years (HR=0.35, 95% CI: 0.15-0.81), male patients (HR=0.48, 95% CI: 0.27-0.84), patients without chronic kidney disease (HR=0.43, 95% CI: 0.23-0.82), and patients with a history of cardiovascular disease (HR=0.63, 95% CI: 0.39-1.02). DR patients with adequate magnesium intake exhibited a lower incidence of all-cause mortality. Further studies are needed to validate our findings and explore the optimal strategy for magnesium supplementation in DR patients.

Diagnostic Value of 3.0 T Magnetic Resonance Imaging in Active Crohn's Disease.

BACKGROUND: Magnetic resonance enteroclysis (MRE) has been widely applied to diagnose Crohn's disease (CD). Magnetic resonance (MR) at 3.0 T improves signal-to-noise ratio (SNR), shortens image acquisition time, and shows more advantages. OBJECTIVE: This study aimed to retrospectively analyze the diagnostic value of 3.0 T MR imaging for active CD. METHODS: 48 CD patients hospitalized in our hospital from January 2021 to December 2022 were selected as the study subjects. These 48 CD patients underwent both double-balloon enteroscopy and 3.0 T MRE. All patients' arterial phase signal, venous phase signal, bowel wall, and bowel lumen of MRE were observed to identify whether they suffered from active CD. Based on the results of enteroscopy, the number of true positives, true negatives, false negatives, and false positives diagnosed by MRE were screened; next, the diagnostic accuracy, sensitivity, and specificity of MRE in assessing active CD were calculated. RESULTS: Of the 48 patients, 39 were diagnosed with small bowel CD by MRE, which was not significantly different from the results of enteroscopy (P>0.05). According to MRE diagnostic results, the arterial phase predominantly presented high signal intensity, and the venous phase mainly presented low signal intensity or isointensity. Small bowel CD lesions were primarily characterized by bowel wall thickening, rare pneumatosis enhancement of the bowel wall, bowel lumen pneumatosis or dilatation, and rare strictures. Besides, MRE presented an accuracy of 93.75%, sensitivity of 97.37%, and specificity of 80.00% in diagnosing CD. CONCLUSION: 3.0 T MR imaging has diagnostic value for active CD and shows certain clinical application value.

Extensive post-transcriptional regulation revealed by integrative transcriptome and proteome analyses in salicylic acid-induced flowering in duckweed (Lemna gibba).

Duckweed is an aquatic model plant with tremendous potential in industrial and agricultural applications. Duckweed rarely flowers which significantly hinders the resource collection and heterosis utilization. Salicylic acid (SA) can significantly induce duckweed to flower; however, the underlying regulatory mechanisms remain largely unknown. In this work, transcriptome and proteome were conducted in parallel to examine the expression change of genes and proteins in Lemna gibba under SA treatment. A high-quality reference transcriptome was generated using Iso-Seq strategy, yielding 42,281 full-length transcripts. A total of 422, 423, and 417 differentially expressed genes (DEGs), as well as 213, 51, and 92 differentially expressed proteins (DEPs), were identified at flower induction, flower initiation, and flowering stages by ssRNA-seq and iTRAQ methods. Most DEGs and DEPs were only regulated at either the transcriptomic or proteomic level. Additionally, DEPs exhibited low expression correlations with the corresponding mRNAs, suggesting that post-transcriptional regulation plays a pivotal role in SA-induced flowering in L. gibba. Specifically, the genes related to photosynthesis, stress, and hormone metabolism were mainly regulated at the mRNA level, those associated with mitochondrial electron transport / ATP synthesis, nucleotide synthesis, and secondary metabolism were regulated at the protein level, while those related to redox metabolism were regulated at the mRNA and/or protein levels. The post-transcriptional regulation of genes relevant to hormone synthesis, transcription factors, and flowering was also extensively analyzed and discussed. This is the first study of integrative transcriptomic and proteomic analyses in duckweed, providing novel insights of post-transcriptional regulation in SA-induced flowering of L. gibba.

Evaluation of nanoplastics-induced redox imbalance in cells, larval zebrafish, and daphnia magna with a superoxide anion radical fluorescent probe.

Nanoplastics (NPs) is a novel plastic contaminant that could be taken up by cells and lead to severe biotoxicity toxicity, NPs in cells can cause oxidant damage by inducing reactive oxygen species (ROS) production and lead to acute inflammation. As a major ROS which related to many kinds of physiological and pathological processes, superoxide anion radical (O2•-) could be utilized as a signal of oxidant damage effected by NPs exposure in vivo. To detect the toxic damage mechanism of NPs, a fluorescence probe Bcy-OTf has been developed to monitor O2•- fluctuations content in cells and aquatic organisms after exposure to NPs. The probe has a high sensitivity (LOD = 20 nM) and a rapid responsive time (within 6 min), and it has high selectivity and low cytotoxicity to analysis the levels of the endogenous O2•-. Endogenous O2•- induced by NPs in living cells, Daphnia magna and larval zebrafish were analyzed. Moreover, the results confirmed the key role of MAPK and NF-κB pathway in NPs stimulation mechanisms in cells. This study indicated that Bcy-OTf can precisely assess the fluctuations of endogenous O2•-, which has potential for applying in further analysis mechanisms of NPs biological risks.

