Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

Efficacy and Safety of Crisaborole Ointment 2% in Chinese Patients Aged ≥ 2 Years with Mild to Moderate Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic immuno-inflammatory skin disease. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild to moderate AD. This post hoc analysis assesses the efficacy and safety of crisaborole in Chinese patients aged ≥ 2 years with mild to moderate AD. METHODS: We evaluated the efficacy and safety of crisaborole in Chinese patients from the vehicle-controlled, phase 3 CrisADe CLEAR study. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily, respectively, for 28 days. The primary endpoint was percent change from baseline in Eczema Area and Severity Index (EASI) total score at day 29. Key secondary endpoints were improvement in Investigator's Static Global Assessment (ISGA), ISGA success, and change from baseline in weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) score. Adverse events were documented. RESULTS: Of 391 patients in the overall study, 237 were from China, 157 assigned to crisaborole and 80 assigned to vehicle. A greater reduction in percent change from baseline in EASI total score at day 29 was shown in the crisaborole vs. vehicle group (least squares mean [LSM]: -66.34 [95% (confidence interval) CI -71.55 to -61.12] vs. -50.18 [95% CI -58.02 to -42.34]). Response rates for achievement of ISGA improvement (43.2% [95% CI 35.4-51.1] vs. 33.4% [95% CI 22.5-44.2]) and ISGA success (31.7% [95% CI 24.3-39.0] vs. 21.5% [95% CI 12.1-30.9]) at day 29 were higher in the crisaborole vs. vehicle group. A greater reduction in change from baseline in weekly average PP-NRS score at week 4 was observed in the crisaborole vs. vehicle group (LSM: -1.98 [95% CI -2.34 to -1.62] vs. -1.08 [95% CI -1.63 to -0.53]). No new safety signals were observed. CONCLUSION: Crisaborole was effective and well tolerated in Chinese patients aged ≥ 2 years with mild to moderate AD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04360187.

Persulfidation and phosphorylation of transcription factor SlWRKY6 differentially regulate tomato fruit ripening.

Cysteine desulfhydrase (LCD) catalyzes the generation of the signaling molecule hydrogen sulfide (H2S) in plants. In this study, we found that H2S can inhibit tomato (Solanum lycopersicum) fruit ripening and SlWRKY6 undergoes differential protein persulfidation in SlLCD1-overexpressing leaves. Then, further study indicated that SlWRKY6 could be persulfidated by H2S at Cys396. By construction of slwrky6 mutants and SlWRKY6-OE lines, we found that SlWRKY6 positively regulates leaf senescence and fruit ripening by activating the transcription of ripening-related genes STAYGREEN 1 (SlSGR1) and Senescence-Associated Gene 12 (SlSAG12). In addition, SlWRKY6 interacted with kinase SlMAPK4 and was phosphorylated at Ser33. Dual luciferase transient expression assays and electrophoretic mobility shift assays indicated that SlWRKY6 persulfidation attenuated its transcriptional regulation of target genes SlSGR1 and SlSAG12, whereas SlWRKY6 phosphorylation by SlMAPK4 activated the transcription of target genes to promote fruit ripening. Moreover, we provided evidence that SlWRKY6 persulfidation attenuated its SlMAPK4-mediated phosphorylation to inhibit tomato fruit ripening. By transient expression of SlWRKY6, SlWRKY6C396A, SlWRKY6S33A and SlWRKY6S33D in slwrky6 fruits, we found that SlWRKY6 persulfidation attenuated the expression of SlSGR1 and SlSAG12 thereby delaying tomato fruit ripening, while SlWRKY6 phosphorylation increased the expression of target genes. As tomato fruits ripened, endogenous H2S production decreased, while SlMAPK4 expression increased. Therefore, our findings reveal a model in which SlWRKY6 persulfidation due to higher endogenous H2S levels in un-ripened fruit inhibits its ability to activate SlSGR1 and SlSAG12 expression, while SlWRKY6 phosphorylation by SlMAPK4 activates its transcriptional activity, thereby promoting tomato fruit ripening.

A novel approach for sludge deep-dewatering via flowing-out enhancement but not relying on cell lysis and bound water release.

