A new pressure-densified orthogonal hard superconducting phase of RhB4.

A new hard superconducting phase of RhB4 with the space group Cmca is predicted, and the phase transition and mechanical and superconducting properties of RhB4 under 300 GPa are studied using first principles. We predict a new high-pressure phase of RhB4 by substituting the most stable Cmca structure of OsB4, known for its excellent mechanical properties. The calculated enthalpy shows that above 112.6 GPa, Cmca is superior to Pmmn as was previously predicted by particle swarm optimization. The stability of the predicted phase is checked using formation enthalpy, elastic constant and phonon dispersion. Additionally, the convex hull of the Rh-B system confirms that the phase is expected to be synthesized experimentally. The Cmca phase is an incompressible hard material with a hardness of 23.75 GPa at 300 GPa attributed to strong intralayer covalent B-B bonds. Furthermore, the phase is a relatively pressure-insensitive superconductor, with a Tc of 8.6 K at 112.6 GPa and a pressure-dependent coefficient of -0.03 K GPa-1. The finding reveals a superconducting hard material that is well-suited for extreme high-pressure environments.

Causal relationship between non-alcoholic fatty liver disease and sarcopenia: a bidirectional Mendelian randomization study.

Introduction: A correlation between non-alcoholic fatty liver disease and sarcopenia is demonstrated, but the causality remains unclear. Our study aims to clarify the point of genetics between non-alcoholic fatty liver disease (NAFLD) and sarcopenia at the level of gene prediction through two-sample Mendelian randomization (MR) analysis. Methods: The study employed the two-sample MR approach to investigate the bi-directional causality between NAFLD and sarcopenia. Published summary statistics were used to obtain instrumental variables (IVs) at the genome-wide significance level. Results: IVW analysis showed that the risk of NAFLD was reduced when walking pace was increased (OR = 0.435, 95%CI 0.240-0.789, p = 0.006); Increasing appendicular lean mass (ALM) decreased the risk of NAFLD (OR = 0.906, 95%CI 0.838-0.980, p = 0.014); Those older than 60 were more likely to suffer from NAFLD if they had low grip strength (OR = 1.411, 95%CI 1.087-1.830, p = 0.0012). In the reverse MR study, weight median analysis showed that NAFLD caused a decrease in ALM (OR = 0.953, 95%CI 0.957-0.994, p = 0.001); whereas NAFLD showed no correlation with usual walking pace or grip strength (all with p > 0.05). MR-Egger regression analysis showed that there was no horizontal pleiotropy in the SNPs (all with p > 0.05). Conclusion: The characteristics related to sarcopenia (usual walking pace, appendicular lean mass and low hand grip strength) may play a causal role in the development of nonalcoholic fatty liver disease, although the underlying mechanisms need to be further investigated. The presence of specific single nucleotide polymorphisms (SNPs) such as rs3747207, rs429358, and rs73001065 has been identified in the PNPLA3, APOE, and MAU2 proteins. These genetic markers represent potential targets for future interventions aimed at addressing, managing, or mitigating the risk of NAFLD.

Differential item functioning in the autism behavior checklist in children with autism spectrum disorder based on a machine learning approach.

Aim: Our study utilized the Rasch analysis to examine the psychometric properties of the Autism Behavior Checklist (ABC) in children with autism spectrum disorder (ASD). Methods: A total of 3,319 children (44.77 ± 23.52 months) were included. The Rasch model (RM) was utilized to test the reliability and validity of the ABC. The GPCMlasso model was used to test the differential item functioning (DIF). Result: The response pattern of this sample showed acceptable fitness to the RM. The analysis supported the unidimensionality assumption of the ABC. Disordered category functions and DIF were found in all items in the ABC. The participants responded to the ABC items differently depending not only on autistic traits but also on age groups, gender, and symptom classifications. Conclusion: The Rasch analysis produces reliable evidence to support that the ABC can precisely depict clinical ASD symptoms. Differences in population characteristics may cause unnecessary assessment bias and lead to overestimated or underestimated symptom severity. Hence, special consideration for population characteristics is needed in making an ASD diagnosis.