Hypoglycemic effect of recrystallized resistant starch on high-fat diet- and streptozotocin-induced type 2 diabetic mice via gut microbiota modulation.

The hypoglycemic effects of two recrystallized resistant starches, A-type (ARS) and B-type (BRS), were investigated in type 2 diabetic mice. Mice were treated with low-, medium-, or high-dose ARS, high-dose BRS, or high-dose ARS combined with BRS (ABRS). After 10 weeks of continuous intervention, the medium-dose ARS group showed a significant reduction in fasting blood glucose, area under the curve of glucose, triglyceride (P < 0.01), and low-density lipoprotein (P < 0.05) levels compared to the model group and an increase in high-density lipoprotein levels (P < 0.01). The peptide YY and glucagon-like peptide-1 levels in the high-dose ARS, BRS, and ABRS groups and the butyric acid yield in the medium-dose ARS and BRS groups were significantly increased (P < 0.01) compared to those in the model group. Medium- and high-dose ARS intervention efficiently increased the relative abundance of beneficial Bacteroidetes, Lactobacillus, Lachnospiraceae_NK4A136_group, and Faecalibaculum, and lowered the ratio of Firmicutes to Bacteroidetes. Overall, ARS exhibited greater advantages than BRS in lowering blood sugar levels.

Environmental impacts of cement kiln co-incineration sewage sludge biodried products in a scale-up trial.

The biodrying technology as a pretreatment technology can overcome the limitations of cement kilns co-incineration sewage sludge (SS) on energy consumption. But the impact of SS biodried products on cement kilns and the route carbon reduction potential of biodrying + cement kilns have not been studied. In this study, SS biodrying and cement kiln co-incineration biodried product trials were conducted to highlight the matrix combustion characteristics, and the impact of biodried products on cement kilns (clinker capacity, coal consumption, and pollutant discharge). The carbon emissions of the four scenarios were assessed based on these results. The results showed that water removal rate reached 65.5 % after 11-day biodrying, and the wet-based lower heating value of the biodried product increased by 76.0 % compared with the initial matrix. Comprehensive combustibility index of the biodried product (0.745 × 10-7 %2℃-3min-2) was better than that of SS (0.433 × 10-7 %2℃-3min-2) although a portion of the organic matter was degraded. Cement kiln co-incineration of biodried products (150 t/d) resulted in per tonne of clinker saved 5.61 kg of coal due to the heat utilization efficiency of biodried products reached to 93.7 %. However, it led to an increase in the emission concentrations of NOX and SO2. Assessment results indicated that the biodrying + cement kiln pathway reduced CO2 emissions by 385.7 kg/t SS. Biodried products have greater potential to reduce emissions as alternative fuels than as fertilizers. This study indicated the advantages of SS biodrying + cement kiln co-incineration route.

Recrystallized resistant starch by encapsulation with konjac glucomannan: Structural changes, digestibility, and its effect on glucose response and short-term satiety in mice.

The effects of the structure and digestibility of konjac glucomannan (KGM)-recrystallized resistant starch complex (KRS3) on the glycemic response and short-term satiety in mice were investigated. KRS3 samples were prepared by recrystallized debranched starch (RS3) at 50 °C, and then combined with KGM. The RS3 and KRS3 samples displayed an A-type pattern and maintained peak temperature values above 110 °C. With an increase in KGM, the swelling power and apparent viscosity of KRS3 increased. The results of in vitro and in vivo digestion revealed that KRS3 with a resistant starch content ranging from 69.4 % to 78.8 % could effectively maintain postprandial blood glucose levels. KRS3, particularly with 0.5 % KGM, slowed gastric emptying of mice from 82.7 % to 36.6 % and intestinal propulsion rate from 60.9 % to 35.3 %, resulting in strong satiety. RS3 combined with KGM could serve as a new approach to develop RS3 based foods with low glycemic responses and high-satiety.

Correction: Individual dairy cow identification based on lightweight convolutional neural network.

[This corrects the article DOI: 10.1371/journal.pone.0260510.].

Quantitative analysis of pyrolysis characteristics and chemical components of tobacco materials based on machine learning.