Effective deep-dewatering is crucial for wastewater sludge management. Currently, the dominant methods focus on promoting cell lysis to release intracellular water, but these techniques often lead to secondary pollution and require stringent conditions, limiting their practical use. This study explores an innovative method using a commercially available complex quaternary ammonium salt surfactant, known as G-agent. This agent remarkably reduces the sludge water content from 98.6 % to 56.8 % with a low dosage (50 mg/g DS) and under neutral pH conditions. This approach surpasses Fenton oxidation in terms of dewatering efficiency and avoids the necessity for cell lysis and bound water release, thereby reducing the risk of secondary pollution in the filtrate, including heavy metals, nitrogen, phosphorus, and other contaminants. The G-agent plays a significant role in destabilizing flocs and enhancing flocculation during the conditioning and initial dewatering stages, effectively reducing the solid-liquid interfacial affinity of the sludge. In the compression filtration stage, the agent's solidification effect is crucial in forming a robust skeleton that improves pore connectivity within the filter cake, leading to increased water permeability, drainage performance and water flow-out efficiency. This facilitates deep dewatering of sludge without cell lysis. The study reveals that the G-agent primarily improves water flow-out efficiency rather than water flowability, indicating that cell lysis and bound water release are not indispensable prerequisites for sludge deep-dewatering. Furthermore, it presents an encouraging prospect for overcoming the limitations associated with conventional sludge deep-dewatering processes.

The isosbestic point in the Raman spectra of the hydration shell.

Isosbestic point is often observed in a series of spectra, but their interpretation is still controversial, such as whether the continuum model can produce an isosbestic point. In order to answer this question, the Raman spectra of hydration shell with continuous distribution structure in different ionic aqueous solutions were separated by Raman ratio spectra, and an isosbestic point was successfully observed. Our experimental results show that the continuum model can indeed produce the isosbestic point. In order to deepen the understanding of the isosbestic point, we calculate the first moment of the Raman spectra and conduct molecular dynamics (MD) simulations. Both experimental and theoretical findings indicate that elevated temperatures lead to increased disorder among water molecules within the hydration shell.

Wearable sensor devices can automatically identify the ON-OFF status of patients with Parkinson's disease through an interpretable machine learning model.

Introduction: Accurately and objectively quantifying the clinical features of Parkinson's disease (PD) is crucial for assisting in diagnosis and guiding the formulation of treatment plans. Therefore, based on the data on multi-site motor features, this study aimed to develop an interpretable machine learning (ML) model for classifying the "OFF" and "ON" status of patients with PD, as well as to explore the motor features that are most associated with changes in clinical symptoms. Methods: We employed a support vector machine with a recursive feature elimination (SVM-RFE) algorithm to select promising motion features. Subsequently, 12 ML models were constructed based on these features, and we identified the model with the best classification performance. Then, we used the SHapley Additive exPlanations (SHAP) and the Local Interpretable Model agnostic Explanations (LIME) methods to explain the model and rank the importance of those motor features. Results: A total of 96 patients were finally included in this study. The naive Bayes (NB) model had the highest classification performance (AUC = 0.956; sensitivity = 0.8947, 95% CI 0.6686-0.9870; accuracy = 0.8421, 95% CI 0.6875-0.9398). Based on the NB model, we analyzed the importance of eight motor features toward the classification results using the SHAP algorithm. The Gait: range of motion (RoM) Shank left (L) (degrees) [Mean] might be the most important motor feature for all classification horizons. Conclusion: The symptoms of PD could be objectively quantified. By utilizing suitable motor features to construct ML models, it became possible to intelligently identify whether patients with PD were in the "ON" or "OFF" status. The variations in these motor features were significantly correlated with improvement rates in patients' quality of life. In the future, they might act as objective digital biomarkers to elucidate the changes in symptoms observed in patients with PD and might be used to assist in the diagnosis and treatment of patients with PD.

Modified lignin can achieve mitigation of ammonia and greenhouse gas emissions simultaneously in composting.

The constant ammonia gas (NH3) and greenhouse gases (GHG) emissions were considered as a deep-rooted problem in composting which caused air pollution and global climate change. To achieve the mitigation of NH3 and GHG, a novel additive derived from wasted straw, with modified structure and functional groups, has been developed. Results showed that the adsorption capacity of modified lignin (ML) for both ammonium and nitrate was significantly increased by 132.5-360.8 % and 313.7-454.3 % comparing with biochar (BC) and phosphogypsum (PG) after reconstructing porous structure and grafting R-COOH, R-SO3H functional groups. The application of ML could reduce 36.3 % NH3 emission during composting compared with control. Furthermore, the synergetic mitigation NH3 and GHG in ML treatment resulted in a reduction of global warming potential (GWP) by 31.0-64.6 % compared with BC and PG. These findings provide evidence that ML can be a feasible strategy to effectively alleviate NH3 and GHG emissions in composting.