Regulatory Mechanisms of Natural Active Ingredients and Compounds on Keratinocytes and Fibroblasts in Mitigating Skin Photoaging.

Background: The mechanism underlying skin photoaging remains elusive because of the intricate cellular and molecular changes that contribute to this phenomenon, which have yet to be elucidated. In photoaging, the roles of keratinocytes and fibroblasts are vital for maintaining skin structure and elasticity. But these cells can get photo-induced damage during photoaging, causing skin morphological changes. Recently, the function of natural active ingredients in treating and preventing photoaging has drawn more attention, with researches often focusing on keratinocytes and fibroblasts. Methods: We searched for studies published from 2007 to January 2024 in the Web of Science, PubMed, and ScienceDirect databases through the following keywords: natural plant, natural plant products or phytochemicals, traditional Chinese Medicine or Chinese herbal, plant extracts, solar skin aging, skin photoaging, and skin wrinkling. This review conducted the accordance of Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Results: In total, 87 researches were included in this review (Figure 1). In keratinocytes, natural compounds may primarily regulate signal pathways such as the NF-κB, MAPK, PI3K/AKT, and Nrf2/ARE pathways, reducing inflammation and cellular damage, thus slowing skin photoaging. Additionally, in fibroblasts, natural active ingredients primarily promote the TGF-ß pathway, inhibit MMPs activity, and enhance collagen synthesis while potentially modulating the mTOR pathway, thereby protecting the dermal collagen network and reducing wrinkle formation. Several trials showed that natural compounds that regulate keratinocytes and fibroblasts responses have significant and safe therapeutic effects. Conclusion: The demand for natural product-based ingredients in sunscreen formulations is rising. Natural compounds show promising anti-photoaging effects by targeting cellular pathways in keratinocytes and fibroblasts, providing potential therapeutic strategies. However, comprehensive clinical studies are needed to verify their efficacy and safety in mitigating photoaging, which should use advanced pharmacological methods to uncover the complex anti-photoaging mechanisms of natural compounds.

Single-incision Retroperitoneal Laparoscopic Resection of Adrenal Tumors in Children.

BACKGROUND: We describe our experience with single-incision retroperitoneal laparoscopic (SIRL) for resection of adrenal tumors in pediatric patients and discuss the technique's clinical value. METHODS: We retrospectively analyzed clinical data of 27 pediatric patients who underwent SIRL between January 2020 and September 2023. Patients with tumors >5 cm in size and those requiring vascular skeletonization surgery or extensive lymph node dissection were excluded. Demographic, perioperative, and prognostic data were collected, and computed tomography (CT) and magnetic resonance imaging were used for preoperative tumor assessment. RESULTS: Of 27 patients, 16 were male and 11 were female; mean age 54 ± 45 months and mean body mass index 17.2 ± 3.6 kg/m2. Mean tumor length, width, and height were 4.1 ± 1.8 cm, 3.3 ± 2.1 cm, and 2.9 ± 1.7 cm, respectively. One patient experienced a diaphragmatic tear, three patients incurred peritoneal damage, and one patient developed postoperative renal artery injury, leading to thrombosis and renal atrophy. No surgery was converted to open surgery, and no intraoperative or postoperative blood transfusions were required. Operative time, blood loss, and postoperative dietary recovery time were satisfactory. No local recurrence or distant metastases were detected during the 6-48 months of follow-up involving outpatient and telephone assessments. CONCLUSIONS: Application of SIRL in pediatric patients with adrenal tumors achieved favorable clinical outcomes with an effective, minimally invasive surgical option for treating children with adrenal tumors. This technique demands a high level of surgical expertise, specialized instruments and experienced surgeons. Our findings indicate that SIRL is safe and provides significant postoperative benefits in pediatric patients. LEVEL OF EVIDENCE: Level IV.

