Optimal Preservation of PFFs in Glycerol Enhances Suitability for Modeling Parkinson's Disease.

Injecting α-synuclein pre-formed fibrils (αSyn PFFs) into various tissues and organs involves converting monomeric αSyn into a fibrillar form, inducing extensive αSyn pathology that effectively models Parkinson's disease (PD). However, the distinct physicochemical properties of αSyn amyloid fibrils can potentially reduce their seeding activity, especially during storage. In this study, it is demonstrated that αSyn PFFs exhibit significant sensitivity to low temperatures, with notable denaturation occurring between -20 and 4 °C, and gradual disassembly persisted even under storage conditions at -80 °C. To mitigate this issue, a commonly used protein stabilizer, glycerol is introduced, which significantly reverses the cold-induced disassembly of PFFs. Remarkably, storing PFFs with 20% glycerol at -80 °C for a month preserved their morphology and seeding activity as freshly prepared PFFs. Glycerol-stabilized αSyn PFFs resulted in compromised neuronal survival, with the extent of these impairments correlating with the formation of αSyn pathology both in vivo and in vitro, indistinguishable from freshly prepared PFFs. Storing sonicated PFFs with 20% glycerol at -80 °C provides an optimal storage method, as sonication is necessary for activating their seeding potential. This approach reduces the frequency of sonication, simplifies handling, and ultimately lowers the overall workload, enhancing the practicality of using PFFs.

Bacillus amyloliquefaciens TL promotes gut health of broilers by the contribution of bacterial extracellular polysaccharides through its anti-inflammatory potential.

The focal point of probiotic efficacy and a crucial factor influencing poultry cultivation lies in the level of intestinal inflammation. In conventional farming processes, the reduction of intestinal inflammation generally proves advantageous for poultry growth. This study investigated the impact of Bacillus amyloliquefaciens TL (B.A.-TL) on inflammatory factor expression at both tissue and cellular levels, alongside an exploration of main active secondary metabolites. The results demonstrated that broiler feeding with a basal diet containing 4 × 109 CFU/kg B.A.-TL markedly enhanced chicken growth performance, concomitant with a significant decrease in the expression of genes encoding inflammatory cytokines (e.g., CCL4, CCR5, XCL1, IL-1ß, IL-6, IL-8, LITAF, and LYZ) in jejunum and ileum tissues. The extracellular polysaccharides of B.A.-TL (EPS-TL) exhibited notable suppression of elevated inflammatory cytokine expression induced by Escherichia coli O55 lipopolysaccharides (LPS) in chicken macrophage-like cells (HD11) and primary chicken embryonic small intestinal epithelial cells (PCIECs). Moreover, EPS-TL demonstrated inhibitory effect on NF-κB signaling pathway activation. These findings suggested that the metabolic product of B.A.-TL (i.e., EPS-TL) could partly mitigate the enhanced expression of inflammatory factors induced by LPS stimulation, indicating its potential as a key component contributing to the anti-inflammatory effects of B.A.-TL.

GeneCompass: deciphering universal gene regulatory mechanisms with a knowledge-informed cross-species foundation model.

Deciphering universal gene regulatory mechanisms in diverse organisms holds great potential for advancing our knowledge of fundamental life processes and facilitating clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms and does not integrate various cell types across species. Recent breakthroughs in single-cell sequencing and deep learning techniques present an unprecedented opportunity to address this challenge. In this study, we built an extensive dataset of over 120 million human and mouse single-cell transcriptomes. After data preprocessing, we obtained 101,768,420 single-cell transcriptomes and developed a knowledge-informed cross-species foundation model, named GeneCompass. During pre-training, GeneCompass effectively integrated four types of prior biological knowledge to enhance our understanding of gene regulatory mechanisms in a self-supervised manner. By fine-tuning for multiple downstream tasks, GeneCompass outperformed state-of-the-art models in diverse applications for a single species and unlocked new realms of cross-species biological investigations. We also employed GeneCompass to search for key factors associated with cell fate transition and showed that the predicted candidate genes could successfully induce the differentiation of human embryonic stem cells into the gonadal fate. Overall, GeneCompass demonstrates the advantages of using artificial intelligence technology to decipher universal gene regulatory mechanisms and shows tremendous potential for accelerating the discovery of critical cell fate regulators and candidate drug targets.

