Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.

JOURNAL/nrgr/04.03/01300535-202504000-00028/figure1/v/2024-07-06T104127Z/r/image-tiff The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration. However, it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains. This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals. Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin. Recently, we showed that the PINK1 kinase is selectively expressed as a truncated form (PINK1-55) in the primate brain. In the present study, we used multiple antibodies, including our recently developed monoclonal anti-PINK1, to validate the selective expression of PINK1 in the primate brain. We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages, which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains. PINK1 was enriched in the membrane-bound fractionations, whereas Parkin was soluble with a distinguishable distribution. Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes, though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress. These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

Natural autophagy modulators in non-communicable diseases: from autophagy mechanisms to therapeutic potential.

Non-communicable diseases (NCDs) are defined as a kind of diseases closely related to bad behaviors and lifestyles, e.g., cardiovascular diseases, cancer, and diabetes. Driven by population growth and aging, NCDs have become the biggest disease burden in the world, and it is urgent to prevent and control these chronic diseases. Autophagy is an evolutionarily conserved process that degrade cellular senescent or malfunctioning organelles in lysosomes. Mounting evidence has demonstrated a major role of autophagy in the pathogenesis of cardiovascular diseases, cancer, and other major human diseases, suggesting that autophagy could be a candidate therapeutic target for NCDs. Natural products/phytochemicals are important resources for drugs against a wide variety of diseases. Recently, compounds from natural plants, such as resveratrol, curcumin, and ursolic acid, have been recognized as promising autophagy modulators. In this review, we address recent advances and the current status of the development of natural autophagy modulators in NCDs and provide an update of the latest in vitro and in vivo experiments that pave the way to clinical studies. Specifically, we focus on the relationship between natural autophagy modulators and NCDs, with an intent to identify natural autophagy modulators with therapeutic potential.

Inhibition of RAN Attenuates Influenza A Virus Replication and Nucleoprotein Nuclear Export.

Nuclear export of the viral ribonucleoprotein (vRNP) is a critical step in the influenza A virus (IAV) life cycle and may be an effective target for the development of anti- IAV drugs. The host factor ras-related nuclear protein (RAN) is known to participates in the life cycle of several viruses, but its role in influenza virus replication remains unknown. In the present study, we aimed to determine the function of RAN in influenza virus replication using different cell lines and subtype strains. We found that RAN is essential for the nuclear export of vRNP, as it enhances the binding affinity of XPO1 toward the viral nuclear export protein NS2. Depletion of RAN constrained the vRNP complex in the nucleus and attenuated the replication of various subtypes of influenza virus. Using in silico compound screening, we identified bepotastine could dissociate the RAN-XPO1-vRNP trimeric complex and exhibit potent antiviral activity against influenza virus both in vitro and in vivo. This study demonstrates the important role of RAN in IAV replication and suggests its potential use as an antiviral agent.

Inhibition of autophagy induced by tetrandrine promotes the accumulation of reactive oxygen species and sensitizes efficacy of tetrandrine in pancreatic cancer.

Pancreatic cancer, characterized by its poor prognosis, exhibits a marked resistance to conventional chemotherapy and immunotherapy, underscoring the urgent need for more effective treatment modalities. In light of this, the present study is designed to assess the potential antineoplastic efficacy of a combined regimen involving tetrandrine, a plant-derived alkaloid, and autophagy inhibitors in the context of pancreatic cancer. Electron microscopy and immunoblots showed that tetrandrine promoted the formation of autophagosomes and the upregulation of LC3II and the downregulation of p62 expression, indicating that tetrandrine induced autophagy in pancreatic cancer cells. Western blot revealed that tetrandrine inhibited the phosphorylation of AKT and mTOR, as well as the expression of Bcl-2, while upregulating Beclin-1 expression. Moreover, tetrandrine promoted the transcription and protein expression of ATG7. Following the combination of autophagy inhibitors and tetrandrine, the apoptotic rate and cell death significantly increased in pancreatic cancer cells. Consistent results were obtained when ATG7 was silenced. Additionally, tetrandrine induced the generation of ROS, which was involved in the activation of autophagy and apoptosis. Further investigation revealed that upon autophagy inhibition, ROS accumulated in pancreatic cancer cells, resulting in decreased mitochondrial membrane potential and further induction of apoptosis. The results of treating subcutaneous xenograft tumors with a combination of tetrandrine and chloroquine validated that autophagy inhibition enhances the toxicity of tetrandrine against pancreatic cancer in vivo. Altogether, our study demonstrates that tetrandrine induces cytoprotective autophagy in pancreatic cancer cells. Inhibiting tetrandrine-induced autophagy promotes the accumulation of ROS and enhances its toxicity against pancreatic cancer.