Huang-Lian-Jie-Du Decoction alleviates diabetic encephalopathy by regulating inflammation and pyroptosis via suppression of AGEs/RAGE/NF-κB pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Cognitive dysfunction associated with diabetes, known as diabetic encephalopathy (DE), is a grave neurodegenerative condition triggered by diabetes, and persistent inflammation plays a vital role in its development. The renowned traditional Chinese medicine Huang-Lian-Jie-Du Decoction (HLJDD) is clinically proven to manage diabetes mellitus and Alzheimer's disease and is famous for its heat-clearing and detoxifying effects. However, the underlying mechanisms through which HLJDD affects DE remain to be elucidated. AIM OF THE STUDY: To explore the beneficial effects of HLJDD on improving cognitive dysfunction in DE mice. STUDY DESIGN AND METHODS: A diabetic mouse was established through a high-fat diet and subsequent administration of streptozotocin over five consecutive days. After the animals were confirmed to have diabetes, they were treated with HLJDD. After oral administration of HLJDD or metformin for 14 weeks, behavioral tests were used to assess their cognitive capacity. Biochemical analyses were then performed to detect levels of glucose metabolism, followed by histological analyses to assess pathological damage. Furthermore, AGEs/RAGE/NF-κB axis related proteins were detected by Western blot or immunofluorescence techniques. An advanced UPLC-Q-Orbitrap HRMS/MS analytical technique utilizing a chemical derivatization strategy was employed for comprehensive metabolic profiling of carbonyl compounds in the plasma of DE mice. RESULTS: Pharmacological assessment revealed that HLJDD effectively mitigated cognitive dysfunction, normalized glucose metabolic imbalances, and repaired neuronal damage in DE mice. It reduced neuroinflammation by attenuating carbonyl stress, deactivating astrocytes and microglia, and preserving dopaminergic neurons. Additionally, metabolomics analysis revealed 18 carbonyl compounds with marked disparities between DE and control mice, with 12 metabolites approaching normal levels post-HLJDD intervention. Further investigations showed that HLJDD regulated inflammation and pyroptosis through suppressing AGEs/RAGE/NF-κB pathways. CONCLUSION: Our study indicated that HLJDD could ameliorate carbonyl stress via the regulation of carbonyl compound metabolism profiling, and inhibiting the AGEs/RAGE/NF-κB pathway, thereby alleviating inflammation and pyroptosis to exert beneficial effects on DE.

Sulfonated Azocalix[4]arene: A Universal and Effective Taste-Masking Agent.

Many active pharmaceutical ingredients have a specific bitter taste. To enhance patient compliance and treatment efficacy, taste-masking agents are crucial in oral drug formulations. Confronting numerous bitter drug molecules with varied structures, the pharmaceutical field strives to explore and develop universal and effective masking approaches. Here, we reported sulfonated azocalix[4]arene (SAC4A), a universal supramolecular masking agent with deep cavity that provides stronger hydrophobic effect and larger interaction area during recognition, allowing high binding affinity to bitter drug molecules. Moreover, bitter drugs could deeply buried in the cavity, with the bitterness effectively masked. As a result, SAC4A can bind to 16 different bitter drugs with high affinities, encompassing alkaloids, flavonoids, terpenoids, and more, while maintaining high biocompatibility. As anticipated, SAC4A effectively masks the unpalatable bitter taste associated with these drugs. Consequently, SAC4A is a promising universal and effective supramolecular masking agent.

Natural Linoleic Acid from Marine Fungus Eutypella sp. F0219 Blocks KEAP1/NRF2 Interaction and Ameliorates MASLD by Targeting FABP4.