Production of α-ketoisovalerate with whey powder by systemic metabolic engineering of Klebsiella oxytoca.

BACKGROUND: Whey, which has high biochemical oxygen demand and chemical oxygen demand, is mass-produced as a major by-product of the dairying industry. Microbial fermentation using whey as the carbon source may convert this potential pollutant into value-added products. This study investigated the potential of using whey powder to produce α-ketoisovalerate, an important platform chemical. RESULTS: Klebsiella oxytoca VKO-9, an efficient L-valine producing strain belonging to Risk Group 1 organism, was selected for the production of α-ketoisovalerate. The leucine dehydrogenase and branched-chain α-keto acid dehydrogenase, which catalyzed the reductive amination and oxidative decarboxylation of α-ketoisovalerate, respectively, were inactivated to enhance the accumulation of α-ketoisovalerate. The production of α-ketoisovalerate was also improved through overexpressing α-acetolactate synthase responsible for pyruvate polymerization and mutant acetohydroxyacid isomeroreductase related to α-acetolactate reduction. The obtained strain K. oxytoca KIV-7 produced 37.3 g/L of α-ketoisovalerate from lactose, the major utilizable carbohydrate in whey. In addition, K. oxytoca KIV-7 also produced α-ketoisovalerate from whey powder with a concentration of 40.7 g/L and a yield of 0.418 g/g. CONCLUSION: The process introduced in this study enabled efficient α-ketoisovalerate production from low-cost substrate whey powder. Since the key genes for α-ketoisovalerate generation were integrated in genome of K. oxytoca KIV-7 and constitutively expressed, this strain is promising in stable α-ketoisovalerate fermentation and can be used as a chassis strain for α-ketoisovalerate derivatives production.

Effects of 60Coγ-irradiation combined with sodium dehydrogenate on post-harvest preservation and physiological indices of Volvariella volvacea.

Volvariella volvacea is a mushroom known for its high palatability and nutritional value. However, it is susceptible to spoilage thus making it challenging to preserve and keep fresh after harvest, resulting in constraints in long-distance transportation and long-term storage. This study aimed to investigate the feasibility of using irradiation and sodium dehydrogenate (SD) as a preservative in the preservation process of V. volvacea. The effects of three treatments of 0.8 kGy 60Coγ irradiation (B), 0.04% SD (C), combined with 0.04% SD and 0.8 kGy 60Coγ irradiation (A) on the postharvest freshness of V. volvacea were investigated. The assessment indices for V. volvacea, including appearance, browning rate, weight loss, respiration rate, MDA content, antioxidant enzyme activities, vitamin C (Vc), and soluble protein content, were measured and compared. The three treatments were compared to determine the changes in storage time over 7 days post-harvest. The results demonstrated that the hardness of the fruiting body exhibited a significant increase of 81.19%, 97.96% and 168.81% in comparison to the control, B and C, respectively, following the application of the treatment A. Compared to the control group, the soluble protein content was significantly increased by 20.28%. Respiration intensity and browning rate were significantly lower in the control treatment, decreasing by 35.07% and 45.49% respectively. On the 6th day of storage, the activities of SOD and POD increased by 81.06% and 73.71%, respectively, compared to the control, which significantly delayed the senescence of the fruiting bodies. The Vc content was significantly increased by 50.27%, 133.90%, and 101.39% in treatment B, which received 0.8 kGy 60Coγ irradiation alone, compared to the control, treatment A, and treatment C, respectively. The treatment C alone significantly reduced respiratory intensity and MDA variables by 39.55% and 31.01%, respectively, compared to the control. The findings can provide theoretical references and technical support for extending the preservation period of V. volvacea after harvesting by using irradiation and sodium dehydrogenate as a preservative.

Super enhanced purification of denatured-refolded ubiquitinated proteins by ThUBD revealed ubiquitinome dysfunction in liver fibrosis.