Covalent Organic Framework Membranes with Patterned High-Density Through-Pores for Ultrafast Molecular Sieving.

The creation of uniformly molecular-sized through-pores within polymeric membranes and the direct evidence of these pores are essential for fundamentally understanding the transport mechanism and improving separation efficiency. Herein, we report an electric-field-assisted interface synthesis approach to fabricating large-area covalent organic framework (COF) membranes that consist of preferentially oriented single-crystalline COF domains. These single-crystalline frameworks were translated into high-density, vertically aligned through-pores across the entire membrane, enabling the direct visualization of membrane pores with an ultrahigh resolution of 2 Å using the low-dose high-resolution transmission electron microscopy technique (HRTEM). The density of directly visualized through-pores was quantified to be 1.2 × 1017 m-2, approaching theoretical predictions. These COF membranes demonstrate ultrahigh solvent permeability, which is 10 times higher than that of state-of-the-art organic solvent nanofiltration membranes. When applied to high-value pharmaceutical separations, their COF membranes exhibit 2 orders of magnitude higher methanol permeance and 20-fold greater enrichment efficiency than their commercial counterparts.

Small-molecule organic electrode materials on carbon-coated aluminum foil for high-performance sodium-ion batteries.

Organic molecular electrode materials are promising candidates in batteries. However, direct application of small molecule materials usually suffers from drastic capacity decay and inefficient utilization of active materials because of their high solubility in organic electrolytes and low electrical conductivity. Herein, a simple strategy is found to address the above issues through coating the small-molecule organic materials on a commercialized carbon-coated aluminum foil (CCAF) as the enhanced electrode. Both the experimental and calculation results confirm that the relatively rough carbon coating on the aluminum foil not only exhibits superior adsorption capacity of small-molecule organic electrode materials with a tight contact interface but also provides continuous electronic conduction channels for the facilitated charge transfer and accelerated reaction kinetics. In addition, the carbon coating also inhibits Al corrosion in electrochemical process. As a result, by using the tetrahydroxy quinone-fused aza-phenazine (THQAP) molecule as an example, the THQAP-CCAF electrode exhibits an excellent rate performance with a high capacity of 220 and 180 mAh g-1 at 0.1 and 2 A/g, respectively, and also a remarkable cyclability with a capacity retention of 77.3% even after 1700 cycles in sodium-ion batteries. These performances are much more superior than that of batteries with the THQAP on bare aluminum foil (THQAP-AF). This work provides a substantial step in the practical application of the small-molecule organic electrode materials for future sustainable batteries.

Learning metabolic dynamics from irregular observations by Bidirectional Time-Series State Transfer Network.

Modeling microbial metabolic dynamics is important for the rational optimization of both biosynthetic systems and industrial processes to facilitate green and efficient biomanufacturing. Classical approaches utilize explicit equation systems to represent metabolic networks, enabling the quantification of pathway fluxes to identify metabolic bottlenecks. However, these white-box models, despite their diverse applications, have limitations in simulating metabolic dynamics and are intrinsically inaccurate for industrial strains that lack information on network structures and kinetic parameters. On the other hand, black-box models do not rely on prior mechanistic knowledge of strains but are built upon observed time-series trajectories of biosynthetic systems in action. In practice, these observations are typically irregular, with discontinuously observed time points across multiple independent batches, each time point potentially containing missing measurements. Learning from such irregular data remains challenging for existing approaches. To address this issue, we present the Bidirectional Time-Series State Transfer Network (BTSTN) for modeling metabolic dynamics directly from irregular observations. Using evaluation data sets derived from both ideal dynamic systems and a real-world fermentation process, we demonstrate that BTSTN accurately reconstructs dynamic behaviors and predicts future trajectories. This approach exhibits enhanced robustness against missing measurements and noise, as compared to the state-of-the-art methods.IMPORTANCEIndustrial biosynthetic systems often involve strains with unclear genetic backgrounds, posing challenges in modeling their distinct metabolic dynamics. In such scenarios, white-box models, which commonly rely on inferred networks, are thereby of limited applicability and accuracy. In contrast, black-box models, such as statistical models and neural networks, are directly fitted or learned from observed time-series trajectories of biosynthetic systems in action. These methods typically assume regular observations without missing time points or measurements. If the observations are irregular, a pre-processing step becomes necessary to obtain a fully filled data set for subsequent model training, which, at the same time, inevitably introduces errors into the resulting models. BTSTN is a novel approach that natively learns from irregular observations. This distinctive feature makes it a unique addition to the current arsenal of technologies modeling metabolic dynamics.

