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.

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.

Health information in short videos about metabolic dysfunction-associated steatotic liver disease: Analysing quality and reliability.

BACKGROUND & AIMS: Short videos, crucial for disseminating health information on metabolic dysfunction-associated steatotic liver disease (MASLD), lack a clear evaluation of quality and reliability. This study aimed to assess the quality and reliability of MASLD-related videos on Chinese platforms. METHODS: Video samples were collected from three platforms (TikTok, Kwai and Bilibili) during the period from November 2019 to July 2023. Two independent reviewers evaluated the integrity of the information contained therein by scoring six key aspects of its content: definition, epidemiology, risk factors, outcomes, diagnosis and treatment. The quality and reliability of the videos were assessed using the Journal of the American Medical Association (JAMA) criteria, the Global Quality Score (GQS) and the modified DISCERN score. RESULTS: A total of 198 videos were included. The video content exhibited an overall unsatisfactory quality, with a primary emphasis on risk factors and treatment, while diagnosis and epidemiology were seldom addressed. Regarding the sources of the videos, the GQS and modified DISCERN scores varied significantly between the platforms (p = .003), although they had generally similar JAMA scores (p = .251). Videos created by medical professionals differed significantly in terms of JAMA scores (p = .046) compared to those created by nonmedical professionals, but there were no statistically significant differences in GQS (p = .923) or modified DISCERN scores (p = .317). CONCLUSIONS: The overall quality and reliability of the videos were poor and varied between platforms and uploaders. Platforms and healthcare professionals should strive to provide more reliable health-related information regarding MASLD.

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.

TikTok and Bilibili as health information sources on gastroesophageal reflux disease: an assessment of content and its quality.

Gastroesophageal reflux disease (GERD) is a global chronic disease. Short video platforms make it easy for patients with GERD to obtain medical information. However, the quality of information from these videos remains uncertain. This study aimed to systematically assess videos related to GERD on TikTok and Bilibili. We conducted a search and gathered 241 Chinese videos related to GERD and recorded the essential information. Two independent evaluators assessed each video based on the completeness of six components of the GERD guidelines, and assessed the quality and reliability of the information in the videos using recognition tools. Finally, videos from different sources were compared. The uploaders of most videos were medical professionals (86.7%, n = 209). The content was mainly about symptoms and treatment. The quality of the videos information varied depending on the sources. Among videos posted on Bilibili, those posted by medical professionals had a lower content score for definition (P < 0.001). Videos produced by non-gastroenterologists had the highest mean modified DISCERN. (The DISCERN scoring tool was initially created for assessing written publications, but nowadays, it is frequently leveraged for appraising various health-related videos. Details can be found in the text) quality of the videos information was acceptable; however, the content varied significantly depending on the type of source used. Videos with broad content should be carefully screened to meet more needs.

Partial Transfer Learning Method Based on Inter-Class Feature Transfer for Rolling Bearing Fault Diagnosis.

Rolling bearing fault diagnosis methods based on transfer learning always assume that the sample classes in the target domain are consistent with those in the source domain during the training phase. However, it is difficult to collect all fault classes in the early stage of mechanical application. The more likely situation is that the training data in the target domain only contain a subset of the entire health state, which will lead to the problem of label imbalance compared with the source domain. The outlier classes in the source domain that do not have corresponding target domain samples for feature alignment will interfere with the feature transfer of other classes. To address this specific challenge, this study introduces an innovative inter-class feature transfer fault diagnosis approach. By leveraging label information, the method distinctively computes the distribution discrepancies among shared classes, thereby circumventing the deleterious influence of outlier classes on the transfer procedure. Empirical evaluations on two rolling bearing datasets, encompassing multiple partial transfer tasks, substantiate that the proposed method surpasses other approaches, offering a novel and efficacious solution for the realm of intelligent bearing fault diagnosis.

A case of Abernethy malformation type I combined with hepatoblastoma.

