Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

[A case of Neonatal generalized atrophic benign epidermolysis bullosa due to variants of COL17A1 gene].

OBJECTIVE: To diagnose and explore the genetic etiology of a neonate with Hereditary epidermolysis bullosa. METHODS: A neonate who was admitted to Suqian Hospital Affiliated to Xuzhou Medical University on July 10, 2021 was selected as the study subject. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. And target gene capture and next-generation sequencing were carried out. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. RESULTS: The child was found to harbor compound heterozygous variants of the COL17A1 gene, namely c.997C>T (p.Q333X) and c.3481dupT (p.Y1161fs*2), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic. CONCLUSION: The child was diagnosed with Generalized atrophic benign epidermolysis bullosa due to the compound heterozygous variants of the COL17A1 gene.

Chronic atrophic gastritis and risk of incident upper gastrointestinal cancers: a systematic review and meta-analysis.

BACKGROUND: Previous literature has explored the relationship between chronic atrophic gastritis (CAG) and isolated cancers within the upper gastrointestinal cancers; However, an integrative synthesis across the totality of upper gastrointestinal cancers was conspicuously absent. The research objective was to assess the relationship between CAG and the risk of incident upper gastrointestinal cancers, specifically including gastric cancer, oesophageal cancer, and oesophagogastric junction cancer. METHODS: Rigorous systematic searches were conducted across three major databases, namely PubMed, Embase and Web of Science, encompassing the timeline from database inception until August 10, 2023. We extracted the necessary odds ratio (OR) and their corresponding 95% confidence interval (CI) for subsequent meta-analysis. Statistical analyses were conducted using Stata 17.0 software. RESULTS: This meta-analysis included a total of 23 articles encompassing 5858 patients diagnosed with upper gastrointestinal cancers. CAG resulted in a statistically significant 4.12-fold elevated risk of incident gastric cancer (OR = 4.12, 95% CI 3.20-5.30). Likewise, CAG was linked to a 2.08-fold increased risk of incident oesophageal cancer (OR = 2.08, 95%CI 1.60-2.72). Intriguingly, a specific correlation was found between CAG and the risk of incident oesophageal squamous cell carcinoma (OR = 2.29, 95%CI 1.77-2.95), while no significant association was detected for oesophageal adenocarcinoma (OR = 0.62, 95%CI 0.17-2.26). Moreover, CAG was correlated with a 2.77-fold heightened risk of oesophagogastric junction cancer (OR = 2.77, 95%CI 2.21-3.46). Notably, for the same type of upper gastrointestinal cancer, it was observed that diagnosing CAG through histological methods was linked to a 33-77% higher risk of developing cancer compared to diagnosing CAG through serological methods. CONCLUSION: This meta-analysis indicated a two- to fourfold increased risk of gastric cancer, oesophageal cancer, and oesophagogastric junction cancer in patients with CAG. Importantly, for the same upper gastrointestinal cancer, the risk of incident cancer was higher when CAG was diagnosed histologically compared to serological diagnosis. Further rigorous study designs are required to explore the impact of CAG diagnosed through both diagnostic methods on the risk of upper gastrointestinal cancers.

Beneficial changes in gut microbiota after phototherapy for neonatal hyperbilirubinemia.

Phototherapy is the most commonly used treatment for neonatal hyperbilirubinemia (NH). Gut microbiota is involved in bilirubin metabolism; however, it is uncertain whether this is affected by phototherapy. The present study included 43 newborns with hyperbilirubinemia and collected fecal samples for high-throughput sequencing before and after phototherapy. Selection α diversity analysis was used to determine the differences in diversity and abundance between the two groups, whereas similarity was determined using ß diversity analysis. Linear discriminant analysis effect size analysis was used to screen for markedly different bacteria. The structure of the gut microbiota in newborns with hyperbilirubinemia changed after phototherapy, with a significant decrease in abundance and diversity. The changes in the key bacterial species were characterized by an increase in the abundance of Streptococcus salivarius and a decrease in the abundance of Escherichia, Klebsiella pneumoniae, Rothia mucilaginosa and Streptococcus oralis. These changes mainly manifested as an increase in beneficial bacteria and a decrease in opportunistic bacteria, which may not be related to the side effects of phototherapy. These results can provide theoretical assistance for microbiological research on the later stages of NH.