DeTAL: Open-Vocabulary Temporal Action Localization with Decoupled Networks.

Pre-trained visual-language (ViL) models have demonstrated good zero-shot capability in video understanding tasks, where they were usually adapted through fine-tuning or temporal modeling. However, in the task of open-vocabulary temporal action localization (OV-TAL), such adaption reduces the robustness of ViL models against different data distributions, leading to a misalignment between visual representations and text descriptions of unseen action categories. As a result, existing methods often strike a trade-off between action detection and classification. Aiming at this issue, this paper proposes DeTAL, a simple but effective two-stage approach for OV-TAL. DeTAL decouples action detection from action classification to avoid the compromise between them, and the state-of-the-art methods for close-set action localization can be handily adapted to OV-TAL, which significantly improves the performance. Meanwhile, DeTAL can easily tackle the scenario where action category annotations are unavailable in the training dataset. In the experiments, we propose a new cross-dataset setting to evaluate the zero-shot capability of different methods. And the results demonstrate that DeTAL outperforms the state-of-the-art methods for OV-TAL on both THUMOS14 and ActivityNet1.3. Code and data are publicly available at https://github.com/vsislab/DeTAL.

A Clinical Study of Antibacterial Medical Textiles Containing Polyhydroxyalkanoate Oligomers for Reduction of Hospital-Acquired Infections.

INTRODUCTION: The prevention and control of hospital-acquired infections remain a significant challenge worldwide, as textiles used in hospital wards are highly involved in transmission processes. Herein, we report a new antibacterial medical fabric used to prepare hospital pillowcases, bottom sheets, and quilt covers for controlling and reducing hospital-acquired infections. METHOD: The medical fabric was composed of blended yarns of staple polyester and degradable poly(3-hydroxybutyrate co-3-hydroxyvalerate)/polylactide fibres, which were then coated with polylactide oligomers, an environmentally friendly and safe antimicrobial agent with excellent thermal stability in high-temperature laundry. A clinical trial was conducted with emphasis on the bacterial species that were closely related to the infection cases in the trial hospital. RESULT: After 7 days of usage, 94% of PET/PHBV/PLA-PLAO fabric could keep less than 20 CFU/100 cm2 of total bacterial amount, meeting hygiene and cleanliness standards. CONCLUSION: This study demonstrates the potential of fabrics containing polyhydroxyalkanoate oligomers as highly effective, safe, and long-lasting antimicrobial medical textiles that can effectively reduce the incidence of hospital-acquired infections.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

Enhancing Carrier Transport in 2D/3D Perovskite Heterostructures through Organic Cation Fluorination.

The interfacial 2D/3D perovskite heterostructures have attracted extensive attention due to their unique ability to combine the high stability of 2D perovskites with the remarkable efficiency of 3D perovskites. However, the carrier transport mechanism within the 2D/3D perovskite heterostructures remains unclear. In this study, the carrier transport dynamics in 2D/3D perovskite heterostructures through a variety of time-resolved spectroscopic measurements is systematically investigated. Time-resolved photoluminescence results reveal nanosecond hole transfer from the 3D to 2D perovskites, with enhanced efficiency through the introduction of fluorine atoms on the phenethylammonium (PEA) cation. Transient absorption measurements unveil the ultrafast picosecond electron and energy transfer from 2D to 3D perovskites. Furthermore, it is demonstrated that the positioning of fluorination on the PEA cations effectively regulates the efficiency of charge and energy transfer within the heterostructures. These insightful findings shed light on the underlying carrier transport mechanism and underscore the critical role of cation fluorination in optimizing carrier transport within 2D/3D perovskite heterostructure-based devices.

Macrophage Migration Inhibitory Factor as a Potential Plasma Biomarker of Cognitive Impairment in Cerebral Small Vessel Disease.