Genomic Alterations and Clinical Characterization in Chinese Patients with Metastatic Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) is increasingly characterized by myriad genomic alterations beyond the well-known factors such as RAS, BRAF, and microsatellite instability (MSI). Novel genomic changes, including ERBB2 amplifications, mutations, and gene fusions, are now recognized as potential targets for precision therapy. This study aims to explore the genomic landscape of a Chinese cohort with mCRC to identify potentially targetable genetic alterations for personalized treatment strategies. METHODS: A total of 500 mCRC patients in China were enrolled, based on which genomic profiling was performed using capture-based targeted sequencing across a panel of 520 genes on tumor tissues to identify prevalent genomic alterations. The mutations were analyzed by optimized proprietary algorithms. MSI and mismatch repair deficiency status were analyzed using the read-count-distribution approach. Besides, the overall survival (OS) related to these molecular changes was estimated. RESULTS: The cohort's genomic profiling revealed TP53 mutations in 78%, APC in 60%, and KRAS in 47% of the patients. MSI-High status was confirmed in 5.8% of cases via a next-generation sequencing (NGS)-based algorithm. ERBB2/HER2 amplifications were found in 12% (60/500) of patients, with potential therapeutic implications for those without concurrent KRAS mutations. A subset of patients (1.2%; 6/500) showed fusions and DNA damage response (DDR) gene mutations (except TP53) that could be targeted therapeutically. The KRAS (G12C) variant was detected in 14 patients (2.8%), and 61 (12.2%) had a BRAF V600E mutation. Notably, survival analysis showed no significant differences in OS between KRAS mutant loci and NRAS mutations (p = 0.436). However, BRAF V600E mutations were associated with a poorer prognosis than BRAF wild-type and non-V600E mutations (16.3 months vs. 29.5 and 31.1 months, respectively; p < 0.001). CONCLUSIONS: This study validates the feasibility of using NGS to detect prognostic and therapeutically actionable genetic variants in Chinese mCRC patients, contributing to understanding the genomic variation within this population and highlighting the potential for personalized medicine in managing mCRC.

Stable and efficient CsPbI3 quantum-dot light-emitting diodes with strong quantum confinement.

Even though lead halide perovskite has been demonstrated as a promising optoelectronic material for next-generation display applications, achieving high-efficiency and stable pure-red (620~635 nm) emission to cover the full visible wavelength is still challenging. Here, we report perovskite light-emitting diodes emitting pure-red light at 628 nm achieving high external quantum efficiencies of 26.04%. The performance is attributed to successful synthesizing strongly confined CsPbI3 quantum dots with good stability. The strong binding 2-naphthalene sulfonic acid ligands are introduced after nucleation to suppress Ostwald ripening, meanwhile, ammonium hexafluorophosphate exchanges long chain ligands and avoids regrowth by strong binding during the purification process. Both ligands enhance the charge transport ability of CsPbI3 quantum dots. The state-of-the-art synthesis of pure red CsPbI3 quantum dots achieves 94% high quantum efficiency, which can maintain over 80% after 50 days, providing a method for synthesizing stable strong confined perovskite quantum dots.

Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors.

BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

Evaluating the efficacy of percutaneous puncture biopsy guided by contrast-enhanced ultrasound for peripheral pulmonary lesions.