Combination of anti-SSA/Ro60 and anti-dsDNA serotype is predictive of belimumab renal response in patients with lupus nephritis.

OBJECTIVES: To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting. METHODS: This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m2 at baseline. Complete renal response (CRR), partial renal response (PRR), no renal response (NRR) and primary efficacy renal response (PERR) were evaluated. Multivariable logistic regression was used to identify risk factors for NRR to belimumab at 6 months. RESULTS: Among the 122 patients enrolled, the proportions of patients achieving CRR, PRR, NRR and PERR were 35.9%, 17.1%, 47.0% and 44.4% at 6 months (n=117) and 55.6%, 19.4%, 26.4% and 58.3% at 12 months (n=72), respectively. Proteinuria, daily prednisone dosage and Systemic Lupus Erythematosus Disease Activity Index 2000 scores significantly decreased at 6 and 12 months (p<0.0001). NRR at 6 months (NRR6) was the strongest negative predictor of CRR at 12 months. Baseline anti-dsDNA positivity inversely predicted NRR6 (OR=0.32,95% CI=0.10 to 0.98, p=0.049), while anti-SSA/Ro60 positively predicted NRR6 (OR=3.16, 95% CI=1.14 to 8.74, p=0.027). The combination of anti-SSA/Ro60 and anti-dsDNA serotype quantitatively predicted belimumab renal response. CONCLUSION: The effectiveness of belimumab was reproducible in Chinese patients with active LN. The simple yet interesting serotype predictive model needs further validation and its possible underlying mechanistic relevance deserves further exploration.

Elabela ameliorates neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling in ischemic stroke.

Pyroptosis signifies a significant form of programmed neuronal demise subsequent to ischemic stroke. In our prior investigations, we demonstrated that the Elabela (ELA)-Apelin receptor (APJ) axis alleviated neuronal death by improving collateral circulation and mitigating ferroptosis in a murine model of middle cerebral artery occlusion (MCAO). However, the connection between ELA and neuronal pyroptosis remains further elucidation. Here, we observed an upregulation of ELA and APJ expression in both murine brain specimens and cultured HT-22 hippocampal neurons exposed to experimental ischemic stroke. ELA administration markedly diminished the infarct size in comparison to controls. ELA treatment ameliorated neurological deficits and anxiety-like symptoms in mice with stroke, concurrently inhibiting pyroptosis and mitochondria fission in neurons. Conversely, ELA knockdown yielded the opposite effects. Utilizing RNA-sequencing analysis, we identified a candidate for pyroptosis priming, Z-DNA-binding protein 1 (ZBP1), which was suppressed in ELA-treated HT-22 neurons during oxygen-glucose deprivation/reperfusion (OGD/R). Subsequent co-immunoprecipitation analyses demonstrated the binding between APJ and ZBP1. Specifically, APJ suppressed ZBP1 to inhibit NLRP3 inflammasome activation and dynamin-related protein 1-mediated mitochondrial fission in neurons. In summary, our findings suggest that ELA functions as a stroke-induced signal limiting neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling, thereby underscoring ELA as a potential therapeutic target for ischemic stroke treatment.

Occurrence and prevalence of per- and polyfluoroalkyl substances in the sediment pore water of mariculture sites: Novel findings of PFASs from the Bohai and Yellow Seas using a newly established analytical method.

A new method for the determination of 26 legacy and emerging per- and polyfluoroalkyl substances (PFASs) in marine sediment pore water was developed using online solid phase extraction coupled with liquid chromatography-tandem mass spectrometry. The proposed method requires only about 1 mL of pore water samples. Satisfactory recoveries of most target PFASs (83.55-125.30 %) were achieved, with good precision (RSD of 1.09-16.53 %), linearity (R2 ≥ 0.990), and sensitivity (MDLs: 0.05 ng/L-5.00 ng/L for most PFASs). Subsequently, the method was applied to determine PFASs in the sediment pore water of five mariculture bays in the Bohai and Yellow Seas of China for the first time. Fifteen PFASs were detected with total concentrations ranging from 150.23 ng/L to 1838.48 ng/L (mean = 636.80 ng/L). The ∑PFASs and PFOA concentrations in sediment pore water were remarkably higher than those in surface seawater (tens of ng/L), indicating that the potential toxic effect of PFASs on benthic organisms may be underestimated. PFPeA was mainly distributed in pore water, and the partition of PFHpA (50.99 %) and PFOA (49.01 %) was almost equal in the solid and liquid phases. The proportions of all other PFASs partitioned in marine sediments were significantly higher than those in pore water.

