Information System Model and Key Technologies of High-Definition Maps in Autonomous Driving Scenarios.

Background: High-definition maps can provide necessary prior data for autonomous driving, as well as the corresponding beyond-line-of-sight perception, verification and positioning, dynamic planning, and decision control. It is a necessary element to achieve L4/L5 unmanned driving at the current stage. However, currently, high-definition maps still have problems such as a large amount of data, a lot of data redundancy, and weak data correlation, which make autonomous driving fall into difficulties such as high data query difficulty and low timeliness. In order to optimize the data quality of high-definition maps, enhance the degree of data correlation, and ensure that they better assist vehicles in safe driving and efficient passage in the autonomous driving scenario, it is necessary to clarify the information system thinking of high-definition maps, propose a complete and accurate model, determine the content and functions of each level of the model, and continuously improve the information system model. Objective: The study aimed to put forward a complete and accurate high-definition map information system model and elaborate in detail the content and functions of each component in the data logic structure of the system model. Methods: Through research methods such as the modeling method and literature research method, we studied the high-definition map information system model in the autonomous driving scenario and explored the key technologies therein. Results: We put forward a four-layer integrated high-definition map information system model, elaborated in detail the content and functions of each component (map, road, vehicle, and user) in the data logic structure of the model, and also elaborated on the mechanism of the combined information of each level of the model to provide services in perception, positioning, decision making, and control for autonomous driving vehicles. This article also discussed two key technologies that can support autonomous driving vehicles to complete path planning, navigation decision making, and vehicle control in different autonomous driving scenarios. Conclusions: The four-layer integrated high-definition map information model proposed by this research institute has certain application feasibility and can provide references for the standardized production of high-definition maps, the unification of information interaction relationships, and the standardization of map data associations.

Three exonic variants in the PHEX gene cause aberrant splicing in a minigene assay.

Background: X-linked hypophosphatemia (XLH, OMIM 307800) is a rare phosphorus metabolism disorder caused by PHEX gene variants. Many variants simply classified as missense or nonsense variants were only analyzed at the DNA level. However, growing evidence indicates that some of these variants may alter pre-mRNA splicing, causing diseases. Therefore, this study aimed to use bioinformatics tools and a minigene assay to ascertain the effects of PHEX variations on pre-mRNA splicing. Methods: We analyzed 174 variants in the PHEX gene described as missense or nonsense variants. Finally, we selected eight candidate variants using bioinformatics tools to evaluate their effects on pre-mRNA splicing using a minigene assay system. The complementary DNA (cDNA) sequence for the PHEX gene (RefSeq NM_000444.6) serves as the basis for DNA variant numbering. Results: Of the eight candidate variants, three were found to cause abnormal splicing. Variants c.617T>G p.(Leu206Trp) and c.621T>A p.(Tyr207*) in exon 5 altered the splicing of pre-mRNA, owing to the activation of a cryptic splice site in exon 5, which produced an aberrant transcript lacking a part of exon 5, whereas variant c.1700G>C p.(Arg567Pro) in exon 16 led to the activation of a cryptic splice site in intron 16, resulting in a partial inclusion of intron 16. Conclusion: Our study employed a minigene system, which has a great degree of flexibility to assess abnormal splicing patterns under the circumstances of patient mRNA samples that are not available, to explore the impact of the exonic variants on pre-mRNA splicing. Based on the aforementioned experimental findings, we demonstrated the importance of analyzing exonic variants at the mRNA level.

Deep learning image reconstruction generates thinner slice iodine maps with improved image quality to increase diagnostic acceptance and lesion conspicuity: a prospective study on abdominal dual-energy CT.