BACKGROUND: The incidence and mortality of lung cancer have increased annually. Accurate diagnosis can help improve therapeutic efficacy of interventions and prognosis. Percutaneous lung biopsy is a reliable method for the clinical diagnosis of lung cancer. Ultrasound-guided percutaneous lung biopsy technology has been widely promoted and applied in recent years. AIM: To investigate the diagnostic value of contrast-enhanced ultrasound (CEUS)-guided percutaneous biopsy in peripheral pulmonary lesions. METHODS: We retrospectively collected data on 237 patients with peripheral thoracic focal lesions who underwent puncture biopsy at Wuxi People's Hospital. The patients were randomly divided into two groups: The CEUS-guided before lesion puncture group (contrast group) and conventional ultrasound-guided group (control group). Analyze the diagnostic efficacy of the puncture biopsy, impact of tumor size, and number of puncture needles and complications were analyzed and compared between the two groups. RESULTS: Accurate pathological results were obtained for 92.83% (220/237) of peripheral lung lesions during the first biopsy, with an accuracy rate of 95.8% (113/118) in the contrast group and 89.9% (107/119) in the control group. The difference in the area under the curve (AUC) between the contrast and the control groups was not statistically significant (0.952 vs 0.902, respectively; P > 0.05). However, when the lesion diameter ≥ 5 cm, the diagnostic AUC of the contrast group was higher than that of the control group (0.952 vs 0.902, respectively; P < 0.05). In addition, the average number of puncture needles in the contrast group was lower than that in the control group (2.58 ± 0.53 vs 2.90 ± 0.56, respectively; P < 0.05). CONCLUSION: CEUS guidance can enhance the efficiency of puncture biopsy of peripheral pulmonary lesions, especially for lesions with a diameter ≥ 5 cm. Therefore, CEUS guidance has high clinical diagnostic value in puncture biopsy of peripheral focal lung lesions.

Distinct Thalamo-Subcortical Circuits Underlie Painful Behavior and Depression-Like Behavior Following Nerve Injury.

Clinically, chronic pain and depression often coexist in multiple diseases and reciprocally reinforce each other, which greatly escalates the difficulty of treatment. The neural circuit mechanism underlying the chronic pain/depression comorbidity remains unclear. The present study reports that two distinct subregions in the paraventricular thalamus (PVT) play different roles in this pathological process. In the first subregion PVT posterior (PVP), glutamatergic neurons (PVPGlu) send signals to GABAergic neurons (VLPAGGABA) in the ventrolateral periaqueductal gray (VLPAG), which mediates painful behavior in comorbidity. Meanwhile, in another subregion PVT anterior (PVA), glutamatergic neurons (PVAGlu) send signals to the nucleus accumbens D1-positive neurons and D2-positive neurons (NAcD1→D2), which is involved in depression-like behavior in comorbidity. This study demonstrates that the distinct thalamo-subcortical circuits PVPGlu→VLPAGGABA and PVAGlu→NAcD1→D2 mediated painful behavior and depression-like behavior following spared nerve injury (SNI), respectively, which provides the circuit-based potential targets for preventing and treating comorbidity.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Primary pulmonary myxoid sarcoma in the interlobar fissure of the left lung lobe: a case report.

