High-fidelity and high-speed wavefront shaping by leveraging complex media.

High-precision light manipulation is crucial for delivering information through complex media. However, existing spatial light modulation devices face a fundamental speed-fidelity tradeoff. Digital micromirror devices have emerged as a promising candidate for high-speed wavefront shaping but at the cost of compromised fidelity due to the limited control degrees of freedom. Here, we leverage the sparse-to-random transformation through complex media to overcome the dimensionality limitation of spatial light modulation devices. We demonstrate that pattern compression by sparsity-constrained wavefront optimization allows sparse and robust wavefront representations in complex media, improving the projection fidelity without sacrificing frame rate, hardware complexity, or optimization time. Our method is generalizable to different pattern types and complex media, supporting consistent performance with up to 89% and 126% improvements in projection accuracy and speckle suppression, respectively. The proposed optimization framework could enable high-fidelity high-speed wavefront shaping through different scattering media and platforms without changes to the existing holographic setups, facilitating a wide range of physics and real-world applications.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Managing immune checkpoint inhibitor-associated gastritis: Insights and strategies.

Immune checkpoint inhibitors (ICIs) are widely used due to their effectiveness in treating various tumors. Immune-related adverse events (irAEs) are defined as adverse effects resulting from ICI treatment. Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects, such as diarrhea and colitis, which may lead to the discontinuation of ICIs.

Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages.

Liver X receptors (LXRs) which link lipid metabolism and inflammation, were overexpressed in experimental rheumatoid arthritis (RA) rats as observed in our previous studies, while suppression of LXRα by silybin ameliorates arthritis and abnormal lipid metabolism. However, the role of LXRs in RA remains undefined. In this study, we investigated the inhibition role of LXRs in the polarization and activation of M1 macrophage by using a special LXRs inverse agonist SR9243, which led to ameliorating the progression of adjuvant-induced arthritis (AIA) in rats. Mechanistically, SR9243 disrupted the LPS/IFN-γ-induced Warburg effect in M1 macrophages, while glycolysis inhibitor 2-DG attenuated the inhibition effect of SR9243 on M1 polarization and the cytokines expression of M1 macrophages including iNOS, TNF-α, and IL-6 in vitro. Furthermore, SR9243 downregulated key glycolytic enzymes, including LDH-A, HK2, G6PD, GLUT1, and HIF-1α in M1 macrophages, which is mediated by increased phosphorylation of AMPK (Thr172) and reduced downstream phosphorylation of mTOR (Ser2448). Importantly, gene silencing of LXRs compromises the inhibition effect of SR9243 on M1 macrophage polarization and activation. Collectively, for the first time, our findings suggest that the LXR inverse agonist SR9243 mitigates adjuvant-induced rheumatoid arthritis and protects against bone erosion by inhibiting M1 macrophage polarization and activation through modulation of glycolytic metabolism via the AMPK/mTOR/HIF-1α pathway.

Microsyringe-assisted visual volume detection based on phase separation: the case of chymosin milk-clotting activity study.

The constantly diverse demand scenarios for rapid on-site analysis have put forward high requirements for developing low-cost and user-friendly visual detection methods. Therefore, developing a visual detection method with simple operation and intuitive results has important practical value in the field of analysis and detection, but it is also challenging. In this work, we propose a microsyringe-assisted visual volume detection method based on phase separation, and apply it to analyze the milk-clotting activity of chymosin. Chymosin can cause phase separation of milk with whey in the mobile phase and curd in the gel state. The network structures of casein in curd can trap water molecules, resulting in separation of whey from curd gradually. Therefore, the analysis of chymosin milk-clotting activity can be realized according to the volume of whey measured using a portable microsyringe. This method shows a good linear correlation when the concentration of chymosin ranges from 1.02 U L-1 to 1020 U L-1 and the limit of detection of this method for chymosin is calculated to be 0.03 U mL-1. This work successfully realizes the visual analysis of chymosin milk-clotting activity based on the enzyme-triggered phase separation. It also shows great promise to be applied in other phase separation-based detection systems with the advantages of high accuracy, great portability and user-friendliness.