BACKGROUND: To assess the improvement of image quality and diagnostic acceptance of thinner slice iodine maps enabled by deep learning image reconstruction (DLIR) in abdominal dual-energy CT (DECT). METHODS: This study prospectively included 104 participants with 136 lesions. Four series of iodine maps were generated based on portal-venous scans of contrast-enhanced abdominal DECT: 5-mm and 1.25-mm using adaptive statistical iterative reconstruction-V (Asir-V) with 50% blending (AV-50), and 1.25-mm using DLIR with medium (DLIR-M), and high strength (DLIR-H). The iodine concentrations (IC) and their standard deviations of nine anatomical sites were measured, and the corresponding coefficient of variations (CV) were calculated. Noise-power-spectrum (NPS) and edge-rise-slope (ERS) were measured. Five radiologists rated image quality in terms of image noise, contrast, sharpness, texture, and small structure visibility, and evaluated overall diagnostic acceptability of images and lesion conspicuity. RESULTS: The four reconstructions maintained the IC values unchanged in nine anatomical sites (all p > 0.999). Compared to 1.25-mm AV-50, 1.25-mm DLIR-M and DLIR-H significantly reduced CV values (all p < 0.001) and presented lower noise and noise peak (both p < 0.001). Compared to 5-mm AV-50, 1.25-mm images had higher ERS (all p < 0.001). The difference of the peak and average spatial frequency among the four reconstructions was relatively small but statistically significant (both p < 0.001). The 1.25-mm DLIR-M images were rated higher than the 5-mm and 1.25-mm AV-50 images for diagnostic acceptability and lesion conspicuity (all P < 0.001). CONCLUSIONS: DLIR may facilitate the thinner slice thickness iodine maps in abdominal DECT for improvement of image quality, diagnostic acceptability, and lesion conspicuity.

Investigation of N-Glycan Functions in Receptor for Advanced Glycation End Products V Domain through Chemical Glycoprotein Synthesis.

The receptor for advanced glycation end products (RAGE) plays a crucial role in inflammation-related pathways and various chronic diseases. Despite the recognized significance of N-glycosylation in the ligand-binding V domain (VD) of RAGE, a comprehensive understanding of the site-activity and structure-activity relationships is lacking due to the challenges in obtaining homogeneous glycoprotein samples through biological expression. Here, we combined chemical and chemoenzymatic approaches to synthesize RAGE-VD and its congeners with Asn3-glycosylation by incorporating precise N-glycan structures. Evaluation of these samples revealed that, in comparison to other RAGE-VD forms, α2,6-sialylated N-glycosylation at the Asn3 site results in more potent inhibition of HMGB1-induced nuclear factor-κB (NF-κB) expression in RAGE-overexpressing cells. Hydrogen/deuterium exchange-mass spectrum analysis revealed a sialylated RAGE-VD-induced interaction region within HMGB1. Conversely, Asn3 N-glycosylation in VD has negligible effects on RAGE-VD/S100B interactions. This study established an approach for accessing homogeneously glycosylated RAGE-VD and explored the modulatory effects of N-glycosylation on the interactions between RAGE-VD and its ligand proteins.

Identification of seven variants in the col4a1 gene that alter RNA splicing by minigene assay.

Type IV collagen is an integral component of basement membranes. Mutations in COL4A1, one of the key genes encoding Type IV collagen, can result in a variety of diseases. It is clear that a significant proportion of mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. Here, we analyzed exonic mutations and intronic mutations described in the COL4A1 gene using bioinformatics programs and identified candidate mutations that may alter the normal splicing pattern through a minigene system. We identified seven variants that induce splicing alterations by disrupting normal splice sites, creating new ones, or altering splice regulatory elements. These mutations are predicted to impact protein function. Our results help in the correct molecular characterization of variants in COL4A1 and may help develop more personalized treatment options.

Impact of Postoperative Radiotherapy on the Prognosis of Early-Stage (pT1-2N0M0) Oral Tongue Squamous Cell Carcinoma.