Novel potential lncRNA biomarker in B cells indicates essential pathogenic pathway activation in patients with SLE.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to cluster B cell-expressing genes of patients with SLE into different gene modules and relate them to clinical features. Based on the results of WGCNA, candidate lncRNA levels were further explored in public bulk and single-cell RNA-sequencing data. In another independent cohort, the levels of the candidate were detected by RT-qPCR and the correlation with disease activity was analysed. RESULTS: WGCNA analysis revealed one gene module significantly correlated with clinical features, which was enriched in type I interferon (IFN) pathway. Among non-coding genes in this module, lncRNA RP11-273G15.2 was differentially expressed in all five subsets of B cells from patients with SLE compared with healthy controls and other autoimmune diseases. RT-qPCR validated that RP11-273G15.2 was highly expressed in SLE B cells and positively correlated with IFN scores (r=0.7329, p<0.0001) and disease activity (r=0.4710, p=0.0005). CONCLUSION: RP11-273G15.2 could act as a diagnostic and disease activity monitoring biomarker for SLE, which might have the potential to guide clinical management.

Fibroblast expression of neurotransmitter receptor HTR2A associates with inflammation in rheumatoid arthritis joint.

The study of neuroimmune crosstalk and the involvement of neurotransmitters in inflammation and bone health has illustrated their significance in joint-related conditions. One important mode of cell-to-cell communication in the synovial fluid (SF) is through extracellular vesicles (EVs) carrying microRNAs (miRNAs). The role of neurotransmitter receptors in the pathogenesis of inflammatory joint diseases, and whether there are specific miRNAs regulating differentially expressed HTR2A, contributing to the inflammatory processes and bone metabolism is unclear. Expression of neurotransmitter receptors and their correlated inflammatory molecules were identified in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium from a scRNA-seq dataset. Immunohistochemistry staining of synovial tissue (ST) from RA and OA patients was performed for validation. Expression of miRNAs targeting HTR2A carried by SF EVs was screened in low- and high-grade inflammation RA from a public dataset and validated by qPCR. HTR2A reduction by target miRNAs was verified by miRNAs mimics transfection into RA fibroblasts. HTR2A was found to be highly expressed in fibroblasts derived from RA synovial tissue. Its expression showed a positive correlation with the degree of inflammation observed. 5 miRNAs targeting HTR2A were decreased in RA SF EVs compared to OA, three of which, miR-214-3p, miR-3120-5p and miR-615-3p, mainly derived from monocytes in the SF, were validated as regulators of HTR2A expression. The findings suggest that fibroblast HTR2A may play a contributory role in inflammation and the pathogenesis of RA. Additionally, targeting miRNAs that act upon HTR2A could present novel therapeutic strategies for alleviating inflammation in RA.

Clinical and metagenomic characteristics of lymphadenopathy related to fever of unknown origin in children.

BACKGROUND: Diagnosis of fever of unknown origin remains challenge for pediatricians. Lymphadenopathy is a separate entity that mainly originates from infection or malignancy. METHODS: 168 patients with FUO accompanied by lymphadenectasis were reviewed. 33 lymph node tissue samples were examined by mNGS. Differences in clinical characteristics were compared among different disease groups. The value of mNGS in diagnosing and improving the clinical situation was assessed. RESULTS: Multivariate analysis revealed that hepatosplenomegaly and LDH levels were associated with infectious diseases. Arthralgia was correlated with non-infectious inflammatory diseases. Weight loss and a node located in supraclavicular region may indicate neoplastic diseases. mNGS-positive rate was 60.60%, higher than that obtained with traditional methods. Treatment for 3/4 patients was adjusted according to the pathogen detected by mNGS, and antibiotics uses was discontinued or degraded in over 1/2 of the patients according to mNGS results. CONCLUSIONS: Clinical characteristics of children with lymphadenopathy related to FUO have limited diagnostic value for distinguishing different kinds of diseases, while mNGS of lymph node tissue serves as a useful tool for identifying infectious diseases, especially those caused by rare pathogens. mNGS results can lead to not only adjustments in targeted treatment but also further confirmation of underlying diseases. IMPACT STATEMENT: 1. The clinical features of children with FUO and lymphadenopathy differ according to disease group,although multivariate analysis indicated little diagnostic value for these features. 2. mNGS on lymph node tissue from children with FUO may serve as a efficient tool for distinguishing infectious diseases from other diseases. This is especially useful when a diagnosis cannot be determined with traditional methods. 3. mNGS targeted treatment can be administered in a timely manner and some underlying diseases can be indicated.