As the pathogenesis of cerebral small vessel disease with cognitive impairment (CSVD-CI) remains unclear, identifying effective biomarkers can contribute to the clinical management of CSVD-CI. This study recruited 54 healthy controls (HCs), 60 CSVD-CI patients, and 57 CSVD cognitively normal (CSVD-CN) patients. All participants underwent neuropsychological assessments and multimodal magnetic resonance imaging. Macrophage migration inhibitory factors (MIFs) were assessed in plasma. The least absolute shrinkage and selection operator model was used to determine a composite marker. Compared with HCs or CSVD-CN patients, CSVD-CI patients had significantly increased plasma MIF levels. In CSVD-CI patients, plasma MIF levels were significantly correlated with multiple cognitive assessment scores, plasma levels of blood-brain barrier (BBB)-related indices, white matter hyperintensity Fazekas scores, and the mean amplitude of low-frequency fluctuation in the right superior temporal gyrus. Higher plasma MIF levels were significantly associated with worse global cognition and information processing speed in CSVD-CI patients. The composite marker (including plasma MIF) distinguished CSVD-CI patients from CSVD-CN and HCs with >80% accuracy. Meta-analysis indicated that blood MIF levels were significantly increased in CSVD-CI patients. In conclusion, plasma MIF is a potential biomarker for early identification of CSVD-CI. Plasma MIF may play a role in cognitive decline in CSVD through BBB dysfunction and changes in white matter hyperintensity and brain activity.

Endovascular treatment of symptomatic severe intracranial atherosclerotic stenosis with a novel intracranial dedicated drug-eluting stent: a more effective treatment approach.

Background: Endovascular treatment of severe intracranial atherosclerotic stenosis (ICAS) using coronary drug-eluting stents (DESs) significantly reduces the risk of in-stent restenosis (ISR) and stroke recurrence. However, there are few reports regarding the treatment of ICAS with intracranial dedicated DES. Herein, we present our experience with the feasibility, safety, and medium-term follow-up outcomes of a novel intracranial DES, named NOVA stent, in patients with symptomatic severe ICAS (≥70%). Methods: From December 2021 to May 2022, patients with symptomatic severe ICAS who underwent implantation of the NOVA stent in our institution were retrospectively analyzed for procedural results, perioperative complications, imaging and clinical follow-up outcomes. Results: Twenty-four patients, 16 (66.7%) with anterior circulation lesions and 8 (33.3%) with posterior circulation lesions, were enrolled. All patients with intracranial ICA (n = 6), middle cerebral artery (n = 10), basilar artery (n = 3), intracranial vertebral artery (n = 3), and the vertebrobasilar junction (n = 2) stenosis were treated successfully using NOVA stents. The severity of stenosis ranged from 75 to 96% (mean 85.9%) before treatment and this was reduced to 0 to 20% (mean 8.6%) immediately after stent placement. Symptomatic distal embolism occurred in one case; however, there were no other perioperative complications. The mean follow-up duration was 12.2 ± 1.06 months. No symptomatic ischemic events occurred during follow-up. Follow-up cerebral angiography was performed in 22 of 24 patients (91.7%), and significant ISR occurred in one patient (4.2%). Conclusion: Our results demonstrate that implantation of the novel intracranial DES NOVA in severe ICAS is feasible, safe, and effective in selected cases, reducing the incidence of ISR, and showing excellent midterm clinical outcomes, providing a promising option for ICAS treatment.

Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma.

Recent studies have highlighted the pivotal roles of T cell transcription factors TCF-1 and TOX in modulating the immune response in cancer, with TCF-1 maintaining CD8+ T cell stemness and TOX promoting T cell exhaustion. The prognostic significance of these factors in lung adenocarcinoma (LUAD) remains a critical area of investigation. The retrospective study included 191 patients with LUAD who underwent surgery, of whom 83% were in stages II and III. These patients were divided into exploratory (n = 135) and validation (n = 56) groups based on the time of diagnosis. Multiplex fluorescence immunohistochemistry was used to examine the infiltration levels of CD8+ T cells, TCF1+ CD8+ T cells, and TOX+ CD8+ T cells. The percentage of CD8+ T cells in tumor was markedly lower than that in stroma (p < 0.05). In tumor-draining lymph nodes (TDLNs) invaded by tumor, the proportion of stem-like TCF1+ CD8+ T cells was significantly decreased (p < 0.01). Importantly, higher infiltration levels of CD8+ T cells and TCF1+ CD8+ T cells were associated with improved disease-free survival (DFS) (p = 0.009 and p = 0.006, respectively) and overall survival (OS) (p = 0.018 and p = 0.010, respectively). This study underscores the potential of TCF1+ CD8+ T cells as prognostic biomarkers in LUAD, providing insights into the tumor immune microenvironment and guiding future therapeutic strategies.

Revealing brain's cognitive process deeply: a study of the consistent EEG patterns of audio-visual perceptual holistic.