PURPOSE: To identify subgroups of patients with early-stage (pT1-2N0M0) oral tongue squamous cell carcinoma (OTSCC) who may benefit from postoperative radiotherapy (PORT). PATIENTS AND METHODS: This retrospective cohort study included 528 patients diagnosed between October 2009 and December 2021. Clinicopathological characteristics and treatments with or without PORT were analyzed for their impact on outcomes. RESULTS: Among 528 patients who underwent radical surgery (median age, 62 years [IQR, 52-69]), 145 (27.5%) also underwent PORT. Multivariate analyses revealed that PORT was associated with improved survival outcomes, whereas moderate-to-poor differentiation, perineural infiltration (PNI), lymphovascular invasion (LVI), and increasing depth of invasion (DOI) were associated with poorer survival outcomes. For patients with moderate-to-poor differentiation, the surgery + PORT group showed improved outcomes compared with the surgery-alone group. After propensity score matching, the results were as follows: overall survival (OS), 97% versus 69%, P = .003; disease-free survival (DFS), 88% versus 50%, P = .001. After excluding cases with PNI/LVI, the differences persisted: OS, 97% versus 82%, P = .040; DFS, 87% versus 64%, P = .012. Similar survival benefits were observed in 104 patients with PNI and/or LVI (OS, 81% v 58%; P = .022; DFS, 76% v 47%; P = .002). In subgroups with DOI >5 mm or close margins, PORT contributed to improved DFS (80% v 64%; P = .006; 92% v 66%; P = .049) but did not significantly affect OS. CONCLUSION: Patients with moderately-to-poorly differentiated pT1-2N0M0 OTSCC benefited from PORT. Our study provided evidence that patients with PNI and/or LVI who underwent PORT had improved survival. PORT also offered DFS benefit among patients with DOI >5 mm.

Valosin-containing protein acts as a target and mediator of S-nitrosylation in the heart through distinct mechanisms.

S-nitrosylation (SNO) is an emerging paradigm of redox signaling protecting cells against oxidative stress in the heart. Our previous studies demonstrated that valosin-containing protein (VCP), an ATPase-associated protein, is a vital mediator protecting the heart against cardiac stress and ischemic injury. However, the molecular regulations conferred by VCP in the heart are not fully understood. In this study, we explored the potential role of VCP in cardiac protein SNO using multiple cardiac-specific genetically modified mouse models and various analytical techniques including biotin switch assay, liquid chromatography, mass spectrometry, and western blotting. Our results showed that cardiac-specific overexpression of VCP led to an overall increase in the levels of SNO-modified cardiac proteins in the transgenic (TG) vs. wild-type (WT) mice. Mass spectrometry analysis identified mitochondrial proteins involved in respiration, metabolism, and detoxification as primary targets of SNO modification in VCP-overexpressing mouse hearts. Particularly, we found that VCP itself underwent SNO modification at a specific cysteine residue in its N-domain. Additionally, our study demonstrated that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis, also experienced increased SNO in response to VCP overexpression. While deletion of inducible nitric oxide synthase (iNOS) in VCP TG mice did not affect VCP SNO, it did abolish SNO modification in mitochondrial complex proteins, suggesting a dual mechanism of regulation involving both iNOS-dependent and independent pathways. Overall, our findings shed light on post-translational modification of VCP in the heart, unveiling a previously unrecognized role for VCP in regulating cardiac protein SNO and offering new insights into its function in cardiac protection.

A novel heterozygous variant of the SALL1 gene with atypical Townes-Brocks syndrome phenotypes in Chinese family.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.

Impacts of Adaptive Statistical Iterative Reconstruction-V and Deep Learning Image Reconstruction Algorithms on Robustness of CT Radiomics Features: Opportunity for Minimizing Radiomics Variability Among Scans of Different Dose Levels.