The research landscape of ferroptosis in neurodegenerative disease: a bibliometric analysis.

Background: Ferroptosis, a newly proposed concept of programmed cell death, has garnered significant attention in research across different diseases in the last decade. Despite thorough citation analyses in neuroscience, there is a scarcity of information on ferroptosis research specifically related to neurodegenerative diseases. Method: The Web of Science Core Collection database retrieved relevant articles and reviews. Data on publications, countries, institutions, authors, journals, citations, and keywords in the included studies were systematically analyzed using Microsoft Excel 2019 and CiteSpace 6.2.R7 software. Result: A comprehensive analysis and visualization of 563 research papers on ferroptosis in neurodegenerative diseases from 2014 to 2023 revealed emerging research hotspots and trends. The number of annual publications in this field of study has displayed a pattern of stabilization in the early years of the decade, followed by a notable increase in the later years and peaking in 2023 with 196 publications. Regarding publication volume and total citations, notable research contributions were observed from countries, institutions, and authors in North America, Western Europe, and China. Current research endeavors primarily focus on understanding the intervention mechanisms of neurodegenerative diseases through the ferroptosis pathway and exploring and identifying potential therapeutic targets. Conclusion: The study highlights key areas of interest and emerging trends in ferroptosis research on neurodegenerative diseases, offering valuable insights for further exploration and potential directions for diagnosing and treating such conditions.

Maryland's Global Budget Revenue Payment Model and Shifts in the Surgical Site of Care Among Medicare Beneficiaries.

OBJECTIVE: To assess the association between the Global Budget Revenue (GBR) payment model and shifts to the outpatient setting for surgical procedures among Medicare fee-for-service beneficiaries in Maryland versus control states. SUMMARY BACKGROUND DATA: The GBR model provides fixed global payments to hospitals to reduce spending growth and incentivize hospitals to reduce the costs of care while improving care quality. Since surgical care is a major contributor to hospital spending, the GBR model might accelerate the ongoing shift from the inpatient to the outpatient setting to generate additional savings. METHODS: A difference-in-differences (DiD) design was used to compare changes in surgical care settings over time from pre-GBR (2011-2013) to post-GBR (2014-2018) for Maryland versus control states for common surgeries that could be performed in the outpatient setting. A cross-sectional approach was used to compare the difference in care settings in 2018 for total knee arthroplasty which was on Medicare's Inpatient-Only List before then. RESULTS: We studied 47,542 surgical procedures from 44,410 beneficiaries in Maryland and control states. GBR's 2014 implementation was associated with an acceleration in the shift from inpatient to outpatient settings for surgical procedures in Maryland (DiD: 3.9 percentage points, 95% CI: 2.3, 5.4). Among patients undergoing total knee arthroplasty in 2018, the proportion of outpatient surgeries in Maryland was substantially higher than that in control states (difference: 27.6 percentage points, 95% CI: 25.6, 29.6). CONCLUSIONS: Implementing Maryland's GBR payment model was associated with an acceleration in the shift from inpatient to outpatient hospital settings for surgical procedures.

Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

Locomotion Control of Cyborg Insects by Charge-Balanced Biphasic Electrical Stimulation.