Ubiquitination is crucial for maintaining protein homeostasis and plays a vital role in diverse biological processes. Ubiquitinome profiling and quantification are of great scientific significance. Artificial ubiquitin-binding domains (UBDs) have been widely employed to capture ubiquitinated proteins. The success of this enrichment relies on recognizing native spatial structures of ubiquitin and ubiquitin chains by UBDs under native conditions. However, the use of native lysis conditions presents significant challenges, including insufficient protein extraction, heightened activity of deubiquitinating enzymes (DUBs) and proteasomes in removing the ubiquitin signal, and purification of a substantial number of contaminant proteins, all of which undermine the robustness and reproducibility of ubiquitinomics. In this study, we introduced a novel approach that combines denatured-refolded ubiquitinated sample preparation (DRUSP) with a tandem hybrid UBD (ThUBD) for ubiquitinomic analysis. The samples were effectively extracted using strongly denatured buffers and subsequently refolded using filters. DRUSP yielded a significantly stronger ubiquitin signal, nearly 3 times greater than that of the Control method. Then, 8 types of ubiquitin chains were quickly and accurately restored; therefore, they were recognized and enriched by ThUBD with high efficiency and no biases. Compared with the Control method, DRUSP showed extremely high efficiency in enriching ubiquitinated proteins, improving overall ubiquitin signal enrichment by approximately 10-fold. Moreover, when combined with ubiquitin chain-specific UBDs, DRUSP had also been proven to be a versatile approach. This new method significantly enhanced the stability and reproducibility of ubiquitinomics research. Finally, DRUSP was successfully applied to deep ubiquitinome profiling of early mouse liver fibrosis with increased accuracy, revealing novel insights for liver fibrosis research.

RAG-seq: A NSR Primed and Transposase Tagmentation Mediated Strand-specific Total RNA Sequencing in Single Cell.

Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cellular diversity with unprecedented resolution. However, many current methods are limited in capturing full-length transcripts and discerning strand orientation. We present RAG-seq, an innovative strand-specific total RNA sequencing technique that combines not-so-random (NSR) primers with Tn5 transposase-mediated tagmentation. RAG-seq overcomes previous limitations by delivering comprehensive transcript coverage and maintaining strand orientation, which is essential for accurate quantification of overlapping genes and detection of antisense transcripts. Through optimized reverse transcription with oligo dT primers, rRNA depletion via Depletion of Abundant Sequences by Hybridization (DASH), and linear amplification, RAG-seq enhances sensitivity and reproducibility, especially for low-input samples and single cells. Application to mouse oocytes and early embryos highlights RAG-seq's superior performance in identifying stage-specific antisense transcripts, shedding light on their regulatory roles during early development. This advancement represents a significant leap in transcriptome analysis within complex biological contexts.

A synchronous-fluorescence analysis method combing with simple one-step extraction for determination of leonurine in traditional Chinese medicine.

Synchronous fluorescence spectroscopy (SFS) technology exhibits significant advantages in identifying target fluorescence signals within complex mixtures of multiple fluorescent compounds, owing to their closely overlapping spectra. In this study, a SFS method is reported for the first time for the direct analysis of leonurine in drugs containing concurrent natural products. By setting the wavelength interval (Δλ) to 30 nm, the characteristic emission peak of leonurine is observed at 307 nm, which increases proportionally with the concentration of leonurine without spectral overlap from other fluorescent species. The limit of detection (LOD) is estimated to be about 0.22 µM, and a low linear range of 0 to 20 µM is obtained. The common cations, anions and concomitant compounds display no interference with the SFS signal of leonurine, supporting the practical application of this method. Thus, we successfully applied this SFS method to detect leonurine in several real samples (leonurus granules, capsules, ointment and pills), in which the good relative standard deviation (RSD) values (0.04-4.24%) and recoveries (95.63-113%) were obtained. As a result, this work provides an efficient and convenient method to identify the target active compound from natural products without complex pre-treatment to diminish the fluorescent chaos that might be serving a potential role in the study of traditional Chinese medicine.

Alleviation of Lipid Disorder and Liver Damage in High-Fat Diet-Induced Obese Mice by Selenium-Enriched Cardamine violifolia with Cadmium Accumulation.