Phosphorus release and realignment in anaerobic digestion of thermal hydrolysis pretreatment sludge - Masking effects from high ammonium.

Waste activated sludge (WAS) is a significant phosphorus (P) repository, and there is a growing interest in P recovery from WAS. Typically, the commercial technology for treating WAS involves thermal hydrolysis pretreatment (THP) coupled with anaerobic digestion (AD). However, there is ongoing debate regarding the transformation and distribution of P throughout this process. To address this, a long-term THP-AD process was operated in this study to comprehensively investigate P transformation and distribution. The results revealed that a substantial biodegradation of dissolved organic nitrogen (DON) raised the pH of the digestate to 8.3 during the AD process. This increased pH facilitated the dissolution of Al, leading to a reduction of 6.92 mg/L of NaOH-P. Simultaneously, sulfate reduction contributed to a decrease of 11.04 mg/L of Bipy-P in the solid. However, the reduction of Bipy-P and NaOH-P in the solid did not result in an improved P release to the supernatant. Conversely, a decrease of 23.60 mg/L P in the aqueous phase was observed after anaerobic digestion. The disappeared P was primarily precipitated with Mg and Ca, driven by the increased pH, and it contributed to the increase of HCl-P in the solid from 107.80 to 144.52 mg/L. These findings were further confirmed by results obtained from scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and solid-state 31P nuclear magnetic resonance (NMR) spectroscopy. This study provides valuable insights into the mechanisms of P transformation during THP-AD process that is nearly opposite from conventional AD system.

A reciprocal association between interpersonal relationship quality and student's positive affect: A three-wave random intercept cross-lagged study in a Chinese primary mathematics learning context.

AIM: This study adopted a three-wave random intercept cross-lagged panel model to explore the longitudinal reciprocal relationships between (a) the teacher-student relationship (TSR) quality and (b) the parent-child relationship (PCR) quality and positive affect among Chinese primary school students. SAMPLES: Two primary school student samples, including 3505 and 2505 students, were tracked with their perceived relationship quality with math teachers and parents and their positive affect levels in mathematics learning over three academic years. RESULTS: The results demonstrated that more closeness with parents could significantly predict students' subsequent higher level of positive affect in mathematics learning. However, more closeness with their math teachers did not show significant prediction. Meanwhile, more conflict with math teachers and parents could significantly predict their subsequent lower degree of perceived positive affect in mathematics learning. That is, a reciprocal association lines in the PCR quality and positive affect, whereas only a unidirectional association exists between the TSR and positive affect. The predictions of the experienced positive affect on their perceived interpersonal relationships with math teachers and parents were stronger than those in the reverse association. CONCLUSIONS: This study identifies that while the effects of closeness with math teachers and parents on positive affect in students' math learning differ, conflict with math teachers and parents indeed harms students' experienced positive affect in math learning. More attention should also be paid to fostering positive affect in math learning.

Non-coding DNA variants for risk in lupus.

Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease that arises from a dynamic interplay between genetics and environmental triggers. The advent of sophisticated genomics technology has catalyzed a shift in our understanding of disease etiology, spotlighting the pivotal role of non-coding DNA variants in SLE pathogenesis. In this review, we present a comprehensive examination of the non-coding variants associated with SLE, shedding light on their role in influencing disease risk and progression. We discuss the latest methodological advancements that have been instrumental in the identification and functional characterization of these genomic elements, with a special focus on the transformative power of CRISPR-based gene-editing technologies. Additionally, the review probes into the therapeutic opportunities that arise from modulating non-coding regions associated with SLE. Through an exploration of the complex network of non-coding DNA, this review aspires to decode the genetic puzzle of SLE and set the stage for groundbreaking gene-based therapeutic interventions and the advancement of precision medicine strategies tailored to SLE management.