This study aims to investigate the influence of adaptive statistical iterative reconstruction-V (ASIR-V) and deep learning image reconstruction (DLIR) on CT radiomics feature robustness. A standardized phantom was scanned under single-energy CT (SECT) and dual-energy CT (DECT) modes at standard and low (20 and 10 mGy) dose levels. Images of SECT 120 kVp and corresponding DECT 120 kVp-like virtual monochromatic images were generated with filtered back-projection (FBP), ASIR-V at 40% (AV-40) and 100% (AV-100) blending levels, and DLIR algorithm at low (DLIR-L), medium (DLIR-M), and high (DLIR-H) strength levels. Ninety-four features were extracted via Pyradiomics. Reproducibility of features was calculated between standard and low dose levels, between reconstruction algorithms in reference to FBP images, and within scan mode, using intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC). The average percentage of features with ICC > 0.90 and CCC > 0.90 between the two dose levels was 21.28% and 20.75% in AV-40 images, and 39.90% and 35.11% in AV-100 images, respectively, and increased from 15.43 to 45.22% and from 15.43 to 44.15% with an increasing strength level of DLIR. The average percentage of features with ICC > 0.90 and CCC > 0.90 in reference to FBP images was 26.07% and 25.80% in AV-40 images, and 18.88% and 18.62% in AV-100 images, respectively, and decreased from 27.93 to 17.82% and from 27.66 to 17.29% with an increasing strength level of DLIR. DLIR and ASIR-V algorithms showed low reproducibility in reference to FBP images, while the high-strength DLIR algorithm provides an opportunity for minimizing radiomics variability due to dose reduction.

Three exonic variants in the COL4A5 gene alter RNA splicing in a minigene assay.

BACKGROUND: X-linked Alport syndrome (XLAS) is an inherited renal disease caused by rare variants of COL4A5 on chromosome Xq22. Many studies have indicated that single nucleotide variants (SNVs) in exons can disrupt normal splicing process of the pre-mRNA by altering various splicing regulatory signals. The male patients with XLAS have a strong genotype-phenotype correlation. Confirming the effect of variants on splicing can help to predict kidney prognosis. This study aimed to investigate whether single nucleotide substitutions, located within three bases at the 5' end of the exons or internal position of the exons in COL4A5 gene, cause aberrant splicing process. METHODS: We analyzed 401 SNVs previously presumed missense and nonsense variants in COL4A5 gene by bioinformatics programs and identified candidate variants that may affect the splicing of pre-mRNA via minigene assays. RESULTS: Our study indicated three of eight candidate variants induced complete or partial exon skipping. Variants c.2678G>C and c.2918G>A probably disturb classic splice sites leading to corresponding exon skipping. Variant c.3700C>T may disrupt splicing enhancer motifs accompanying with generation of splicing silencer sequences resulting in the skipping of exon 41. CONCLUSION: Our study revealed that two missense variants positioned the first nucleotides of the 5' end of COL4A5 exons and one internal exonic nonsense variant caused aberrant splicing. Importantly, this study emphasized the necessity of assessing the effects of SNVs at the mRNA level.

Biosynthesis of Epipyrone A Reveals a Highly Specific Membrane-Bound Fungal C-Glycosyltransferase for Pyrone Galactosylation.

Epipyrone A is a unique C-galactosylated 4-hydroxy-2-pyrone derivative with an antifungal potential from the fungus Epicoccum nigrum. We elucidated its biosynthesis via heterologous expression and characterized an unprecedented membrane-bound pyrone C-glycosyltransferase biochemically. Molecular docking and mutagenesis experiments suggested a possible mechanism for the heterocyclic C-glycosylation and the importance of a transmembrane helix for its catalysis. These results expand the repertoire of C-glycosyltransferases and provide new insights into the formation of C-glycosides in fungi.

Tracking endogenous proteins based on RNA editing-mediated genetic code expansion.