This article encountered an extremely rare case of a 2-year-old male with Abernethy malformation Type I combined with hepatoblastoma. Furthermore, the medical history was characterized by several other abnormalities: gross facial asymmetry and cardiac defects，thus, diagnosis of Goldenhar syndrome in the setting of Abernethy type I was made. In this article, we exhibit the typical clinical presentation and Pathology imaging features of this disease.

A novel discrete linkage-type electrode for radiofrequency-induced intestinal anastomosis.

INTRODUCTION: For decades, radiofrequency (RF)-induced tissue fusion has garnered great attention due to its potential to replace sutures and staples for anastomosis of tissue reconstruction. However, the complexities of achieving high bonding strength and reducing excessive thermal damage present substantial limitations of existing fusion devices. MATERIALS AND METHODS: This study proposed a discrete linkage-type electrode to carry out ex vivo RF-induced intestinal anastomosis experiments. The anastomotic strength was examined by burst pressure and shear strength test. The degree of thermal damage was monitored through an infrared thermal imager. And the anastomotic stoma fused by the electrode was further investigated through histopathological and ultrastructural observation. RESULTS: The burst pressure and shear strength of anastomotic tissue can reach 62.2 ± 3.08 mmHg and 8.73 ± 1.11N, respectively, when the pressure, power and duration are 995 kPa, 160 W and 13 s, and the thermal damage can be controlled within limits. Histopathological and ultrastructural observation indicate that an intact and fully fused stomas with collagenic crosslink can be formed. CONCLUSION: The discrete linkage-type electrode presents favorable efficiency and security in RF-induced tissue fusion, and these results are informative to the design of electrosurgical medical devices with controllable pressure and energy delivery.

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.

Inhibition of astroglial hemichannels ameliorates infrasonic noise induced short-term learning and memory impairment.

As a kind of environmental noise, infrasonic noise has negative effects on various human organs. To date, research has shown that infrasound impairs cognitive function, especially the ability for learning and memory. Previously, we demonstrated that impaired learning and memory induced by infrasound was closely related with glia activation; however, the underlying mechanisms remain unclear. Connexin 43 hemichannels (Cx43 HCs), which are mainly expressed in hippocampal astrocytes, are activated under pathological conditions, lending support to the hypothesis that Cx43 HCs might function in the impaired learning and memory induced by infrasound. This study revealed that that blocking hippocampal Cx43 HCs or downregulating hippocampal Cx43 expression significantly alleviated impaired learning and memory induced by infrasound. We also observed that infrasound exposure led to the abundant release of glutamate and ATP through Cx43 HCs. In addition, the abundant release of glutamate and ATP depended on proinflammatory cytokines. Our finds suggested that the enhanced release of ATP and glutamate by astroglial Cx43 HCs may be involved in the learning and memory deficits caused by infrasound exposure.

Higher oxidative balance scores are associated with lower nonalcoholic fatty liver disease and not with fibrosis in US adults.

BACKGROUND AND AIMS: Little research have focused on the relationship between systemic oxidative stress status and NAFLD and fibrosis. The Oxidative Balance Score (OBS) is employed to evaluate whole-body lifestyle and diet exposures related to oxidative stress, with higher OBS scores implying exposure to more antioxidants. This study aimed to explore whether OBS is correlated with NAFLD and NAFLD-related fibrosis. METHODS AND RESULTS: 12,223 participants from NHANES 2003-2018 were enrolled in this study. NAFLD was defined as USFLI ≥30 and liver fibrosis was determined as FIB-4 ≥ 2.67. OBS was scored by 20 lifestyle and dietary factors. Weighted logistic regression and restricted cubic splines were used to assess the association between OBS and NAFLD and fibrosis. The prevalence of NAFLD was 29.67%. There was a significant negative correlation between OBS, dietary OBS, lifestyle OBS and NAFLD and no correlation with NAFLD-related fibrosis. Compared to the lowest quartile, the adjusted ORs for the highest quartile of OBS, lifestyle OBS, dietary OBS and NAFLD were 0.55(95%CI:0.35,0.85), 0.12(95%CI:0.08,0.16), 0.70(95%CI:0.52,0.94) respectively. In stratified analyses, lifestyle OBS was negatively associated with NAFLD across gender, dietary OBS was only negatively correlated with NAFLD in men, and any OBS was not observed to be relevant to NAFLD-related fibrosis. CONCLUSIONS: OBS was negatively associated with NAFLD, but not with NAFLD-related fibrosis. The findings underline the significance of adhering to an antioxidant lifestyle and diet, which can help prevent NAFLD but seems to be ineffective in preventing fibrosis in individuals with NAFLD.