BACKGROUND/OBJECTIVES: As a hyperaccumulator of selenium (Se), Cardamine violifolia (Cv) and its peptide extract could ameliorate the negative effects of a high-fat diet (HFD). However, the effects of the coaccumulation of cadmium (Cd) in Se-enriched Cv (Cv2) and the potential confounding effect on the roles of enriched Se remain unknown. We aimed to investigate whether Cv2 could alleviate HFD-induced lipid disorder and liver damage. METHODS: Three groups of 31-week-old female mice were fed for 41 weeks (n = 10-12) with a control Cv-supplemented diet (Cv1D, 0.15 mg Se/kg, 30 µg Cd/kg, and 10% fat calories), a control Cv-supplemented HFD (Cv1HFD, 45% fat calories), and a Cv2-supplemented HFD (Cv2HFD, 1.5 mg Se/kg, 0.29 mg Cd/kg, and 45% fat calories). Liver and serum were collected to determine the element concentrations, markers of liver injury and lipid disorder, and mRNA and/or protein expression of lipid metabolism factors, heavy metal detoxification factors, and selenoproteins. RESULTS: Both Cv1HFD and Cv2HFD induced obesity, and Cv2HFD downregulated Selenoi and upregulated Dio3 compared with Cv1D. When comparing Cv2HFD against Cv1HFD, Cv2 increased the liver Se and Cd, the protein abundance of Selenoh, and the mRNA abundance of 10 selenoproteins; reduced the serum TG, TC, and AST; reduced the liver TG, lipid droplets, malondialdehyde, and mRNA abundance of Mtf1 and Mt2; and differentially regulated the mRNA levels of lipid metabolism factors. CONCLUSIONS: Cv2 alleviated HFD-induced lipid dysregulation and liver damage, which was probably associated with its unique Se speciation. However, further research is needed to explore the interaction of plant-coenriched Se and Cd and its effects on health.

Deep learning-based reconstruction improves the image quality of low-dose CT enterography in patients with inflammatory bowel disease.

PURPOSE: Lifelong re-examination of CT enterography (CTE) in patients with inflammatory bowel disease (IBD) may be necessary, and reducing radiation exposure during CT examinations is crucial. We investigated the potential application of deep learning reconstruction (DLR) in CTE to reduce radiation dose and improve image quality in IBD. METHODS: Thirty-six patients with known or suspected IBD were prospectively recruited to the low-dose CTE (LDCTE) group, while forty patients were retrospectively selected from previous clinical standard-dose CTE (STDCTE) scans as controls. STDCTE images were reconstructed with hybrid-IR (adaptive iterative dose reduction 3-dimensional [AIDR3D], standard setting); LDCTE images were reconstructed with AIDR3D and DLR (Advanced Intelligence ClearIQ Engine [AiCE], Body mild/standard/strong, Sharp Body mild/standard/strong setting). The effective radiation dose (ED), image noise, signal-to-noise ratio (SNR), overall image quality, subjective image noise, and diagnostic effectiveness were compared between the LDCTE and STDCTE groups. RESULTS: Compared with STDCTE, the ED of LDCTE was lower by 54.1% (p<0.001). Compared with STDCTE-AIDR3D, LDCTE-AIDR3D reconstruction objective image noise and SNR were greater (p<0.05), the subjective overall image quality was lower (p<0.05), and the diagnostic efficiency was lower (AUC=0.52, p<0.05). The SNRs of reconstructedimages of LDCTE-AiCE Body Strong and LDCTE-AiCE Body Sharp standard/strong groups were greater than that of STDCTE-AIDR3D group (all p<0.05), and the diagnostic performance was better than or comparable to that of STDCTE; the AUCs were 0.83, 0.76 and 0.76, respectively CONCLUSION: Compared with STDCTE with AIDR3D, LDCTE with DLR effectively reduced the radiation dose and improve image quality in IBD patients.

CPMKG: a condition-based knowledge graph for precision medicine.

Personalized medicine tailors treatments and dosages based on a patient's unique characteristics, particularly its genetic profile. Over the decades, stratified research and clinical trials have uncovered crucial drug-related information-such as dosage, effectiveness, and side effects-affecting specific individuals with particular genetic backgrounds. This genetic-specific knowledge, characterized by complex multirelationships and conditions, cannot be adequately represented or stored in conventional knowledge systems. To address these challenges, we developed CPMKG, a condition-based platform that enables comprehensive knowledge representation. Through information extraction and meticulous curation, we compiled 307 614 knowledge entries, encompassing thousands of drugs, diseases, phenotypes (complications/side effects), genes, and genomic variations across four key categories: drug side effects, drug sensitivity, drug mechanisms, and drug indications. CPMKG facilitates drug-centric exploration and enables condition-based multiknowledge inference, accelerating knowledge discovery through three pivotal applications. To enhance user experience, we seamlessly integrated a sophisticated large language model that provides textual interpretations for each subgraph, bridging the gap between structured graphs and language expressions. With its comprehensive knowledge graph and user-centric applications, CPMKG serves as a valuable resource for clinical research, offering drug information tailored to personalized genetic profiles, syndromes, and phenotypes. Database URL: https://www.biosino.org/cpmkg/.