BACKGROUND: Primary pulmonary myxoid sarcoma (PPMS) is a rare, low-grade malignant tumor, constituting approximately 0.2% of all lung tumors. Despite its rarity, PPMS possesses distinctive histological features and molecular alterations, notably the presence of EWSR1-CREB1 gene fusion. However, its precise tissue origin remains elusive, posing challenges in clinical diagnosis. CASE DEMONSTRATION: A 20-year-old male patient underwent a routine physical examination 6 months prior, revealing a pulmonary mass. Following surgical excision, microscopic evaluation unveiled predominantly short spindle-shaped tumor cells organized in a fascicular, beam-like, or reticular pattern. The stromal matrix exhibited abundant mucin, accompanied by lymphocytic and plasma cell infiltration, with Russell bodies evident in focal areas. Immunophenotypic profiling revealed positive expression of vimentin and epithelial membrane antigen in tumor cells, whereas smooth muscle actin and S-100, among others, were negative. Ki-67 proliferation index was approximately 5%. Subsequent second-generation sequencing identified the characteristic EWSR1-CREB1 gene fusion. The definitive pathological diagnosis established PPMS. The patient underwent no adjuvant chemotherapy or radiotherapy and remained recurrence-free during a 30-month follow-up period. CONCLUSIONS: We report a rare case of PPMS located within the left lung lobe interlobar fissure, featuring Russell body formation within the tumor stroma, a novel finding in PPMS. Furthermore, the histomorphological characteristics of this case highlight the diagnostic challenge it poses, as it may mimic inflammatory myofibroblastic tumor, extraskeletal myxoid chondrosarcoma, or hemangiopericytoma-like fibrous histiocytoma. Therefore, accurate diagnosis necessitates an integrated approach involving morphological, immunohistochemical, and molecular analyses.

Dramatic response to crizotinib through MET phosphorylation inhibition in rare TFG-MET fusion advanced squamous cell lung cancer.

With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.

Ureido-Ionic Liquid Mediated Conductive Hydrogel: Superior Integrated Properties for Advanced Biosensing Applications.

Ionic conductive hydrogels (ICHs) have recently gained prominence in biosensing, indicating their potential to redefine future biomedical applications. However, the integration of these hydrogels into sensor technologies and their long-term efficacy in practical applications pose substantial challenges, including a synergy of features, such as mechanical adaptability, conductive sensitivity, self-adhesion, self-regeneration, and microbial resistance. To address these challenges, this study introduces a novel hydrogel system using an imidazolium salt with a ureido backbone (UL) as the primary monomer. Fabricated via a straightforward one-pot copolymerization process that includes betaine sulfonate methacrylate (SBMA) and acrylamide (AM), the hydrogel demonstrates multifunctional properties. The innovation of this hydrogel is attributed to its robust mechanical attributes, outstanding strain responsiveness, effective water retention, and advanced self-regenerative and healing capabilities, which collectively lead to its superior performance in various applications. Moreover, this hydrogel  exhibited broad-spectrum antibacterial activity. Its potential for biomechanical monitoring, especially in tandem with contact and noncontact electrocardiogram (ECG) devices, represents a noteworthy advancement in precise real-time cardiac monitoring in clinical environments. In addition, the conductive properties of the hydrogel make it an ideal substrate for electrophoretic patches aimed at treating infected wounds and consequently enhancing the healing process.

Polystyrene nanoplastics of different particle sizes regulate the polarization of pro-inflammatory macrophages.

Microplastics (MPs) are defined as plastic particles smaller than 5 mm in size, and nanoplastics (NPs) are those MPs with a particle size of less than 1000 nm or 100 nm. The prevalence of MPs in the environment and human tissues has raised concerns about their potential negative effects on human health. Macrophages are the major defence against foreign substances in the intestine, and can be polarized into two types: the M1 phenotype and the M2 phenotype. However, the effect of NPs on the polarization of macrophages remains unclear. Herein, we selected polystyrene, one of the most plastics in the environment and controlled the particle sizes at 50 nm and 500 nm respectively to study the effects on the polarization of macrophages. We used mouse RAW264.7 cell line models in this macrophage-associated study. Experiments on cell absorption showed that macrophages could quickly ingest polystyrene nanoplastics of both diameters with time-dependent uptake. Compared to the untreated group and 10 µg/mL treatment group, macrophages exposed to 50 µg/mL groups (50 nm and 500 nm) had considerably higher levels of CD86, iNOS, and TNF-α, but decreased levels of aCD206, IL-10, and Arg-1. According to these findings, macrophage M1 and M2 polarization can both be induced and inhibited by 50 µg/mL 50 nm and 500 nm polystyrene nanoplastics. This work provided the first evidence of a possible MPs mode of action with appropriate concentration and size through the production of polarized M1, providing dietary and environmental recommendations for people, particularly those with autoimmune and autoinflammatory illnesses.

A model for identifying potentially inappropriate medication used in older people with dementia: a machine learning study.