To investigate the quantitative relationship between the pyrolysis characteristics and chemical components of tobacco materials, various machine learning methods were used to establish a quantitative analysis model of tobacco. The model relates the thermal weight loss rate to 19 chemical components, and identifies the characteristic temperature intervals of the pyrolysis process that significantly relate to the chemical components. The results showed that: 1) Among various machine learning methods, partial least squares (PLS), support vector regression (SVR) and Gaussian process regression (GPR) demonstrated superior regression performance on thermogravimetric data and chemical components. 2) The PLS model showed the best performance on fitting and prediction effects, and has good generalization ability to predict the 19 chemical components. For most components, the determination coefficients R 2 are above 0.85. While the performance of SVR and GPR models was comparable, the R 2 for most chemical components were below 0.75. 3) The significant temperature intervals for various chemical components were different, and most of the affected temperature intervals were within 130°C-400°C. The results can provide a reference for the materials selection of cigarette and reveal the possible interactions of various chemical components of tobacco materials in the pyrolysis process.

Artificial nonenzymatic antioxidant Prussian blue/KGM-BSA nanocomposite hydrogel dressing as ROS scavenging for diabetic wound healing.

The process of diabetic wound healing was influenced by the excessive proliferation of reactive oxygen species (ROS). Therefore, in the process of healing diabetic wounds, it was crucial to removing ROS. This study designed composited nanoparticles: KBP, consisted by Konjac glucomannan, bovine serum albumin, and Prussian blue. Then they were embedded in Konjac glucomannan and hydroxypropyl trimethylammonium chloride chitosan composite hydrogel (KH), The KBP@KH hydrogel finally achieved excellent efficacy in diabetic wound healing. The in vitro and in vivo experiments demonstrated that KPB nanoparticles exhibited favorable ROS scavenging capability and biosafety. The KBP@KH hydrogel not only effectively eliminated ROS from diabetic wounds, but also exhibited excellent wound adaptability. The KBP@KH hydrogel facilitated angiogenesis and suppressed the production of inflammatory factors. Overall, the KBP@KH hydrogel dressing was characterized by its user-friendly nature, safety, and high efficiency.

N-rich chitosan-derived porous carbon materials for efficient CO2 adsorption and gas separation.

Capturing and separating carbon dioxide, particularly using porous carbon adsorption separation technology, has received considerable research attention due to its advantages such as low cost and ease of regeneration. In this study, we successfully developed a one-step carbonization activation method using freeze-thaw pre-mix treatment to prepare high-nitrogen-content microporous nitrogen-doped carbon materials. These materials hold promise for capturing and separating CO2 from complex gas mixtures, such as biogas. The nitrogen content of the prepared carbon adsorbents reaches as high as 13.08 wt%, and they exhibit excellent CO2 adsorption performance under standard conditions (1 bar, 273 K/298 K), achieving 6.97 mmol/g and 3.77 mmol/g, respectively. Furthermore, according to Ideal Adsorption Solution Theory (IAST) analysis, these materials demonstrate material selectivity for CO2/CH4 (10 v:90 v) and CO2/CH4 (50 v:50 v) of 33.3 and 21.8, respectively, at 1 bar and 298 K. This study provides a promising CO2 adsorption and separation adsorbent that can be used in the efficient purification process for carbon dioxide, potentially reducing greenhouse gas emissions in industrial and energy production, thus offering robust support for addressing climate change and achieving more environmentally friendly energy production and carbon capture goals.

Metabolic GWAS-based dissection of genetic basis underlying nutrient quality variation and domestication of cassava storage root.

BACKGROUND: Metabolites play critical roles in regulating nutritional qualities of plants, thereby influencing their consumption and human health. However, the genetic basis underlying the metabolite-based nutrient quality and domestication of root and tuber crops remain largely unknown. RESULTS: We report a comprehensive study combining metabolic and phenotypic genome-wide association studies to dissect the genetic basis of metabolites in the storage root (SR) of cassava. We quantify 2,980 metabolic features in 299 cultivated cassava accessions. We detect 18,218 significant marker-metabolite associations via metabolic genome-wide association mapping and identify 12 candidate genes responsible for the levels of metabolites that are of potential nutritional importance. Me3GT, MeMYB4, and UGT85K4/UGT85K5, which are involved in flavone, anthocyanin, and cyanogenic glucoside metabolism, respectively, are functionally validated through in vitro enzyme assays and in vivo gene silencing analyses. We identify a cluster of cyanogenic glucoside biosynthesis genes, among which CYP79D1, CYP71E7b, and UGT85K5 are highly co-expressed and their allelic combination contributes to low linamarin content. We find MeMYB4 is responsible for variations in cyanidin 3-O-glucoside and delphinidin 3-O-rutinoside contents, thus controlling SR endothelium color. We find human selection affects quercetin 3-O-glucoside content and SR weight per plant. The candidate gene MeFLS1 is subject to selection during cassava domestication, leading to decreased quercetin 3-O-glucoside content and thus increased SR weight per plant. CONCLUSIONS: These findings reveal the genetic basis of cassava SR metabolome variation, establish a linkage between metabolites and agronomic traits, and offer useful resources for genetically improving the nutrition of cassava and other root crops.