Origins of black carbon from anthropogenic emissions and open biomass burning transported to Xishuangbanna, Southwest China.

Black carbon (BC) has importance regarding aerosol composition, radiative balance, and human exposure. This study adopted a backward-trajectory approach to quantify the origins of BC from anthropogenic emissions (BCAn) and open biomass burning (BCBB) transported to Xishuangbanna in 2017. Haze months, between haze and clean months, and clean months in Xishuangbanna were defined according to daily PM2.5 concentrations of >75, 35-75, and <35 µg/m3, respectively. Results showed that the transport efficiency density (TED) of BC transported to Xishuangbanna was controlled by the prevailing winds in different seasons. The yearly contributions to the effective emission intensity of BCAn and BCBB transported to Xishuangbanna were 52% and 48%, respectively. However, when haze occurred in Xishuangbanna, the average BCAn and BCBB contributions were 23% and 77%, respectively. This suggests that open biomass burning (BB) becomes the dominant source in haze months. Myanmar, India, and Laos were the dominant source regions of BC transported to Xishuangbanna during haze months, accounting for 59%, 18%, and 13% of the total, respectively. Furthermore, India was identified as the most important source regions of BCAn transported to Xishuangbanna in haze months, accounting for 14%. The two countries making the greatest contributions to BCBB transported to Xishuangbanna were Myanmar and Laos in haze months, accounting for 55% and 13%, respectively. BC emissions from Xishuangbanna had minimal effects on the results of the present study. It is suggested that open BB in Myanmar and Laos, and anthropogenic emissions in India were responsible for poor air quality in Xishuangbanna.

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Necroptosis is one of the regulated cell death, which involves receptor interacting protein kinase (RIPK) 1/RIPK3/mixed lineage kinase domain like protein (MLKL) signaling pathway. Among them, MLKL is the final execution of necroptosis. The formation of RIPK1/RIPK3/MLKL necrosome induces the phosphorylated MLKL, and the activated MLKL penetrates into the membrane bilayer to form membrane pores, which damages the integrity of the membrane and leads to cell death. In addition to participating in necroptosis, MLKL is also closely related to other cell death, such as NETosis, pyroptosis, and autophagy. Therefore, MLKL is involved in the pathological processes of various diseases related to abnormal cell death pathways (such as cardiovascular diseases, neurodegenerative diseases and cancer), and may be a therapeutic target of multiple diseases. Understanding the role of MLKL in different cell death can lay a foundation for seeking various MLKL-related disease targets, and also guide the development and application of MLKL inhibitors.

Identification of two novel variants of BCS1L gene in a patient with classical GRACILE syndrome.

BCS1L pathogenic variants cause widely different clinical phenotypes. Disease phenotypes can be as mild as Björnstad syndrome, characterized by pili torti (abnormal flat twisted hair shafts) and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death. BCS1L pathogenic variants are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving renal and hepatic pathologies, hypotonia, and developmental delays. So far, all patients with GRACILE syndrome carry a homozygous p.Ser78Gly variant in BCS1L gene by reviewing articles. A 24-day-old boy presented with typical clinical phenotype of GRACILE syndrome. The Whole Exome Sequencing confirmed that the patient had a missense variant (c.245C > T, p.Ser82Leu) and a small deletion (c.231_232delCA, p. Ser78Cysfs*9) in BCS1L gene inherited from his father and mother separately, he died at 5 months of age. We reported a patient with GRACILE syndrome and identified two novel variants in BCS1L gene. Our study expands the mutational spectrum of BCS1L gene associated with GRACILE syndrome and will be beneficial for genetic diagnosis.

