Enhancing ozone catalytic decomposition through acid treatment of α-MnO2 for improved activity and humidity resistance.

Post-etching method using dilute acid solutions is an effective technology to modulate the surface compositions of metal-oxide catalysts. Here the α-MnO2 catalyst treated with 0.1 mol/L nitric acid exhibits higher ozone decomposition activity at high relative humidity than the counterpart treated with acetic acid. Besides the increases in surface area and lattice dislocation, the improved activity can be due to relatively higher Mn valence on the surface and newly-formed Brønsted acid sites adjacent to oxygen vacancies. The remnant nitro species deposited on the catalyst by nitric acid treatment is ideal hydrophobic groups at ambient conditions. The decomposition route is also proposed based on the DRIFTS and DFT calculations: ozone is facile to adsorb on the oxygen vacancy, and the protonic H of Brønsted acid sites bonds to the terminal oxygen of ozone to accelerate its cleavage to O2, reducing the reaction energy barrier of O2 desorption.

Integrated non-targeted metabolomics and lipidomics reveal mechanisms of fluorotelomer sulfonates-induced toxicity in human hepatocytes.

Fluorotelomer sulfonates (FTSs) are widely used as novel substitutes for perfluorooctane sulfonate, inevitably leading to FTSs accumulation in various environmental media and subsequent exposure to humans. This accumulation eventually poses environmental hazards and health risks. However, their toxicity mechanisms remain unclear. Herein, the mechanisms of two FTSs (6:2 and 8:2 FTS) induced toxicity in human hepatocellular carcinoma cells were investigated via non-targeted metabolomics and lipidomics based on liquid chromatography-high resolution mass spectrometry. Our results revealed that amino acid, purine, acylcarnitine and lipid levels were significantly perturbed by 6:2 and 8:2 FTS exposure. The effects of 8:2 FTS exposure were largely characterized by up-regulation of pyruvate metabolism pathway and down-regulation of purine metabolism pathway, whereas the opposite trends were induced by 6:2 FTS exposure. The opposite trends were confirmed by the mRNA expression levels of four key genes (glyoxalase 1, adenylosuccinate lyase, inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2) determined by real-time PCR. Common lipid perturbations included significantly increased ceramide/sphingomyelin ratios, and obvious accumulation of hexosylceramides and lysoglycerophospholipids. 6:2 FTS exposure induced sharp accumulation of glycerides, including monoglycerides, diglycerides and triglycerides. 8:2 FTS exposure induced decreased levels of acylcarnitines and fatty acids. Both of 6:2 and 8:2 FTS exposure induced increased levels of intracellular reactive oxygen species, an imbalance in energy metabolism homeostasis, and mitochondrial dysfunction. The results of integrated omics analysis are expected to serve as valuable information for the health risk assessment of 6:2 FTS and 8:2 FTS.

Melt-blown polypropylene nonwoven as an efficient and eco-economic sorbent for pipette tip micro-solid phase extraction for the determination of tyrosine kinase inhibitors.

BACKGROUND: The detection of tyrosine kinase inhibitors (TKIs) in biological fluids is essential due to their critical role in cancer therapy and the variability in individual drug metabolism, which necessitates precise dosing. Traditional methods for analyzing TKIs in biological fluids, such as blood plasma, typically involve complex sample preparation techniques that can be resource-intensive, environmentally burdensome, and not sufficiently sensitive for low-concentration analytes. There is a pressing need for more efficient, economical, and environmentally friendly methods that can enhance sensitivity and throughput without compromising accuracy. RESULTS: This study explores the use of melt-blown polypropylene nonwoven (MBPP), commonly found in face masks, as a novel sorbent for pipette-tip micro-solid phase extraction (PT-µSPE). MBPP demonstrated excellent hydrophobicity and significant mesoporous adsorption capacity. An extraction device was fashioned by inserting a segment of MBPP (15 mg) into a 200 µL disposable plastic pipette tip, which was then attached to a 2.5 mL disposable plastic syringe. The MBPP's fabric form removes the need for a frit, allowing the extraction process to be completed in just 3 min through simple plunger manipulation. The method achieved extraction recoveries ranging from 60.5 % to nearly 100 %. Subsequent method validation using liquid chromatography-tandem mass spectrometry (LC-MS/MS) showed satisfactory linearity (coefficient of determination R2 > 0.993), accuracy (relative recoveries: 86.3%-114.8 %), and precision (relative standard deviation: 3.4%-11.3 %), with detection limits between 0.022 and 0.135 ng mL-1. SIGNIFICANCE: The introduction of MBPP for PT-µSPE represents a significant advancement in the bioanalytical detection of TKIs, offering a highly efficient, cost-effective, and environmentally sustainable method. It compares favorably with existing techniques, offering advantages in terms of cost, environmental impact, and ease of use. This approach has the potential to be widely adopted for routine monitoring of TKIs in clinical settings.