Comparison of Efficacy and Safety of Different Guided Technologies Combined With Ultrathin Bronchoscopic Biopsy for Peripheral Pulmonary Lesions.

INTRODUCTION: Various bronchoscopic guidance techniques have emerged to improve the diagnostic yield of peripheral pulmonary lesions (PPLs), especially when combined with ultra-thin bronchoscopy. However, uncertainties exists in the convenience, accuracy rate, and complications of these techniques. We compared the feasibility, accuracy rate, and complication rates of transbronchial biopsy of PPLs sampled by the standard thin-layer CT navigation combined with ultrathin bronchoscopy (CTNUTB), the Lungpro virtual navigation combined with ultrathin bronchoscopy (VNUTB), and electromagnetic navigation combined with ultrathin bronchoscopy (ENUTB). METHODS: Retrospectively identified were 256 patients sampled with transbronchial biopsy of PPLs. Eligible patients referred for CTNUTB, VNUTB, and ENUTB from January 2017 to December 2021 were included. We comprehensively compared the accuracy rate, feasibility, and complication rates for each method. RESULTS: There was no significant difference in the accuracy rate of CTNUTB, VNUTB, and ENUTB (p = 0.293). The operation time via Lungpro navigation was the shortest (14.4 min, p < 0.001). The planning time via CT planning was the shortest (7.36 min, p < 0.001). There was no difference in the incidence of complications such as hemorrhage, pneumonia, and pneumothorax (p = 0.123). Besides, ENUTB costs more than $2000, while CTNUTB and VNUTB cost only about $130-230. CONCLUSION: CTNUTB is still the main bronchoscopy method we recommended, which has low cost, simple operation, and safety no less than the others. In contrast, ENUTB provides a higher accuracy rate for small diameter nodules (less than 2 cm), which has a high use value and is worth promoting in the future.

[Genetic and clinical analysis of two children with microcephaly and mental retardation due to a frameshifting variant of CASK gene].

OBJECTIVE: To explore the clinical and genetic characteristics of two children with mental retardation and microcephaly. METHODS: Two children who had visited the Anhui Children's Hospital respectively on March 12 and June 22, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from them and their parents, and subjected to chromosomal karyotyping and whole exome sequencing analyses. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. RESULTS: Chromosomal karyotyping and copy number detection of the two children had found no abnormality. Whole exome sequencing revealed that child 1 has harbored a c.471delT (p.Pro157Profs*9) frameshifting variant of the CASK gene, whilst child 2 has harbored a c.1259_1269delCTGAGAATAAC (p.Pro420fs*27) frameshifting variant of the CASK gene. Sanger sequencing confirmed that both variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants were rated as pathogenic (PVS1+PS2+PP3). CONCLUSION: The de novo variants of the CASK gene probably underlay the pathogenesis of mental retardation and microcephaly in both children.

DEFINE: A Prospective, Randomized, Phase 4 Trial to Assess a Protease Inhibitor-based Regimen Switch Strategy to Manage Integrase Inhibitor-related Weight Gain.