Role of abnormal energy metabolism in the progression of chronic kidney disease and drug intervention.

Chronic kidney disease (CKD) is a severe clinical syndrome with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal kidney function and energy metabolism disorders are increasingly recognized as an important player in CKD. Energy metabolism disorders are characterized by ATP deficits and reactive oxygen species increase. Oxygen and mitochondria are essential for ATP production, hypoxia and mitochondrial dysfunction both affect the energy production process. Renin-angiotensin and adenine signaling pathway also play important regulatory roles in energy metabolism. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease. Currently, drugs with clinically clear renal function protection, such as Angiotensin II Type 1 receptor blockers and fenofibrate, have been proven to improve energy metabolism disorders. The sodium-glucose co-transporter inhibitors 2 that can mediate glucose metabolism disorders not only delay the progress of diabetic nephropathy, but also have significant protective effects in non-diabetic nephropathy. Hypoxia-inducible factor enhances ATP production to the kidney by improving renal oxygen supply and increasing glycolysis, and the mitochondria targeted peptides (SS-31) plays a protective role by stabilizing the mitochondrial inner membrane. Moreover, several drugs are being studied and are predicted to have potential renal protective properties. We propose that the regulation of energy metabolism represents a promising strategy to delay the progression of CKD.

WRKY Transcription Factors Actively Respond to Fusarium oxysporum in Lilium regale.

The WRKY transcription factors form a plant-specific superfamily important for regulating plant development, stress responses, and hormone signal transduction. In this study, many WRKY genes (LrWRKY1-35) were identified in Lilium regale, which is a wild lily species highly resistant to Fusarium wilt. These WRKY genes were divided into three classes (I to III) based on a phylogenetic analysis. The Class-II WRKY transcription factors were further divided into five subclasses (IIa, IIb, IIc, IId, and IIe). Moreover, the gene expression patterns based on a quantitative real-time PCR analysis revealed the WRKY genes were differentially expressed in the L. regale roots, stems, leaves, and flowers. Additionally, the expression of the WRKY genes was affected by an infection by Fusarium oxysporum as well as by salicylic acid, methyl jasmonate, ethephon, and hydrogen peroxide treatments. Moreover, the LrWRKY1 protein was localized to the nucleus of onion epidermal cells. The recombinant LrWRKY1 protein purified from Escherichia coli bound specifically to DNA fragments containing the W-box sequence, and a yeast one-hybrid assay indicated that LrWRKY1 can activate transcription. A co-expression assay in tobacco (Nicotiana tabacum) confirmed LrWRKY1 regulates the expression of LrPR10-5. Furthermore, the overexpression of LrWRKY1 in tobacco and the Oriental hybrid 'Siberia' (susceptible to F. oxysporum) increased the resistance of the transgenic plants to F. oxysporum. Overall, LrWRKY1 regulates the expression of the resistance gene LrPR10-5 and is involved in the defense response of L. regale to F. oxysporum. This study provides valuable information regarding the expression and functional characteristics of L. regale WRKY genes.

Time-Frequency Distribution Map-Based Convolutional Neural Network (CNN) Model for Underwater Pipeline Leakage Detection Using Acoustic Signals.

Detection technology of underwater pipeline leakage plays an important role in the subsea production system. In this paper, a new method based on the acoustic leak signal collected by a hydrophone is proposed to detect pipeline leakage in the subsea production system. Through the pipeline leakage test, it is found that the radiation noise is a continuous spectrum of the medium and high-frequency noise. Both the increase in pipe pressure and the diameter of the leak hole will narrow the spectral structure and shift the spectrum center towards the low frequencies. Under the same condition, the pipe pressure has a greater impact on the noise; every 0.05 MPa increase in the pressure, the radiation sound pressure level increases by 6-7 dB. The time-frequency images were obtained by processing the acoustic signals using the Ensemble Empirical Mode Decomposition (EEMD) and Hilbert-Huang transform (HHT), and fed into a two-layer Convolutional Neural Network (CNN) for leakage detection. The results show that CNN can correctly identify the degree of pipeline leakage. Hence, the proposed method provides a new approach for the detection of pipeline leakage in underwater engineering applications.