The integration of electronic stimulation devices with insects in the context of cyborg insect systems has great application potential, particularly in the fields of environmental monitoring, urban surveillance, and rescue missions. Despite considerable advantages compared to the current robot technology, including flexibility, durability, and low energy consumption, this integration faces certain challenges related to the potential risk of charge accumulation caused by prolonged and repetitive electrical stimulations. To address these challenges, this study proposes a universal system for remote signal output control using infrared signals. The proposed system integrates high-precision digital-to-analog converters capable of generating customized waveform electrical stimulation signals within defined ranges. This enhances the accuracy of locomotion control in cyborg insects while maintaining real-time control and dynamic parameter adjustment. The proposed system is verified by experiments. The experimental results show that the signals generated by the proposed system have a success rate of over 76.25% in controlling the turning locomotion of cyborg insects, which is higher than previously reported results. In addition, the charge-balanced characteristics of these signals can minimize muscle tissue damage, thus substantially enhancing control repeatability. This study provides a comprehensive solution for the remote control and monitoring of cyborg insects, whose flexibility and adaptability can meet various application and experimental requirements. The results presented in this study lay a robust foundation for further advancement of various technologies, particularly those related to cyborg insect locomotion control systems and wireless control mechanisms for cyborg insects.

Current Progress of Ferroptosis Study in Hepatocellular Carcinoma.

Ferroptosis, an emerging type of programmed cell death, is initiated by iron-dependent and excessive ROS-mediated lipid peroxidation, which eventually leads to plasma membrane rupture and cell death. Many canonical signalling pathways and biological processes are involved in ferroptosis. Furthermore, cancer cells are more susceptible to ferroptosis due to the high load of ROS and unique metabolic characteristics, including iron requirements. Recent investigations have revealed that ferroptosis plays a crucial role in the progression of tumours, especially HCC. Specifically, the induction of ferroptosis can not only inhibit the growth of hepatoma cells, thereby reversing tumorigenesis, but also improves the efficacy of immunotherapy and enhances the antitumour immune response. Therefore, triggering ferroptosis has become a new therapeutic strategy for cancer therapy. In this review, we summarize the characteristics of ferroptosis based on its underlying mechanism and role in HCC and provide possible therapeutic applications.

Aspirin suppresses hepatocellular carcinoma progression by inhibiting platelet activity.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. Platelets (PLTs) are known to play a key role in the maintenance of liver homeostasis and the pathophysiological processes of a variety of liver diseases. Aspirin is the most classic antiplatelet agent. However, the molecular mechanism of platelet action and whether aspirin can affect HCC progression by inhibiting platelet activity need further study. AIM: To explore the impact of the antiplatelet effect of aspirin on the development of HCC. METHODS: Platelet-rich plasma, platelet plasma, pure platelet, and platelet lysate were prepared, and a coculture model of PLTs and HCC cells was established. CCK-8 analysis, apoptosis analysis, Transwell analysis, and real-time polymerase chain reaction (RT-PCR) were used to analyze the effects of PLTs on the growth, metastasis, and inflammatory microenvironment of HCC. RT-PCR and Western blot were used to detect the effects of platelet activation on tumor-related signaling pathways. Aspirin was used to block the activation and aggregation of PLTs both in vitro and in vivo, and the effect of PLTs on the progression of HCC was detected. RESULTS: PLTs significantly promoted the growth, invasion, epithelial-mesenchymal transition, and formation of an inflammatory microenvironment in HCC cells. Activated PLTs promoted HCC progression by activating the mitogen-activated protein kinase/protein kinase B/signal transducer and activator of transcription three (MAPK/ AKT/STAT3) signaling axis. Additionally, aspirin inhibited HCC progression in vitro and in vivo by inhibiting platelet activation. CONCLUSION: PLTs play an important role in the pathogenesis of HCC, and aspirin can affect HCC progression by inhibiting platelet activity. These results suggest that antiplatelet therapy has promising application prospects in the treatment and combined treatment of HCC.

Utilizing Raman spectroscopy for urinalysis to diagnose acute kidney injury stages in cardiac surgery patients.