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based antiretroviral therapies have been associated with greater weight gain in people living with HIV versus on protease inhibitor (PI)-based regimens. The DEFINE study investigated whether switching from an InSTI- to a PI-based regimen could mitigate/reverse weight gain. METHODS: DEFINE (NCT04442737) was a randomized, 48-week, open-label, prospective, phase 4 study in virologically suppressed adults with HIV-1 and ≥10% weight gain on InSTI+tenofovir alafenamide (TAF)/emtricitabine (FTC) (<36 months pre-screening). Participants either switched immediately to darunavir/cobicistat/emtricitabine/TAF (D/C/F/TAF) or continued InSTI+TAF/FTC during Weeks 0-24 then switched to D/C/F/TAF for Weeks 24-48. The primary endpoint was least squares (LS) mean (95% confidence interval [CI]) percent weight change from baseline to Week 24. RESULTS: Overall, 103 adults were randomized (D/C/F/TAF, n=53; InSTI+TAF/FTC, n=50); 30% female; 61% Black/African American. No significant difference in weight change was observed at Week 24 (LS mean change: D/C/F/TAF, 0.63% [95%CI: -0.44, 1.70] vs InSTI+TAF/FTC, -0.24% [-1.35, 0.87]; p=0.24); however, a trend towards weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to Week 48, -0.36% [-1.77, 1.06]), particularly in subgroups at higher weight gain risk (eg, females, Black/African Americans). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms. CONCLUSIONS: While no significant change in body weight was observed at 24 weeks after switching from InSTI+TAF/FTC to D/C/F/TAF among adults with weight gain, a trend towards weight loss emerged with longer time post-ARV switch, supporting further investigation of antiretroviral selection/switch for weight management.

Cyclosporine-induced alopecia:a case report, FDA adverse event reporting system analysis and literature assessment.

Cyclosporine is a potent immunosuppressive drug for various immune-mediated diseases in children. Cyclosporine's expected therapeutic effect also carries a wide range of side effects. One of the most common and intriguing dermatological side effects is hypertrichosis. However, recent reports have recognized alopecia as a potential adverse effect of cyclosporine. Here, we report a case of a 29-month-old boy diagnosed with aplastic anemia. During cyclosporine therapy, the patient presented with hair loss on the scalp, which and subsequently spread to the eyebrows and eyelashes. The alopecic symptoms were not relieved following topical minoxidil liniment interventions. When the cyclosporine was discontinued, a remarkable improvement was observed in the scalp, with complete hair regrowth. Data concerning cyclosporine from the FDA Adverse Event Reporting System (FAERS) database were extracted from January 2004 to January 2023. Within FAERS, our post-marketing pharmacovigilance analysis detected the reporting association of cyclosporine and alopecia. In monotherapy, cyclosporine-induced alopecia was observed in 118 cases, and tacrolimus-induced alopecia signals were detected in 197 cases. Although the potential mechanism of medication-induced hair loss is unclear, we identified a potential correlation between alopecia and cyclosporine, and it is still necessary to adequately recognize and clinically monitor this paradoxical reaction.

Risk factors and nomogram predictive model of severe postoperative complications in elderly patients with intertrochanteric fractures.

Objective: To analyze risk factors of severe postoperative complications in elderly patients with intertrochanteric fractures (ITF), and to construct a predictive model. Methods: The medical records of 316 elderly patients with ITF who underwent surgical treatment in Suzhou Hospital of Integrated Traditional Chinese and Western Medicine from January 2020 to December 2022 were retrospectively analyzed. Univariate and multivariate logistic regression analyses were performed to identify risk factors of severe postoperative complications. A nomogram prediction model was constructed using the RMS package of R4.1.2 software. Accuracy and stability of the model was assessed using the receiver operating characteristic (ROC) curve, Hosmer-Lemeshow goodness-of-fit test, and decision curve analysis. Results: Age, American Society of Anesthesiologists (ASA) grading, combined medical diseases, preoperative bedridden condition, frailty, and preoperative albumin levels were all risk factors for severe postoperative complications in ITF patients were noted. These factors were then used to build a risk prediction model that had an area under the ROC curve (AUC) of 0.899 (95% confidence interval (CI): 0.846-0.951). The internal validation results of the Bootstrap method showed that the C-index value of the model was 0.899, and the calibration curve had a good fit with the ideal curve. Conclusions: Age, ASA grading, combined medical diseases, preoperative bedridden condition, frailty, and preoperative albumin levels were independent risk factors for severe postoperative complications in elderly ITF patients. The constructed prediction model based on the above risk factors has a high predictive value.

Reconstruction of Ferromagnetic/Paramagnetic Cobalt-Based Electrocatalysts under Gradient Magnetic Fields for Enhanced Oxygen Evolution.