Automated kapok fiber-based pipette-tip solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry for rapid and sensitive analysis of tyrosine kinase inhibitors in plasma.

This study delineates the development of a novel automated pipette-tip solid-phase extraction (SPE) methodology, employing kapok fiber as a naturally efficient and cost-effective adsorbent for the selective extraction of eleven tyrosine kinase inhibitors (TKIs) from plasma. The uniqueness of this method lies in its assembly, where kapok fibers are ingeniously wrapped around a stainless-steel spring within the pipette tip, ensuring an obstruction-free central space for effortless solution aspiration and dispensation. This design significantly minimizes backpressure, enhancing operational efficiency and ensuring compatibility with pipettors, including the implementation of an electric pipettor to streamline the sample preparation process and facilitate automation. The method's analytical performance, rigorously validated through liquid chromatography-tandem mass spectrometry, exhibits outstanding linearity in ranges of 0.1/0.5-200 ng mL-1 (R² > 0.993), commendable accuracy (86.3%-114.8%), and consistent precision (3.4-11.3%), alongside remarkably low detection limits that span from 0.024 to 0.130 ng mL-1. The assembly of kapok fiber within the pipette tip, in this unique configuration, results in a practical, cost-effective, eco-friendly, and automated pipette-tip SPE method. This innovation signifies a significant advancement in bioanalytical methodologies, offering an efficient and sustainable approach for extracting analytes from complex biological samples. This process notably enhances both the sensitivity and selectivity of subsequent instrumental analyses.

Mechanisms of Bone Morphogenetic Protein 2 in Respiratory Diseases.

PURPOSE OF REVIEW: Bone morphogenetic protein 2 (BMP2) belongs to the transforming growth factor-ß (TGF-ß) superfamily and plays an important role in regulating embryonic development, angiogenesis, osteogenic differentiation, tissue homeostasis, and cancer invasion. Increasing studies suggest BMP2 is involved in several respiratory diseases. This study aimed to review the role and mechanisms of BMP2 in respiratory diseases. RECENT FINDINGS: BMP2 signaling pathway includes the canonical and non-canonical signaling pathway. The canonical signaling pathway is the BMP2-SMAD pathway, and the non-canonical signaling pathway includes mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. The BMP2 is related to pulmonary hypertension (PH), lung cancer, pulmonary fibrosis (PF), asthma, and chronic obstructive pulmonary disease (COPD). BMP2 inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), promotes the apoptosis of PASMCs to reduce pulmonary vascular remodeling in PH, which is closely related to the canonical and non-canonical pathway. In addition, BMP2 stimulates the proliferation and migration of cells to promote the occurrence, colonization, and metastasis of lung cancer through the canonical and the non-canonical pathway. Meanwhile, BMP2 exert anti-fibrotic function in PF through canonical signaling pathway. Moreover, BMP2 inhibits airway inflammation to maintain airway homeostasis in asthma. However, the signaling pathways involved in asthma are poorly understood. BMP2 inhibits the expression of ciliary protein and promotes squamous metaplasia of airway epithelial cells to accelerate the development of COPD. In conclusion, BMP2 may be a therapeutic target for several respiratory diseases.

KRAS mutation promotes the colonization of Fusobacterium nucleatum in colorectal cancer by down-regulating SERTAD4.