Introduction: To investigate the brain's cognitive process and perceptual holistic, we have developed a novel method that focuses on the informational attributes of stimuli. Methods: We recorded EEG signals during visual and auditory perceptual cognition experiments and conducted ERP analyses to observe specific positive and negative components occurring after 400ms during both visual and auditory perceptual processes. These ERP components represent the brain's perceptual holistic processing activities, which we have named Information-Related Potentials (IRPs). We combined IRPs with machine learning methods to decode cognitive processes in the brain. Results: Our experimental results indicate that IRPs can better characterize information processing, particularly perceptual holism. Additionally, we conducted a brain network analysis and found that visual and auditory perceptual holistic processing share consistent neural pathways. Discussion: Our efforts not only demonstrate the specificity, significance, and reliability of IRPs but also reveal their great potential for future brain mechanism research and BCI applications.

GLUT3 transcriptional activation by ZEB1 fuels the Warburg effect and promotes ovarian cancer progression.

Ovarian cancer (OvCa) is characterized by early metastasis and high mortality rates, underscoring the need for deeper understanding of these aspects. This study explores the role of glucose transporter 3 (GLUT3) driven by zinc finger E-box-binding homeobox 1 (ZEB1) in OvCa progression and metastasis. Specifically, this study explored whether ZEB1 promotes glycolysis and assessed the potential involvement of GLUT3 in this process in OvCa cells. Our findings revealed that ZEB1 and GLUT3 were excessively expressed and closely correlated in OvCa. Mechanistically, ZEB1 activates the transcription of GLUT3 by binding to its promoter region. Increased expression of GLUT3 driven by ZEB1 dramatically enhances glycolysis, and thus fuels Warburg Effect to promote OvCa progression and metastasis. Consistently, elevated ZEB1 and GLUT3 expression in clinical OvCa is correlated with poor prognosis, reinforcing the profound contribution of ZEB1-GLUT3 axis to OvCa. These results suggest that activation of GLUT3 expression by ZEB1 is crucial for the proliferation and metastasis of OvCa via fueling glycolysis, shedding new light on OvCa treatment.

KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer's disease.

BACKGROUND: Epidemiological studies have revealed a correlation between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes. AIM: To determine the effects of KAT7 on insulin patients with AD. METHODS: APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aß stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aß, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3ß, total GSK3ß, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A. RESULTS: KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aß accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3ß to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion. CONCLUSION: We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

Genome-wide sequencing reveals geographical variations in the thermal adaptation of an aquaculture species with frequent seedling introductions.

Climate change and human activity are essential factors affecting marine biodiversity and aquaculture, and understanding the impacts of human activities on the genetic structure to increasing high temperatures is crucial for sustainable aquaculture and marine biodiversity conservation. As a commercially important bivalve, the Manila clam Ruditapes philippinarum is widely distributed along the coast of China, and it has been frequently introduced from Fujian Province, China, to other regions for aquaculture. In this study, we collected four populations of Manila clams from different areas to evaluate their thermal tolerance by measuring cardiac performance and genetic variations using whole-genome resequencing. The upper thermal limits of the clams showed high variations within and among populations. Different populations displayed divergent genetic compositions, and the admixed population was partly derived from the Zhangzhou population in Fujian Province, implying a complex genomic landscape under the influence of local genetic sources and human introductions. Multiple single nucleotide polymorphisms (SNPs) were associated with the cardiac functional traits, and some of these SNPs can affect the codon usage and the structural stability of the resulting protein. This study shed light on the importance of establishing long-term ecological and genetic monitoring programs at the local level to enhance resilience to future climate change.

Meta-analysis addressing the potential of antibiotic resistance gene elimination through aerobic composting.

The significant increase in antibiotic resistance genes (ARGs) in organic solid wastes (OSWs) has emerged as a major threat to the food chain. Aerobic composting is a widely used technology for OSW management, with the potential to influence the fate of AGRs. However, the variability of the ARG elimination effects reported in different studies has highlighted the uncertainty regarding the effects of composting on ARGs. To identify the potential of composting in reducing ARG and the factors (e.g., composting technologies and physiochemical properties) influence ARG changes, a meta-analysis was conducted with a database including 4,232 observations. The abundances of ARGs and mobile genetic elements (MGEs) can be substantially reduced by 74.3% and 78.8%, respectively, via aerobic composting. During composting, the ARG levels in chicken and swine manure tended to be reduced more significantly (81.7% and 78.0%) compared to those in cattle manure (52.3%) and sewage sludge (32.6%). The reduction rate of sulfonamide resistant genes was only 35.3%, which was much lower than those of other types. MGEs and composting duration (CD) were identified as the most important factors driving ARG changes during composting. These findings provide a comprehensive insight into the effects of composting on ARG reduction, which may help prevent the transmission in food systems.