Ectopic lipid accumulation induced lipotoxicity plays a crucial role in exacerbating the development of metabolic dysfunction-associated steatotic liver disease (MASLD), which affects over 30% of the worldwide population and 85% of the obese population. The growing demand for effective therapeutic agents highlights the need for high-efficacy lipotoxicity ameliorators and relevant therapeutic targets in the fight against MASLD. This study aimed to discover natural anti-lipotoxic and anti-MASLD candidates and elucidate the underlying mechanism and therapeutic targets. Utilizing palmitic acid (PA)-induced HepG-2 and primary mouse hepatocyte models, we identified linoleic acid (HN-002), a ligand of fatty acid binding protein 4 (FABP4), from the marine fungus Eutypella sp. F0219. HN-002 dose-dependently prevented lipid overload-induced hepatocyte damage and lipid accumulation, inhibited fatty acid esterification, and ameliorated oxidative stress. These beneficial effects were associated with improvements in mitochondrial adaptive oxidation. HN-002 treatment enhanced lipid transport into mitochondria and oxidation, inhibited mitochondrial depolarization, and reduced mitochondrial ROS (mtROS) level in PA-treated hepatocytes. Mechanistically, HN-002 treatment disrupted the interaction between KEAP1 and NRF2, leading to NRF2 deubiquitylation and nuclear translocation, which activated beneficial metabolic regulation. In vivo, HN-002 treatment (20 mg/kg/per 2 days, i. p.) for 25 days effectively reversed hepatic steatosis and liver injury in the fast/refeeding plus high-fat/high-cholesterol diet induced MASLD mice. These therapeutic effects were associated with enhanced mitochondrial adaptive oxidation and activation of NRF2 signaling in the liver. These data suggest that HN-002 would be an interesting candidate for MASLD by improving mitochondrial oxidation via the FABP4/KEAP1/NRF2 axis. The discovery offers new insights into developing novel anti- MASLD agents derived from marine sources.

An Agent-Based Method for Feature Recognition and Path Optimization of Computer Numerical Control Machining Trajectories.

In recent years, artificial intelligence technology has seen increasingly widespread application in the field of intelligent manufacturing, particularly with deep learning offering novel methods for recognizing geometric shapes with specific features. In traditional CNC machining, computer-aided manufacturing (CAM) typically generates G-code for specific machine tools based on existing models. However, the tool paths for most CNC machines consist of a series of collinear motion commands (G01), which often result in discontinuities in the curvature of adjacent tool paths, leading to machining defects. To address these issues, this paper proposes a method for CNC system machining trajectory feature recognition and path optimization based on intelligent agents. This method employs intelligent agents to construct models and analyze the key geometric information in the G-code generated during CNC machining, and it uses the MCRL deep learning model incorporating linear attention mechanisms and multiple neural networks for recognition and classification. Path optimization is then carried out using mean filtering, Bézier curve fitting, and an improved novel adaptive coati optimization algorithm (NACOA) according to the degree of unsmoothness of the path. The effectiveness of the proposed method is validated through the optimization of process files for gear models, pentagram bosses, and maple leaf models. The research results indicate that the CNC system machining trajectory feature recognition and path optimization method based on intelligent agents can significantly enhance the smoothness of CNC machining paths and reduce machining defects, offering substantial application value.

Spokewise Total Syntheses of Four Erythrina Alkaloids and Telescoped Syntheses of Six Additional Alkaloids.

Based on rich sulfur-involving chemical transformations, a novel spokewise synthetic strategy, a subclass of the collective strategies, has been developed to concisely synthesize four erythrina alkaloids through a single-step transformation from a common synthetic precursor. Moreover, six additional erythrina alkaloids have also been synthesized by subsequent 1-2 steps chemical transformations. The current synthetic approaches provide a valuable platform for collective total syntheses of erythrina alkaloids and pseudo-natural erythrina alkaloids.

[Two cases of neonatal Legionella pneumonia]. / 新生儿嗜肺军团菌肺炎2例.

Patient 1, a 12-day-old female infant, presented with fever, cough, dyspnea, and elevated infection markers, requiring respiratory support. Metagenomic next-generation sequencing (mNGS) of blood and bronchoalveolar lavage fluid revealed Legionella pneumophila (LP), leading to diagnoses of LP pneumonia and LP sepsis. The patient was treated with erythromycin for 15 days and azithromycin for 5 days, resulting in recovery and discharge. Patient 2, an 11-day-old female infant, presented with dyspnea, fever, elevated infection markers, and multiple organ dysfunction, requiring mechanical ventilation. mNGS of blood and cerebrospinal fluid indicated LP, leading to diagnoses of LP pneumonia, LP sepsis, and LP intracranial infection. The patient was treated with erythromycin for 19 days and was discharged after recovery. Neonatal LP pneumonia lacks specific clinical symptoms, and azithromycin is the preferred antimicrobial agent. The use of mNGS can provide early and definitive diagnosis for severe neonatal pneumonia of unknown origin.