This study explores and verifies potential molecular targets through which KRAS mutations regulate the colonization of Fusobacterium nucleatum (FN) in colorectal cancer (CRC). This study combined multiple bioinformatics methods and biological assays. Through The Cancer Genome Atlas, Gene Expression Omnibus, Human Protein Atlas, immunohistochemistry, and co-culture assays, we further confirmed the differential expression of SERTAD4 in CRC. We delved deeper into examining how expression of SERTAD4 is linked with immune cell infiltration and the enrichment of potential pathways. Lastly, through bacterial phenotypic assays, we validated the function of SERTAD4. As a molecule associated with KRAS mutations and FN infection, the expression levels of SERTAD4 were downregulated in CRC. The diagnostic efficacy of SERTAD4 for CRC is not inferior to that of CEA. Low expression of SERTAD4 is associated with poorer overall survival in CRC. Correlation analysis found that increased expression of SERTAD4 is associated with various immune cell infiltrations and immune checkpoint genes. Finally, bacterial adhesion and invasion assays verify that SERTAD4 inhibits the adhesion and invasion abilities of FN in CRC. This study demonstrates that SERTAD4 exerts a protective role in CRC by inhibiting the colonization of FN.

Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer.

BACKGROUND: Current evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear. METHODS: This study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity. RESULTS: This study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice. CONCLUSIONS: The findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.

QTL detection for grain shape and fine mapping of two novel locus qGL4 and qGL6 in rice.

Rice grain size and grain weight, which have a great influence on rice quality and yield, are complex quantitative traits that are mediated by grain length (GL), grain width (GW), length-to-width ratio (LWR), and grain thickness (GT). In this study, the BC1F2 and BC1F2:3 populations derived from a cross between two indica rice varieties, Guangzhan 63-4S (GZ63-4S) and Dodda, were used to locate quantitative trait loci (QTL) related to grain size. A total of 30 QTL associated with GL, GW and LWR were detected, of which six QTL were scanned repeatedly in both populations. Two QTL, qGL4 and qGL6, were selected for genetic effect validation and were subsequently fine mapped to 2.359 kb and 176 kb, respectively. LOC_Os04g52240 (known as OsKS2/OsKSL2), which encoding an ent-beyerene synthase and as the only gene found in 2.359 kb interval, was proposed to be the candidate for qGL4. Moreover, the grains of qGL4 homozygous mutant plants generated by the CRISPR-Cas9 system became shorter and wider. In addition, the qGL4 allele from GZ63-4S contributes to the increase of yield per plant. Our study not only laid the foundation for further functional study of qGL4 and map-based cloning of qGL6, but also provided genetic resources for the development of high yield and good quality rice varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01502-8.

STING Agonist Delivered by Neutrophil Membrane-Coated Gold Nanoparticles Exerts Synergistic Tumor Inhibition with Radiotherapy.

Radiotherapy (RT) is one of the major treatments for cancers and a promising initiator of immune response. Gold nanoparticles are a promising radiosensitizer. In this study, we sought to optimize the drug delivery efficiency of gold nanoparticles and explore their function in delivering stimulator of interferon genes (STING) agonists with or without RT. Gold nanoparticles covalent to MSA-2 (MSA-Au) were mixed with cRGD-modified neutrophil membranes to obtain M-Au@RGD-NM. We explored the treatment efficiency of M-Au@RGD-NM combined with RT. Immune cell regulation and STING pathway activation were detected. We successfully prepared M-Au@RGD-NM with significant tumor suppression by induction of ROS and the resulting DNA damage. In vivo dynamic imaging showed that M-Au@RGD-NM was mainly targeted to radiated tumors. Tumor-bearing mice showed significant tumor inhibition following a combination therapy. M-Au@RGD-NM significantly activated the STING pathway and regulated the whole-body immune response. Locally radiated tumors showed dendritic cells mature, CD8+ T cells upregulation, and M1 polarization, with systematic immune response demonstrated by CD8+ T cell infiltration in abscopal tumors. In this study, we synthesized M-Au@RGD-NM loading MSA-2. Following characterization, we found that RT-based M-Au@RGD-NM treatment achieved good antitumor effects, tumor RT enhancement, and induction of an immune response via STING activation.

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer.

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

Acceleration of Orthodontic Tooth Movement: A Bibliometric and Visual Analysis.