Protein labeling approaches are important to study proteins in living cells, and genome editing tools make it possible to tag endogenous proteins to address the concerns associated with overexpression. Here we established RNA editing-mediated noncanonical amino acids (ncAAs) protein tagging (RENAPT) to site-specifically label endogenous proteins with ncAAs in living cells. RENAPT labels protein in a temporary and nonheritable manner and is not restricted by protospacer adjacent motif sequence. Using a fluorescent ncAA or ncAA with a bio-orthogonal reaction handle for subsequent dye labeling, we demonstrated that a variety of endogenous proteins can be imaged at their specific subcellular locations. In addition, two proteins can be tagged individually and simultaneously using two different ncAAs. Furthermore, endogenous ion channels and neuron-specific proteins can be real-time labeled in primary neurons. Thus, RENAPT presents a promising platform with broad applicability for tagging endogenous proteins in living cells to study their localization and functions.

Analyzing the Correlation Between Serum Biomarkers and Child-Pugh Score in Liver Cirrhosis.

Objective: This study aimed to analyze the diagnostic efficacy of serum biomarkers in liver cirrhosis patients categorized by Child-Pugh scores. Methods: An observational cross-sectional study design was employed. A total of 110 liver cirrhosis patients, classified according to Child-Pugh scores and 60 healthy individuals were included in this study. Serum levels of adenosine deaminase (ADA), adiponectin (APN), matrix metalloproteinase-2 (MMP-2), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. Results: The levels of ADA, APN, MMP-2, ALP, ALT, and AST were significantly higher in the study group compared to the control group (P < .05). Furthermore, these levels increased with the severity of liver cirrhosis, with higher levels observed in patients with Child-Pugh class C. The positive diagnostic rates for joint detection in Child-Pugh class A, B, and C were 93.75% (30/32), 100% (34/34), and 100% (44/44), respectively. Conclusions: Combined detection of serum biomarkers improves the diagnostic efficacy of liver cirrhosis. The diagnostic rates were higher when considering Child-Pugh scores, with the highest rates observed in class C.

Potential Biocontrol Microorganisms Causing Attenuated Pathogenicity in Plasmopara viticola.

A phenomenon of pathogenicity attenuation of Plasmopara viticola was consistently observed during its subculture on grape. To clarify the causes of attenuated pathogenicity of P. viticola, culturable microbes were isolated from the P. viticola mass (mycelia, sporangiophores, and sporangia) in each generation and tested for their biocontrol efficacies on grape downy mildew (GDM). The results showed that the incidence of GDM decreased with the increase in the number of subculture times on both vineyard-collected leaves and grape leaves from in vitro-grown seedlings. The number of culturable microbial taxa on the surface of P. viticola decreased, whereas the population densities of four specific strains (i.e., K2, K7, P1, and P5) increased significantly with the increase in subculture times. Compared with the control, the biocontrol efficacies of the bacterial strain K2 reached 87.5%, and those of both fungal strains P1 and P5 reached 100.0%. Based on morphological characteristics and molecular sequences, strains K2, P1, and P5 were identified as Curtobacterium herbarum, Thecaphora amaranthi, and Acremonium sclerotigenum, respectively, and these three strains survived very well and multiplied on the surface of P. viticola. As the number of times P. viticola was subcultured increased, all three of these strains became the predominant strains, leading to greater P. viticola inhibition, attenuated P. viticola pathogenicity, and effective GDM biological control. To the best of our knowledge, this is the first report of C. herbarum and T. amaranthi having biological control activity against GDM.

Functional analysis of the CTNS gene exonic variants predicted to affect splicing.

Cystinosis is a severe, monogenic systemic disease caused by variants in CTNS gene. Currently, there is growing evidence that exonic variants in many diseases can affect pre-mRNA splicing. The impact of CTNS gene exonic variants on splicing regulation may be underestimated due to the lack of routine studies at the RNA level. Here, we analyzed 59 exonic variants in the CTNS gene using bioinformatics tools and identified candidate variants that may induce splicing alterations by minigene assays. We identified six exonic variants that induce splicing alterations by disrupting the ratio of exonic splicing enhancers/exonic splicing silencers (ESEs/ESSs) or by interfering with the recognition of classical splice sites, or both. Our results help in the correct molecular characterization of variants in cystinosis and inform emerging therapies. Furthermore, our work suggests that the combination of in silico and in vitro assays facilitates to assess the effects of DNA variants driving rare genetic diseases on splicing regulation and will enhance the clinical utility of variant functional annotation.