BACKGROUND: The successful treatment and improvement of acute kidney injury (AKI) depend on early-stage diagnosis. However, no study has differentiated between the three stages of AKI and non-AKI patients following heart surgery. This study will fill this gap in the literature and help to improve kidney disease management in the future. METHODS: In this study, we applied Raman spectroscopy (RS) to uncover unique urine biomarkers distinguishing heart surgery patients with and without AKI. Given the amplified risk of renal complications post-cardiac surgery, this approach is of paramount importance. Further, we employed the partial least squares-support vector machine (PLS-SVM) model to distinguish between all three stages of AKI and non-AKI patients. RESULTS: We noted significant metabolic disparities among the groups. Each AKI stage presented a distinct metabolic profile: stage 1 had elevated uric acid and reduced creatinine levels; stage 2 demonstrated increased tryptophan and nitrogenous compounds with diminished uric acid; stage 3 displayed the highest neopterin and the lowest creatinine levels. We utilized the PLS-SVM model for discriminant analysis, achieving over 90% identification rate in distinguishing AKI patients, encompassing all stages, from non-AKI subjects. CONCLUSIONS: This study characterizes the incidence and risk factors for AKI after cardiac surgery. The unique spectral information garnered from this study can also pave the way for developing an in vivo RS method to detect and monitor AKI effectively.

Noviherbaspirillum album sp. nov., an airborne bacteria isolated from an urban area of Beijing, China.

A Gram-negative, ellipsoidal to short-rod-shaped, motile bacterium was isolated from Beijing's urban air. The isolate exhibited the closest kinship with Noviherbaspirillum aerium 122213-3T, exhibiting 98.4 % 16S rRNA gene sequence similarity. Phylogenetic analyses based on 16S rRNA gene sequences and genomes showed that it clustered closely with N. aerium 122213-3T, thus forming a distinct phylogenetic lineage within the genus Noviherbaspirillum. The average nucleotide identity and digital DNA-DNA hybridization values between strain I16B-00201T and N. aerium 122213-3T were 84.6 and 29.4 %, respectively. The respiratory ubiquinone was ubiquinone 8. The major fatty acids (>10 %) were summed feature 3 (C16:1ω6c/C16:1ω7c, 43.3 %), summed feature 8 (C18:1ω7c/C18:1ω6c, 15.9 %) and C12:0 (11.0 %). The polyamine profile showed putrescine as the predominant compound. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, unknown lipids and unknown phosphatidylaminolipids. The phenotypic, phylogenetic and chemotaxonomic results consistently supported that strain I16B-00201T represented a novel species of the genus Noviherbaspirillum, for which the name Noviherbaspirillum album sp. nov. is proposed, with I16B-00201T (=CPCC 100848T=KCTC 52095T) designated as the type strain. Its DNA G+C content is 59.4 mol%. Pan-genome analysis indicated that some Noviherbaspirillum species possess diverse nitrogen and aromatic compound metabolism pathways, suggesting their potential value in pollutant treatment.

Predicting Provider Workload Using Predicted Patient Risk Score and Social Determinants of Health in Primary Care Setting.

BACKGROUND: Provider burnout due to workload is a significant concern in primary care settings. Workload for primary care providers encompasses both scheduled visit care and non-visit care interactions. These interactions are highly influenced by patients' health conditions or acuity, which can be measured by the Adjusted Clinical Group (ACG) score. However, new patients typically have minimal health information beyond social determinants of health (SDOH) to determine ACG score. OBJECTIVES: This study aims to assess new patient workload by first predicting the ACG score using SDOH, age, and gender and then using this information to estimate the number of appointments (scheduled visit care) and non-visit care interactions. METHODS: Two years of appointment data were collected for patients who had initial appointment requests in the first year and had the ACG score, appointment, and non-visit care counts in the subsequent year. State-of-art machine learning algorithms were employed to predict ACG scores and compared with current baseline estimation. Linear regression models were then used to predict appointments and non-visit care interactions, integrating demographic data, SDOH, and predicted ACG scores. RESULTS: The machine learning methods showed promising results in predicting ACG scores. Besides the decision tree, all other methods performed at least 9% better in accuracy than the baseline approach which had an accuracy of 78%. Incorporating SDOH and predicted ACG scores also significantly improved the prediction for both appointments and non-visit care interactions. The R 2 values increased by 95.2 and 93.8%, respectively. Furthermore, age, smoking tobacco, family history, gender, usage of injection birth control, and ACG were significant factors for determining appointments. SDOH factors such as tobacco usage, physical exercise, education level, and group activities were strongly correlated with non-visit care interactions. CONCLUSION: The study highlights the importance of SDOH and predicted ACG scores in predicting provider workload in primary care settings.