Brain organoid maturation and implantation integration based on electrical signals input.

INTRODUCTION: Brain organoids are believed to be able to regenerate impaired neural circuits and reinstate brain functionality. The neuronal activity of organoids is considered a crucial factor for restoring host function after implantation. However, the optimal stage of brain organoid post-transplantation has not yet been established. External electrical signal plays a crucial role in the physiology and development of a majority of human tissues. However, whether electrical input modulates the development of brain organoids, making them ideal transplant donors, is elusive. METHODS: Bioelectricity was input into cortical organoids by electrical stimulation (ES) with a multi-electrode array (MEA) to obtain a better-transplanted candidate with better viability and maturity, realizing structural-functional integration with the host brain. RESULTS: We found that electrical stimulation facilitated the differentiation and maturation of organoids, displaying well-defined cortical plates and robust functional electrophysiology, which was probably mediated via the pathway of calcium-calmodulin (CaM) dependent protein kinase II (CAMK II)-protein kinase A (PKA)-cyclic-AMP response binding protein (pCREB). The ES-pretreated D40 organoids displayed superior cell viability and higher cell maturity, and were selected to transplant into the damaged primary sensory cortex (S1) of host. The enhanced maturation was exhibited within grafts after transplantation, including synapses and complex functional activities. Moreover, structural-functional integration between grafts and host was observed, conducive to strengthening functional connectivity and restoring the function of the host injury. CONCLUSION: Our findings supported that electrical stimulation could promote the development of cortical organoids. ES-pretreated organoids were better-transplanted donors for strengthening connectivity between grafts and host. Our work presented a new physical approach to regulating organoids, potentially providing a novel translational strategy for functional recovery after brain injury. In the future, the development of 3D flexible electrodes is anticipated to overcome the drawbacks of 2D planar MEA, promisingly achieving multimodal stimulation and long-term recordings of brain organoids.

Shenqi Sanjie Granules induce Hmox1-mediated ferroptosis to inhibit colorectal cancer.

Background: Because adverse reactions or drug resistance are often found after current chemotherapies for metastatic colorectal cancer (mCRC), new treatments are still in demand. Shenqi Sanjie Granules (SSG), an antitumor compound preparation of traditional Chinese medicine, has been recognized for its ability in clinical practice of oncotherapy. Nevertheless, the precise effects of SSG in colorectal cancer (CRC) and underlying mechanisms through which SSG inhibits CRC remain uncertain. The current study aimed to evaluate the anti-CRC activity of the Chinese herbal compound preparation SSG and investigate the underlying mechanisms of action. Materials and methods: Initially, nine distinct cancer cell lines, including five CRC cell lines, one breast cancer cell line, two lung adenocarcinoma cell lines and one cervical cancer cell line, were used to evaluate the antitumor activity of SSG, and the mouse CRC cell line CT26 were used for further research. In vitro experiments utilizing diverse assays were conducted to assess the inhibitory effects of the SSG on CT26. Furthermore, subcutaneous syngeneic mouse model and AOM (azoxymethane)/DSS (dextran sodium sulfate) induced in-situ colitis-related mouse CRC model were used to evaluate the antitumor potential and biotoxicity of SSG in vivo. To elucidate the underlying molecular mechanisms, transcriptome sequencing and network pharmacology analysis were performed. Meanwhile, verification is carried out with quantitative real-time PCR (qRT-PCR) and flow cytometry (FCM) analysis. Results: Our in vitro inhibition study showed that SSG could effectively inhibit CRC cell line CT26 growth and metastasis, and induce cell death. Neither of apoptosis inhibitor, necroptosis inhibitor, ferroptosis inhibitor, but the combination of the three diminished SSG-induced cell death, suggesting that multiple cell death pathways were involved. Both the syngeneic CRC model and the in-situ CRC model indicated SSG inhibited CRC in vivo with few toxic side effects. Further mechanistic study suggested SSG treatment activated the ferroptosis pathway, particularly mediated by Hmox1, which was upregulated scores of times. Network pharmacology analysis indicated that the active ingredients of SSG, including Quercetin, Luteolin and Kaempferol were potential components directly upregulated Hmox1 expression. Conclusions: Collectively, our findings indicate that the administration of SSG has the potential to inhibit CRC both in vitro and in vivo. The mechanism by which this compound preparation exerts its action is, at least partly, the induction of ferroptosis through upregulating Hmox-1 by its three active ingredients Quercetin, Luteolin and Kaempferol.