Adult localized Langerhans cell histiocytosis: A case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disease of Langerhans cells with unknown pathogenesis. An increasing number of clinicians recognize that LCH has a wide clinical spectrum and a highly varied course. Adults rarely develop LCH. Here, we report a case of adult localized LCH. CASE SUMMARY: A 32-year-old woman presented with plaques and ulcers on the vulva and crissum, accompanied by pain that persisted for more than one year. Physical examination revealed a red-infiltrating plaque with ulcerations and exudates in the vulva and crissum. Pathological examination revealed a diffuse infiltration of lymphocytes, eosinophilic granulocytes, and histiocytoid cells in the superficial dermis. Proliferative histiocytoid cells showed mild atypia, partly with kidney-shaped nuclei. Immunohistochemical examination showed that the histiocytoid cells were positive for S100 protein and CD1 and weakly positive for CD68 (20% +), with a Ki-67 index of 30%. Laboratory tests did not reveal any other systemic damage. The patient was diagnosed with adult localized LCH and was prescribed oral prednisone (20 mg) once daily. The skin lesions gradually improved and are still being followed-up. CONCLUSION: Adult localized LCH is rare and must be differentiated from other common conditions.

Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity. However, the precise mechanisms responsible for the combined impact of corona virus disease 2019 (COVID-19) and diabetes have not yet been elucidated, and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited. To investigate the disease pathogenesis, K18-hACE2 transgenic (hACE2 Tg) mice with a leptin receptor deficiency (hACE2-Lepr -/-) or high-fat diet (hACE2-HFD) background were generated. The two mouse models were intranasally infected with a 5×10 5 median tissue culture infectious dose (TCID 50) of SARS-CoV-2, with serum and lung tissue samples collected at 3 days post-infection. The hACE2-Lepr -/- mice were then administered a combination of low-molecular-weight heparin (LMWH) (1 mg/kg or 5 mg/kg) and insulin via subcutaneous injection prior to intranasal infection with 1×10 4 TCID 50 of SARS-CoV-2. Daily drug administration continued until the euthanasia of the mice. Analyses of viral RNA loads, histopathological changes in lung tissue, and inflammation factors were conducted. Results demonstrated similar SARS-CoV-2 susceptibility in hACE2 Tg mice under both lean (chow diet) and obese (HFD) conditions. However, compared to the hACE2-Lepr +/+ mice, hACE2-Lepr -/- mice exhibited more severe lung injury, enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α, and increased apoptosis. Moreover, combined LMWH and insulin treatment effectively reduced disease progression and severity, attenuated lung pathological changes, and mitigated inflammatory responses. In conclusion, pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection, and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes.

Nuclear translocation of thioredoxin-1 promotes colorectal cancer development via modulation of the IL-6/STAT3 signaling axis through interaction with STAT3.