BACKGROUND: Prolonged orthodontic treatment duration has long been a concern for orthodontists and patients, leading to a surge in publications on accelerated orthodontic tooth movement (OTM). This study aims to investigate the knowledge landscape, hotspots, and research trends in acceleration of OTM using bibliometric and visual analyses. METHODS: A comprehensive search was conducted in the Web of Science (WOS) Core Collection to identify relevant publications related to acceleration of OTM. R Biblioshiny, VOS viewer, and a bibliometric online analysis platform were used to conduct the bibliometric and visualization analysis. Curve fitting and correlation analysis were performed to examine the correlation global and country economics and publication trends, and to predict publication numbers. RESULTS: A total of 647 articles on accelerated OTM were included in the analysis, with clinical and non-clinical publications accounting for 43.59% and 31.22%, respectively. The annual publication numbers exhibited an upward trend, correlating positively with both global gross domestic product (GDP) (r = 0.915, P < .001) and the GDP of individual countries/regions (r = 0.976, P < .001). China produced the most documents (94), while the USA led in citation count (2758) and international collaborations. Wilcko WM was the top-cited author, with eight of the top 10 authors from the USA and the remainder from Asia. Keywords such as 'tooth movement', 'corticotomy', 'piezocision' and 'low-level laser therapy' were the most prominent themes, while topics like 'micro-osteoperforation', 'plasma', 'gingival crevicular fluid' and 'pain' have become recent research hotspots and frontiers. CONCLUSIONS: This study provides a comprehensive overview of the research on accelerated OTM, highlighting hotspots and frontiers, fostering collaboration among authors and countries/regions, and contributing to future research endeavours.

A sophisticated mechanism governs Pol ζ activity in response to replication stress.

DNA polymerase ζ (Pol ζ) plays an essential role in replicating damaged DNA templates but contributes to mutagenesis due to its low fidelity. Therefore, ensuring tight control of Pol ζ's activity is critical for continuous and accurate DNA replication, yet the specific mechanisms remain unclear. This study reveals a regulation mechanism of Pol ζ activity in human cells. Under normal conditions, an autoinhibition mechanism keeps the catalytic subunit, REV3L, inactive. Upon encountering replication stress, however, ATR-mediated phosphorylation of REV3L's S279 cluster activates REV3L and triggers its degradation via a caspase-mediated pathway. This regulation confines the activity of Pol ζ, balancing its essential role against its mutations causing potential during replication stress. Overall, our findings elucidate a control scheme that fine tunes the low-fidelity polymerase activity of Pol ζ under challenging replication scenarios.

Small molecule valproic acid enhances ventral patterning of human neural tube organoids by regulating Wnt and Shh signalling.

Valproic acid (VPA), a clinically approved small molecule, has been reported to activate Wnt signalling that is critical for dorsal-ventral (DV) patterning of neural tube. However, little is known about the impact of VPA on DV patterning process. Here, we show that even though VPA has a negative impact on the early formation of human neural tube organoids (hNTOs), it significantly enhances the efficiency of ventrally patterned hNTOs, when VPA is added during the entire differentiation process. RNA sequencing and RT-qPCR analysis demonstrates VPA activates endogenous Wnt signalling in hNTOs. Surprisingly, transcriptome analysis also identifies upregulation of genes for degradation of GLI2 and GLI3 proteins, whose truncated fragment are transcriptional repressors of Shh signalling. The Western-blot analysis confirms the increase of GLI3R proteins after VPA treatment. Thus, VPA might enhance ventral patterning of hNTOs through both activating Wnt, which can antagonise Shh signalling by inducing GLI3 expression, and/or inhibiting Shh signalling by inducing GLI protein degradation. We further obtain results to show that VPA still increases patterning efficiency of hNTOs with a weak influence on their early formation when the initiation time of VPA is delayed and its duration is reduced. Taken together, this study demonstrates that VPA enhances the generation of more reproducible hNTOs with ventral patterning, opening the avenues for the applications of hNTOs in developmental biology and regenerative medicine.

SIMpat: A Synthetic Benchmark for Similarity Metrics on Patient Representations.