Closed-Loop Deep Brain Stimulation With Reinforcement Learning and Neural Simulation.

Deep Brain Stimulation (DBS) is effective for movement disorders, particularly Parkinson's disease (PD). However, a closed-loop DBS system using reinforcement learning (RL) for automatic parameter tuning, offering enhanced energy efficiency and the effect of thalamus restoration, is yet to be developed for clinical and commercial applications. In this research, we instantiate a basal ganglia-thalamic (BGT) model and design it as an interactive environment suitable for RL models. Four finely tuned RL agents based on different frameworks, namely Soft Actor-Critic (SAC), Twin Delayed Deep Deterministic Policy Gradient (TD3), Proximal Policy Optimization (PPO), and Advantage Actor-Critic (A2C), are established for further comparison. Within the implemented RL architectures, the optimized TD3 demonstrates a significant 67% reduction in average power dissipation when compared to the open-loop system while preserving the normal response of the simulated BGT circuitry. As a result, our method mitigates thalamic error responses under pathological conditions and prevents overstimulation. In summary, this study introduces a novel approach to implementing an adaptive parameter-tuning closed-loop DBS system. Leveraging the advantages of TD3, our proposed approach holds significant promise for advancing the integration of RL applications into DBS systems, ultimately optimizing therapeutic effects in future clinical trials.

Population pharmacokinetics of nirmatrelvir/ritonavir in critically ill Chinese COVID-19 patients and recommendations for medication use: a two-center retrospective study.

BACKGROUND: This study aimed to establish population pharmacokinetics (PPK) models of nirmatrelvir/ritonavir in critically ill Chinese patients with the coronavirus disease 2019 (COVID-19) infection, explore factors affecting the pharmacokinetics (PK) of nirmatrelvir/ritonavir. METHODS: A total of 285 serum samples and clinical data were collected from 152 patients. The PPK models of nirmatrelvir/ritonavir were analyzed using nonlinear mixed-effect modeling (NONMEM) approach. The optimal dosing regimen for patients with different renal function was determined using Monte Carlo simulations. RESULTS: The population typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of nirmatrelvir were 2.26 L/h and 15.3 L, respectively. Notably, creatinine clearance (CrCL) significantly influenced the PK variation of nirmatrelvir. Monte Carlo simulations suggested that patients with mild-to-moderate renal impairment experienced a 22.0-59.9% increase in the area under the curve (AUC) when they were administered a standard dose of nirmatrelvir compared to those with normal renal function. The AUC in patients with severe renal impairment after administration of 150 mg q12h nirmatrelvir was similar to that in patients with normal renal function after administration of 300 mg q12h nirmatrelvir. CONCLUSIONS: PPK modeling and simulation provided a reference for the rational clinical application of nirmatrelvir/ritonavir in critically ill Chinese patients.

Extracellular vesicles for the treatment of ulcerative colitis: A systematic review and meta-analysis of animal studies.