The rational manipulation of the surface reconstruction of catalysts is a key factor in achieving highly efficient water oxidation, but it is a challenge due to the complex reaction conditions. Herein, we introduce a novel in situ reconstruction strategy under a gradient magnetic field to form highly catalytically active species on the surface of ferromagnetic/paramagnetic CoFe2O4@CoBDC core-shell structure for electrochemical oxygen evolution reaction (OER). We demonstrate that the Kelvin force from the cores' local gradient magnetic field modulates the shells' surface reconstruction, leading to a higher proportion of Co2+ as active sites. These Co sites with optimized electronic configuration exhibit more favorable adsorption energy for oxygen-containing intermediates and lower the activation energy of the overall catalytic reaction. As a result, a significant enhancement in OER performance is achieved with a large current density increment about 128 % at 1.63 V and an overpotential reduction by 28 mV at 10 mA cm-2 after reconstruction. Interestingly, after removing the external magnetic field, the activity could persist for over 100 h. This work showcases the directional surface reconstruction of catalysts under a gradient magnetic field for enhanced water oxidation.

ALDH2 deficiency augments atherosclerosis through the USP14-cGAS-dependent polarization of proinflammatory macrophages.

The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism commonly exists in the East Asian populations and is associated with high risks of cardiovascular disease (CVD). However, the cellular and molecular mechanisms that underlie the ALDH2 rs671 mutant-linked high CVD remain elusive. Here, we show that macrophages derived from human ALDH2 rs671 carriers and ALDH2 knockout mice exhibited an enhanced pro-inflammatory macrophage phenotype and an impaired anti-inflammatory macrophage phenotype. Transplanting bone marrow from ALDH2-/-ApoE-/- to ApoE-/- mice significantly increased atherosclerotic plaque growth and pro-inflammatory macrophage polarization in vivo. Mechanistically, ALDH2 inhibited activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Pharmacological inhibition of cGAS by RU.521 completely neutralized ALDH2-deficiency-induced macrophage polarization. In-depth mechanistic investigation showed that ALDH2 accelerated cGAS K48-linked polyubiquitination degradation at lysine 282 in macrophages by reducing the interaction between ubiquitin-specific protease 14 (USP14) and cGAS, mainly through its enzymatic role in mitigating 4-hydroxy-2-nonenal (4-HNE) accumulation. Consistently, USP14 knockdown in bone marrow cells alleviated proinflammatory responses in macrophages and protected against atherosclerosis. Our findings provide new mechanistic insights of ALDH2 deficiency-associated proinflammation and atherosclerosis and new therapeutic and preventive paradigms for treatment of atherosclerosis-associated CVD.

From onset to blindness: a comprehensive analysis of RPGR-associated X-linked retinopathy in a large cohort in China.

BACKGROUND: Variants in the RPGR are the leading cause of X-linked retinopathies (XLRPs). Further in-depth investigation is needed to understand the natural history. METHODS: Review of all case records, molecular genetic testing results, best-corrected visual acuity (BCVA), retinal imaging data (including fundus autofluorescence imaging and optical coherence tomography (OCT)), static visual field (VF) assessments and full-field electroretinogram. RESULTS: Genetic testing was conducted on 104 male patients from 89 family pedigrees, identifying 22 novel variants and 1 de novo variant. The initial symptoms appeared in 78.2% of patients at a median age of 5 years. BCVA declined at a mean rate of 0.02 (IQR, 0-0.04) logarithm of the minimum angle of resolution per year, with a gradual, non-linear decrease over the first 40 years. Autofluorescence imaging revealed macular atrophy at a median age of 36.1 (IQR, 29.9-43.2) years. Patients experienced blindness at a median age of 42.5 (IQR, 32.9-45.2) years according to WHO visual impairment categories. OCT analysis showed a mean ellipsoid zone narrowing rate of 23.3 (IQR, -1.04-22.29) µm/month, with an accelerated reduction in the first 40 years (p<0.01). The median age at which ERG no longer detected a waveform was 26.5 (IQR, 20.5-32.8) years. Comparison by variant location indicated faster progression in patients with exon 1-14 variants during the initial two decades, while those with ORF15 variants showed accelerated progression from the third decade. CONCLUSIONS: We provide a foundation for determining the treatment window and an objective basis for evaluating the therapeutic efficacy of gene therapy for XLRP.