Similarity and clustering tasks based on data extracted from electronic health records on the patient level suffer from the curse of dimensionality and the lack of inter-patient data comparability. Indeed, for many health institutions, there are many more variables, and ways of expressing those variables to represent patients than patients sharing the same set of data. To lower redundancy and increase interoperability one strategy is to map data to semantic-driven representations through medical knowledge graphs such as SNOMED-CT. However, patient similarity metrics based on this knowledge-graph information lack quantitative evaluation and comparisons with pure data-driven methods. The reasons are twofold, firstly, it is hard to conceptually assess and formalize a gold-standard similarity between patients resulting in poor inter-annotator agreement in qualitative evaluations. Secondly, the community has been lacking a clear benchmark to compare existing metrics developed by scientific communities coming from various fields such as ontology, data science, and medical informatics. This study proposes to leverage the known challenges of evaluating patient similarities by proposing SIMpat, a synthetic benchmark to quantitatively evaluate available metrics, based on controlled cohorts, which could later be used to assess their sensibility regarding aspects such as the sparsity of variables or specificities of patient disease patterns.

Beyond Tokens: Fair Evaluation of French Large Language Models for Clinical Named Entity Recognition.

Named Entity Recognition (NER) models based on Transformers have gained prominence for their impressive performance in various languages and domains. This work delves into the often-overlooked aspect of entity-level metrics and exposes significant discrepancies between token and entity-level evaluations. The study utilizes a corpus of synthetic French oncological reports annotated with entities representing oncological morphologies. Four different French BERT-based models are fine-tuned for token classification, and their performance is rigorously assessed at both token and entity-level. In addition to fine-tuning, we evaluate ChatGPT's ability to perform NER through prompt engineering techniques. The findings reveal a notable disparity in model effectiveness when transitioning from token to entity-level metrics, highlighting the importance of comprehensive evaluation methodologies in NER tasks. Furthermore, in comparison to BERT, ChatGPT remains limited when it comes to detecting advanced entities in French.

RGD-modified ZIF-8 nanoparticles as a drug carrier for MR imaging and targeted drug delivery in myocardial infarction.

Aim: A multifunctional nanoplatform has been developed to enhance the targeting capability and biosafety of drug/siRNA for better diagnosis and treatment of myocardial infarction (MI).Materials & methods: The nanoplatform's chemical properties, biodistribution, cardiac magnetic resonance imaging (MRI) capabilities, therapeutic effects and biocompatibility were investigated.Results: The nanoplatform exhibited MI-targeting properties and pH-sensitivity, allowing for effective cardiac MRI and delivery of drugs to the infarcted myocardium. The GCD/Qt@ZIF-RGD demonstrated potential as a reliable MRI probe for MI diagnosis. Moreover, the GCD/si-SHP1/Qt@ZIF-RGD effectively suppressed SHP-1 expression, increased pro-angiogenesis gene expression and reduced cell apoptosis in HUVECs exposed to hypoxia/reoxygenation.Conclusion: Our newly developed multifunctional drug delivery system shows promise as a nanoplatform for both the diagnosis and treatment of MI.

[Box: see text].

Improving the performance of kesterite solar cells by solution germanium alloying.

Cation substitution is an effective strategy to regulate the defects/electronic properties of kesterite Cu2ZnSn(S,Se)4 (CZTSSe) absorbers and improve the device photovoltaic performance. Here, we report Ge alloying kesterite Cu2Zn(Sn,Ge)(S,Se)4 (CZTGSSe) via a solution approach. The results demonstrate that the same chemical reaction of Ge4+ to Sn4+ ensures homogeneous Ge incorporation in the whole range of concentrations (from 0 to unit). Ge alloying promotes grain growth and linearly enlarges the absorber band gap by solely raising the conduction band minimum, which maintains a "spike" conduction band offset at the heterojunction interface until 15% alloying concentration and thus facilitates effective charge carrier collection. A promising efficiency of 11.57% has been achieved at 15% Ge alloying concentration with a significant enhancement in open-circuit voltage and fill factor. By further 10% Ag alloying to improve the absorber film morphology, a champion device with an efficiency of 12.25% has been achieved without an antireflective coating. This result emphasizes the feasibility of achieving homogeneous and controllable Ge alloying of kesterite semiconductors through the solution method, paving the way for further improvement and optimization of device performance.

Organophosphate flame retardants tris (2-butoxyethyl) phosphate (TBEP) and tris (2-chloroethyl) phosphate (TCEP) disrupt human motor neuron development by differentially affecting their survival and differentiation.