BACKGROUND: Older adults with dementia often face the risk of potentially inappropriate medication (PIM) use. The quality of PIM evaluation is hindered by researchers' unfamiliarity with evaluation criteria for inappropriate drug use. While traditional machine learning algorithms can enhance evaluation quality, they struggle with the multilabel nature of prescription data. AIM: This study aimed to combine six machine learning algorithms and three multilabel classification models to identify correlations in prescription information and develop an optimal model to identify PIMs in older adults with dementia. METHOD: This study was conducted from January 1, 2020, to December 31, 2020. We used cluster sampling to obtain prescription data from patients 65 years and older with dementia. We assessed PIMs using the 2019 Beers criteria, the most authoritative and widely recognized standard for PIM detection. Our modeling process used three problem transformation methods (binary relevance, label powerset, and classifier chain) and six classification algorithms. RESULTS: We identified 18,338 older dementia patients and 36 PIMs types. The classifier chain + categorical boosting (CatBoost) model demonstrated superior performance, with the highest accuracy (97.93%), precision (95.39%), recall (94.07%), F1 score (95.69%), and subset accuracy values (97.41%), along with the lowest Hamming loss value (0.0011) and an acceptable duration of the operation (371s). CONCLUSION: This research introduces a pioneering CC + CatBoost warning model for PIMs in older dementia patients, utilizing machine-learning techniques. This model enables a quick and precise identification of PIMs, simplifying the manual evaluation process.

Signal of dementia with proton pump inhibitor after minimizing competition bias: an updated disproportionality analysis.

OBJECTIVE: The association between proton pump inhibitor (PPI) and dementia was controversial. The aim of current study was to perform an updated pharmacovigilance analysis of the association between dementia event and PPI treatment after minimizing competition bias. METHODS: We gathered cases reported with PPI treatment based on the United States food and drug administration adverse event reporting system database from 2004 to 2023. We employed disproportionality algorithms, including reporting odds ratio (ROR) and the information component (IC), to detect the association between dementia event and PPI. We investigated the affection of event competition bias on the current disproportionality signal detection. RESULTS: We finally included a total of 776,191 PPI cases, 1813 cases in the dementia group. Analyzing primary suspect PPIs, we detected significant association between dementia and PPI (ROR = 1.38, 95%CI 1.22 to 1.56; IC = 0.46, 95%CI 0.04 to 0.86). After excluded PPI case with renal injury event, the strength of dementia signal increased. Omeprazole (589 cases), pantoprazole (514 cases) and esomeprazole (386 cases) were the top three PPI reported with dementia events. CONCLUSION: The current pharmacovigilance study identified significant association between dementia and PPIs, except vonoprazan and tegoprazan, especially taking competition bias into account. Further high-quality prospective study still needed.

Simultaneous Defect Passivation and Co-catalyst Engineering Leads to Superior Photocatalytic Hydrogen Evolution on Metal Halide Perovskites.

Metal halide perovskites (MHPs) have emerged as attractive candidates for producing green hydrogen via photocatalytic pathway. However, the presence of abundant defects and absence of efficient hydrogen evolution reaction (HER) active sites on MHPs seriously limit the solar-to-chemical (STC) conversion efficiency. Herein, to address this issue, we present a bi-functionalization strategy through decorating MHPs with a molecular molybdenum-sulfur-containing co-catalyst precursor. By virtue of the strong chemical interaction between lead and sulfur and the good dispersion of the molecular co-catalyst precursor in the deposition solution, a uniform and intimate decoration of the MHPs surface with lead sulfide (PbS) and amorphous molybdenum sulfide (MoSx) co-catalysts is obtained simultaneously. We show that the PbS co-catalyst can effectively passivate the Pb-related defects on the MHPs surface, thus retarding the charge recombination and promoting the charge transfer efficiency significantly. The amorphous MoSx co-catalyst further promotes the extraction of photogenerated electrons from MHPs and facilitates the HER catalysis. Consequently, drastically enhanced photocatalytic HER activities are obtained on representative MHPs through the synergistic functionalization of PbS and MoSx co-catalysts. A solar-to-chemical (STC) conversion efficiency of ca. 4.63% is achieved on the bi-functionalized FAPbBr3-xIx, which is among the highest values reported for MHPs.