Dual-functional mediators of high-entropy Prussian blue analogues for lithiophilicity and sulfiphilicity in Li-S batteries.

Lithium-sulfur (Li-S) batteries are considered promising next-generation energy storage systems due to their high energy density (2600 W h kg-1) and cost-effectiveness. However, the shuttle effect of lithium polysulfides in sulfur cathodes and uncontrollable Li dendrite growth in Li metal anodes significantly impede the practical application of Li-S batteries. In this study, we address these challenges by employing a high-entropy Prussian blue analogue Mn0.4Co0.4Ni0.4Cu0.4Zn0.4[Fe(CN)6]2 (HE-PBA) composite containing multiple metal ions as a dual-functional mediator for Li-S batteries. Specifically, the HE-PBA composite provides abundant metal active sites that efficiently chemisorb lithium polysulfides (LiPSs) to facilitate fast redox conversion kinetics of LiPSs. In Li metal anodes, the exceptional lithiophilicity of the HE-PBA ensures a homogeneous Li ion flux, resulting in uniform Li deposition while mitigating the growth of Li dendrites. As a result, our work demonstrates outstanding long-term cycling performance with a decay rate of only 0.05% per cycle over 1000 cycles at 2.0 C. The HE-PBA@Cu/Li anode maintains a stable overpotential even after 600 h at 0.5 mA cm-2 under the total areal capacity of 1.0 mA h cm-2. This study showcases the application potential of the HE-PBA in Li-S batteries and encourages further exploration of prospective high-entropy materials used to engineer next-generation batteries.

Near-gapless genome and transcriptome analyses provide insights into fruiting body development in Lentinula edodes.

Fruiting body development in macrofungi is an intensive research subject. In this study, high-quality genomes were assembled for two sexually compatible monokaryons from a heterokaryotic Lentinula edodes strain WX1, and variations in L. edodes genomes were analyzed. Specifically, differential gene expression and allele-specific expression (ASE) were analyzed using the two monokaryotic genomes and transcriptome data from four different stages of fruiting body development in WX1. Results revealed that after aeration, mycelia sensed cell wall stress, pheromones, and a decrease in CO2 concentration, leading to up-regulated expression in genes related to cell adhesion, cell wall remodeling, proteolysis, and lipid metabolism, which may promote primordium differentiation. Aquaporin genes and those related to proteolysis, mitosis, lipid, and carbohydrate metabolism may play important roles in primordium development, while genes related to tissue differentiation and sexual reproduction were active in fruiting body. Several essential genes for fruiting body development were allele-specifically expressed and the two nuclear types could synergistically regulate fruiting body development by dominantly expressing genes with different functions. ASE was probably induced by long terminal repeat-retrotransposons. Findings here contribute to the further understanding of the mechanism of fruiting body development in macrofungi.

Evaluation of the effectiveness and safety of sequential vaccination with inactivated SARS-CoV-2 vaccine and Ad5-nCoV booster in pediatric liver transplant recipients.

Amidst the COVID-19 pandemic, uncertainty persists among caregivers regarding the vaccination of pediatric liver transplant recipients (PLTRs). This study evaluates the immunogenicity and safety of COVID-19 vaccination in this vulnerable population. A cohort of 30 PLTRs underwent sequential vaccinations with an inactivated SARS-CoV-2 vaccine followed by an Ad5-nCoV booster. We collected and analyzed blood samples pre-vaccination and four weeks post-vaccination to quantify antibody and IGRA (IFN-γ Release Assay) levels. We also documented any adverse reactions occurring within seven days post-vaccination and monitored participants for infections over six months post-vaccination, culminating in a comprehensive statistical analysis. The Ad5-nCoV booster substantially elevated IgG (T1: 18.01, 20%; T2: 66.61, 55%) and nAb (T1: 119.29, 8%; T2: 3799.75, 80%) levels, as well as T-cell responses, in comparison to the initial dose. The first dose was associated with some common adverse reactions, such as injection site pain (13.3%) and fever (16.6%), but a low rate of systemic reactions (16.0%). There was no significant difference in Omicron infection rates or RTPCR conversion times between vaccinated and unvaccinated groups. Notably, following Omicron infection, vaccinated individuals exhibited significantly higher SARS-CoV-2 IgG and nAb titers (average IgG: 231.21 vs. 62.09 S/CO, p = 0.0003; nAb: 5246.11 vs. 2592.07 IU/mL, p = 0.0002). The use of inactivated vaccines followed by an Ad5-nCoV booster in PLTRs is generally safe and elicits a robust humoral response, albeit with limited T-cell responses.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

NUS1 Variants Cause Lennox-Gastaut Syndrome Related to Unfolded Protein Reaction Activation.

NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In this study, we identified two de novo variants of NUS1, a missense variant (c.868 C > T/p.R290C) and a splice site variant (c.792-2 A > G), in two unrelated LGS patients using trio-based whole-exome sequencing performed in a cohort of 165 LGS patients. Both variants were absent in the gnomAD population and showed a significantly higher observed number of variants than expected genome-wide. The R290C variant was predicted to damage NUS1 and decrease its protein stability. The c.792-2 A > G variant caused premature termination of the protein. Knockdown of NUS1 activated the UPR pathway, resulting in apoptosis of HEK293T cells. Supplementing cells with expression of wild-type NUS1, but not the mutant (R290C), rescued UPR activation and apoptosis in NUS1 knockdown cells. Compared to wild-type Drosophila, seizure-like behaviors and excitability in projection neurons were significantly increased in Tango14 (homolog of human NUS1) knockdown and Tango14R290C/+ knock-in Drosophila. Additionally, abnormal development and a small body size were observed in both mutants. Activated UPR signaling was also detected in both mutants. Thus, NUS1 is a causative gene for LGS with dominant inheritance. The pathogenicity of these variants is related to the UPR signaling activation, which may be a common pathogenic mechanism of DEE.

Research in the application of artificial intelligence to lung cancer diagnosis.

The morbidity and mortality rates in lung cancer are high worldwide. Early diagnosis and personalized treatment are important to manage this public health issue. In recent years, artificial intelligence (AI) has played increasingly important roles in early screening, auxiliary diagnosis, and prognostic assessment. AI uses algorithms to extract quantitative feature information from high-volume and high-latitude data and learn existing data to predict disease outcomes. In this review, we describe the current uses of AI in lung cancer-focused pathomics, imageomics, and genomics applications.

Can "Risk-Sharing" Mechanisms Help Clonal Aquatic Plants Mitigate the Stress of Nanoplastics?

Most aquatic plants applied to ecological restoration have demonstrated a clonal growth pattern. The risk-spreading strategy plays a crucial role in facilitating clonal plant growth under external environmental stresses via clonal integration. However, the effects of different concentrations of nanoplastics (NPs) on the growth traits of clonal aquatic plants are not well understood. Therefore, this study aimed to investigate the impact of NPs exposure on seedlings of parent plants and connected offspring ramets. A dose response experiment (0.1, 1, and 10 mg L-1) showed that the growth of Eichhornia crassipes (water hyacinth) was affected by 100 nm polystyrene nanoplastics after 28 days of exposure. Tracer analysis revealed that NPs are accumulated by parent plants and transferred to offspring ramets through stolon. Quantification analysis showed that when the parent plant was exposed to 10 mg L-1 NPs alone for 28 days, the offspring ramets contained approximately 13 ± 2 µg/g NPs. In the case of connected offspring ramets, leaf and root biomass decreased by 24%-51% and 32%-51%, respectively, when exposed to NP concentrations ranging from 0.1 to 10 mg L-1. Excessive enrichment of NPs had a detrimental effect on the photosynthetic system, decreasing the chlorophyll content and nonphotochemical quenching. An imbalance in the antioxidant defense systems, which were unable to cope with the oxidative stress caused by NP concentrations, further damaged various organs. The root system can take up NPs and then transfer them to the offspring through the stolon. Interference effects of NPs were observed in terms of root activity, metabolism, biofilm composition, and the plant's ability to purify water. However, the risk-spreading strategy employed by parent plants (interconnected offspring ramets) offered some relief from NP-induced stress, as it increased their relative growth rate by 1 to 1.38 times compared to individual plants. These findings provide substantial evidence of the high NP enrichment capacity of E. crassipes for ecological remediation. Nevertheless, we must also remain aware of the environmental risk associated with the spread of NPs within the clonal system of E. crassipes, and contaminated cloned individuals need to be precisely removed in a timely manner to maintain normal functions.