Air pollution characteristics and their relationship with emissions and meteorology in the Yangtze River Delta region during 2014-2016.

With rapid economic growth and urbanization, the Yangtze River Delta (YRD) region in China has experienced serious air pollution challenges. In this study, we analyzed the air pollution characteristics and their relationship with emissions and meteorology in the YRD region during 2014-2016. In recent years, the concentrations of all air pollutants, except O3, decreased. Spatially, the PM2.5, PM10, SO2, and CO concentrations were higher in the northern YRD region, and NO2 and O3 were higher in the central YRD region. Based on the number of non-attainment days (i.e., days with air quality index greater than 100), PM2.5 was the largest contributor to air pollution in the YRD region, followed by O3, PM10, and NO2. However, particulate matter pollution has declined gradually, while O3 pollution worsened. Meteorological conditions mainly influenced day-to-day variations in pollutant concentrations. PM2.5 concentration was inversely related to wind speed, while O3 concentration was positively correlated with temperature and negatively correlated with relative humidity. The air quality improvement in recent years was mainly attributed to emission reductions. During 2014-2016, PM2.5, PM10, SO2, NOx, CO, NH3, and volatile organic compound (VOC) emissions in the YRD region were reduced by 26.3%, 29.2%, 32.4%, 8.1%, 15.9%, 4.5%, and 0.3%, respectively. Regional transport also contributed to the air pollution. During regional haze periods, pollutants from North China and East China aggravated the pollution in the YRD region. Our findings suggest that emission reduction and regional joint prevention and control helped to improve the air quality in the YRD region.

Plasmonic enhancement of the upconversion fluorescence in YVO4:Yb³âº, Er³âº nanocrystals based on the porous Ag film.

The upconversion luminescence (UCL) enhancement based on the surface plasmonic resonance (SPR) of noble metals is a promising way to improve UCL efficiency. However, it is still a challenge to achieve stable and effective UCL enhancement. Here, we present the preparation of the porous Ag/YVO4:Yb(3+), Er(3+) composite film via a simple double annealing method. It is exciting to observe that a maximum 36-fold ((2)H11/2-(4)I15/2) and 30-fold ((4)S3/2-(4)I15/2) UCL enhancement in the porous Ag/YVO4:Yb(3+), Er(3+) composite film, attributed to the effective coupling between SPR and the excitation light by adjusting the SPR peak to the excitation wavelength, controlling the effective coupling distance and improving the scattering-absorption ratio. Furthermore, the enhancement factor strongly depended on the excitation power and the Er(3+) concentration.

Optimizing the hydrolysis-acidification stage in municipal wastewater treatment: comparison of immobilized fillers and granular sludge.

The decomposition of organic macromolecules in sewage currently benefits substantially from hydrolysis-acidification. The full use of its qualities can help domestic sewage to biodegrade more quickly, which promotes the subsequent aerobic reactions. This study evaluated the hydrolysis-acidification performance of granular sludge and filler in residential sewage. Both forms were highly effective at producing volatile fatty acids (VFAs) at the beginning of the reaction, but the granular sludge gradually disintegrated over time, particularly at low temperatures. The production of VFAs decreased (68.08 mg/L), and the effluent dissolved organic nitrogen (DON) increased (6.23 mg/L). However, the effluent of fillers remained at a lower level (1.3 mg/L) and produced more VFAs (74.13 mg/L). High-throughput sequencing revealed that the filler included a greater quantity of hydrolytic-acidifying bacteria than the granular sludge, which resulted in higher performance. In this study, the optimal form of utilizing hydrolytic acidifying bacteria was discussed to provide a theoretical basis to improve the full utilization of organic matter in domestic sewage and the removal of as much total nitrogen as possible.