Background: Extracellular vesicles (EVs) are being considered as a potential therapeutic option for ulcerative colitis (UC), and numerous preclinical studies have been conducted on the use of EVs for UC. Methods: A systematic review was conducted to compare the therapeutic effects of mammalian EVs and placebo on UC in animal models, along with a meta-analysis comparing naïve (unmodified) EVs and placebo. The search was performed in four databases (PubMed, Web of Science, Scopus, and EMBASE) up to September 13th, 2023. The primary outcomes included disease activity index (DAI), colonic mucosal damage index (CMDI), and adverse effects (PROSPERO ID: CRD42023458039). Results: A total of 69 studies were included based on pre-determined criteria, involving 1271 animals. Of these studies, 51 measured DAI scores, with 98 % reporting that EVs could reduce DAI scores. Additionally, 5 studies reported CMDI and all showed that EVs could significantly reduce CMDI. However, only 3 studies assessed adverse effects and none reported any significant adverse effects. The meta-analysis of these studies (40 studies involving 1065 animals) revealed that naïve EVs could significantly decrease the DAI score (SMD = -3.00; 95 % CI: -3.52 to -2.48) and CMDI (SMD = -2.10; 95 % CI: -2.85 to -1.35). Conclusion: The results indicate that mammalian EVs have demonstrated therapeutic benefits in animal models of UC; however, the safety profile of EVs remains inadequate which highlights the need for further research on safety outcomes.

Krüppel-like transcription factor 14 alleviates alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress in pulmonaryfibrosis.

Pulmonary fibrosis (PF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia, occurring primarily in older adults with poor prognosis. Alveolar epithelial cell (AEC) senescence is the critical pathological mechanism of PF. However, the molecular mechanisms regulating AEC senescence in PF are incompletely understood. Herein, we provided evidence to support the function of Krüppel-like factor 14 (KLF14), a novel Krüppel-like transcription factor, in the regulation of AEC senescence during PF. We confirmed that the expression of KLF14 was up-regulated in PF patients and mice treated with bleomycin (BLM). KLF14 knockdown resulted in more pronounced structural disruption of the lung tissue and swelling of the alveolar septum, which led to significantly increased mortality in BLM-induced PF mice. Mechanistically, RNA-seq analysis indicated that KLF14 decreased the senescence of AECs by inhibiting endoplasmic reticulum (ER) stress. Furthermore, the pharmacological activation of KLF14 conferred protection against PF in mice. In conclusion, our findings reveal a protective role for KLF14 in preventing AECs from senescence and shed light on the development of KLF14-targeted therapeutics for PF.

Non-invasive metabolic biomarkers in initial cognitive impairment in patients with diabetes: A systematic review and meta-analysis.

AIM: Diabetic cognitive impairment (DCI), considered one of the most severe and commonly overlooked complications of diabetes, has shown inconsistent findings regarding the metabolic profiles in DCI patients. This systematic review and meta-analysis aimed to identify dysregulated metabolites as potential biomarkers for early DCI, providing valuable insights into the underlying pathophysiological mechanisms. MATERIALS AND METHODS: A systematic search of four databases, namely PubMed, Embase, Web of Science and Cochrane, was conducted up to March 2024. Subsequently, a qualitative review of clinical studies was performed followed by a meta-analysis of metabolite markers. Finally, the sources of heterogeneity were explored through subgroup and sensitivity analyses. RESULTS: A total of 774 unique publications involving 4357 participants and the identification of multiple metabolites were retrieved. Of these, 13 clinical studies reported metabolite differences between the DCI and control groups. Meta-analysis was conducted for six brain metabolites and two metabolite ratios. The results revealed a significant increase in myo-inositol (MI) concentration and decreases in glutamate (Glu), Glx (glutamate and glutamine) and N-acetylaspartate/creatine (NAA/Cr) ratios in DCI, which have been identified as the most sensitive metabolic biomarkers for evaluating DCI progression. Notably, brain metabolic changes associated with cognitive impairment are more pronounced in type 2 diabetes mellitus than in type 1 diabetes mellitus, and the hippocampus emerged as the most sensitive brain region regarding metabolic changes associated with DCI. CONCLUSIONS: Our results suggest that MI, Glu, and Glx concentrations and NAA/Cr ratios within the hippocampus may serve as metabolic biomarkers for patients with early-stage DCI.