Background: Thioredoxin 1 (Trx-1) is a small redox protein predominantly localized in the cytoplasm. Its expression is increased in several cancers, including colorectal cancer (CRC). However, the function of Trx-1 translocation to the nucleus in cancer is not clear. In this study, we investigated the role of Trx-1 nuclear translocation in development of CRC. Methods: Expression of Trx-1 and STAT3 was analyzed by Western blot and immunofluorescence. Endogenous interaction of Trx-1, STAT3, and karyopherin α1 in CRC cells was analyzed by co-immunoprecipitation. Trx-1 and pSTAT3 nuclear staining in human CRC tissues was analyzed by immunohistochemistry. A mouse model of AOM/DSS induced colitis-associated cancer (CAC) was utilized to investigate the antitumor effect of PX-12, a Trx-1 inhibitor. A knockin mouse with the Txn1(KK81-82EE) mutation was generated via CRISPR/Cas9, and CAC was induced in knockin and wild-type mice. Results: Nuclear translocation of Trx-1 was induced by IL-6, and inhibition of this translocation reversed IL-6-induced epithelial-to-mesenchymal transition, invasion and metastasis. Karyopherin α1 was found to specifically mediate IL-6-induced translocation of the Trx-1-pSTAT3 complex into the nucleus. Nuclear Trx-1 expression was closely correlated with lymph node metastasis and distant metastasis in human CRC. In addition, nuclear staining of Trx-1 showed significant positive correlation with nuclear staining of pSTAT3 in human CRC tissues. PX-12, an inhibitor of Trx-1, significantly impaired the activation of STAT3 and suppressed the development of AOM/DSS-induced CAC in mice. Moreover, AOM/DSS-induced nuclear Trx-1 expression was suppressed in Txn1(KK81-82EE) mice, which inhibited STAT3 activation and cancer progression. Conclusions: These results provide new insights into the mechanisms of STAT3 activation triggered by IL-6 and identify nuclear translocation of Trx-1 as a potential therapeutic target for the treatment of CRC and CAC.

Identified eleven exon variants in PKD1 and PKD2 genes that altered RNA splicing by minigene assay.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic multisystem disease caused primarily by mutations in the PKD1 gene or PKD2 gene. There is increasing evidence that some of these variants, which are described as missense, synonymous or nonsense mutations in the literature or databases, may be deleterious by affecting the pre-mRNA splicing process. RESULTS: This study aimed to determine the effect of these PKD1 and PKD2 variants on exon splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 19 candidate single nucleotide alterations, 11 variants distributed in PKD1 (c.7866C > A, c.7960A > G, c.7979A > T, c.7987C > T, c.11248C > G, c.11251C > T, c.11257C > G, c.11257C > T, c.11346C > T, and c.11393C > G) and PKD2 (c.1480G > T) were identified to result in exon skipping. CONCLUSIONS: We confirmed that 11 variants in the gene of PKD1 and PKD2 affect normal splicing by interfering the recognition of classical splicing sites or by disrupting exon splicing enhancers and generating exon splicing silencers. This is the most comprehensive study to date on pre-mRNA splicing of exonic variants in ADPKD-associated disease-causing genes in consideration of the increasing number of identified variants in PKD1 and PKD2 gene in recent years. These results emphasize the significance of assessing the effect of exon single nucleotide variants in ADPKD at the mRNA level.

Adaptive forward collision warning system for hazmat truck drivers: Considering differential driving behavior and risk levels.

The risky driving behavior of hazmat truck drivers is a crucial factor in many severe traffic accidents. In-vehicle Advanced Driving Assistance Systems (ADAS), integrating vehicle active safety and driver assistance technology, has been installed into hazmat trucks aiming to reduce driving risks during emergencies. This paper presents an enhanced dynamic Forward Collision Warning (FCW) model tailored for hazmat truck drivers with different driving characteristics and risk levels. Our objective is to determine the optimal moment to alert drivers during risky situations. The novelty of our approach lies in analyzing the driver's response mechanism to the warning by considering their characteristics and real-time driving risk levels. We employ a multi-objective optimization method that integrates real-time driving risk, driver acceptance, and driving comfort to calculate the optimal warning time. Our findings indicate that the appropriate warning time is similar for all drivers under high-level risks, while significant differentiation exists for different driver categories under mid-level and low-level risks. Additionally, aggressive drivers tend to follow leading vehicles closely and exhibit lower deceleration intentions when faced with dangers compared to normal and cautious drivers. Our research outcomes enable the development of user profiles for hazmat truck drivers based on extensive historical driving records, facilitating the analysis of driver response differences to FCWs. This enhances driving safety and improves driver trust in ADAS systems.