Mounting evidence in animal experiments proves that early life stage exposure to organophosphate flame retardants (OPFRs) affects the locomotor behavior and changes the transcriptions of central nervous system genes. Unfortunately, their effect on human motor neuron (MN) development, which is necessary for body locomotion and survival, has not yet characterized. Here, we utilized a spinal cord MN differentiation model from human embryonic stem cells (ESCs) and adopted this model to test the effects of two typical OPFRs tris (2-butoxyethyl) phosphate (TBEP) and tris (2-chloroethyl) phosphate (TCEP), on MN development and the possible mechanisms underlying. Our findings revealed TBEP exerted a much more inhibitory effect on MN survival, while TCEP exhibited a stronger stimulatory effect on ESCs differentiation into MN, and thus TBEP exhibited a stronger inhibition on MN development than TCEP. RNA sequencing analysis identified TBEP and TCEP inhibited MN survival mainly by disrupting extracellular matrix (ECM)-receptor interaction. Focusing on the pathway guided MN differentiation, we found both TBEP and TCEP activated BMP signaling, whereas TCEP simultaneously downregulated Wnt signaling. Collectively, this is the first study demonstrated TBEP and TCEP disrupted human MN development by affecting their survival and differentiation, thereby raising concern about their potential harm in causing MN disorders.

Infectious mononucleosis complicated by transitory Epstein-Barr virus infection of T and natural killer cells.

Epstein-Barr virus (EBV) typically infects B cells in infectious mononucleosis (IM), but a rare case shows EBV infection in T cells. Seven cases of lymphoproliferative disorder caused by EBV-positive cytotoxic T/natural killer (NK) cell proliferation in the lymph nodes, termed IM with transient EBV infection of T and NK cells (EBV + T/NK cells in IM), are reported here. The purpose of the study is to describe clinicopathological features of EBV + T/natural killer (NK) cells in IM of the lymph node. We retrospectively analysed seven cases of Chinese children and young people adults with EBV + T/NK cells in IM. We used morphological observation, immunohistochemical staining, EB virus in situ hybridisation detection, and analysis of T-cell receptor gene rearrangement. The patients were healthy prior to illness, experiencing sudden onset occurring in all the patients, with high fever as the first symptom, followed by lymphadenopathy and hepatosplenomegaly. Diagnosis occurred < 1.5 months of symptom onset. Most lymphocytes in lesions expressed CD3 and Granzyme B or TIA-1 and lacked CD5. CD56 was expressed in numerous cells in 5 of the 7 cases. EBV-encoded RNA (EBER) was detected in medium-to-large-sized cells (50-100 cells per cell/high-power field). T-cell receptor (TCR) gene rearrangement was seen in six cases, with monoclonal rearrangement in four cases. Treatment was conservative treatment but not chemotherapy. Four received anti-HLH therapy and others anti-inflammatory treatment. All patients survived with relapse after long-term clinical observation and follow-up. EBV + T/NK cells in IM can elicit malignant features that mimic T/NK-cell lymphoma pathologically and benign features mimicking IM clinically. These findings indicate that EBV + T/NK cells in IM could serve as valuable diagnosis. Additional clinical information, including age of onset (children and young people), nature of onset (sudden), disease course (short), symptoms (systemic), EBV infection status (acute), and lymph node involvement, is crucial for accurate diagnosis and prognostic evaluation.

Model-informed drug development in pediatric, pregnancy and geriatric drug development: States of the art and future.

The challenges of drug development in pediatric, pregnant and geriatric populations are a worldwide concern shared by regulatory authorities, pharmaceutical companies, and healthcare professionals. Model-informed drug development (MIDD) can integrate and quantify real-world data of physiology, pharmacology, and disease processes by using modeling and simulation techniques to facilitate decision-making in drug development. In this article, we reviewed current MIDD policy updates, reflected on the integrity of physiological data used for MIDD and the effects of physiological changes on the drug PK, as well as summarized current MIDD strategies and applications, so as to present the state of the art of MIDD in pediatric, pregnant and geriatric populations. Some considerations are put forth for the future improvements of MIDD including refining regulatory considerations, improving the integrity of physiological data, applying the emerging technologies, and exploring the application of MIDD in new therapies like gene therapies for special populations.