A ratiometric fluorescence sensor for detection of organophosphorus pesticides based on enzyme-regulated multifunctional Fe-based metal-organic framework.

The residues of organophosphorus pesticides (OPs) are increasing environmental pollution and public health concerns. Thus, the development of simple, convenient and sensitive method for detection of OPs is crucial. Herein, a multifunctional Fe-based MOF with fluorescence, catalytic and adsorption, is synthesized by a simple one-pot hydrothermal method. The ratiometric fluorescence sensor for detection of OPs is constructed by using only one multifunctional sensing material. The NH2-MIL-101(Fe) is able catalyze the o-phenylenediamine (OPD) into 2,3-diaminophenazine (DAP) in the presence of H2O2. The generated DAP can significantly quench the intrinsic fluorescence of NH2-MIL-101(Fe) by the fluorescence resonance energy transfer (FRET) and internal filtration effect (IFE), while producing a new measurable fluorescence. Without immobilization or molecular imprinting, pyrophosphate ion (PPi) can inhibit the peroxidase-like activity of the NH2-MIL-101(Fe) by chelating with Fe3+/Fe2+ redox couple. Moreover, PPi can also be hydrolyzed by alkaline phosphatase (ALP), the presence of OPs inhibits the activity of ALP, resulting in the increase of extra PPi preservation and signal changes of ratiometric fluorescence, the interactions of ALP with different OPs are explored by molecular docking, the OPs (e.g., glyphosate) interact with crucial amino acid residues (Asp, Ser, Ala, Lys and Arg) are indicated. The proposed sensor exhibits excellent detection performance for OPs with the detection limit of 18.7 nM, which provides a promising strategy for detection of OPs.

Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP.

Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.

AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.

The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

Antifouling Asymmetric Block Copolymer Nanofilms via Freestanding Interfacial Polymerization for Efficient and Sustainable Water Purification.

Membrane materials that resist nonspecific or specific adsorption are urgently required in widespread applications. In water purification, inevitable membrane fouling not only limits separation performance, but also remarkably increases operation requirements, and augments extra maintenance costs and higher energy consumption. In this work, we report a freestanding interfacial polymerization (IP) fabrication strategy for in-situ creation of asymmetric block copolymer (BCP) nanofilms with antifouling properties, greatly outperforming the conventional surface post-modification approaches. The resultant asymmetric BCP nanofilms with highly-dense, highly-hydrophilic polyethylene glycol (PEG) brushes, can be readily formed via a typical IP process of a double-hydrophilic BCP composed of an antifouling PEG block and a membrane-forming multiamine block. The asymmetric BCP nanofilms have been applied for efficient and sustainable natural water purification, demonstrating extraordinary antifouling capabilities accompanied with superior separation performance far beyond commercial polyamide nanofiltration membranes. The antifouling behaviors of BCP nanofilms derived from the combined effect of the hydration layer, electrostatic repulsion and steric hindrance were further elucidated by water flux and fouling resistance in combination with all-atom molecular dynamics simulation. This work opens up a new avenue for large-scale and low-cost creation of broad-spectrum, asymmetric membrane materials with diverse functional "defect-free" surfaces in real-world applications.

Pharmacokinetics-Pharmacodynamics Modeling for Evaluating Drug-Drug Interactions in Polypharmacy: Development and Challenges.

Polypharmacy is commonly employed in clinical settings. The potential risks of drug-drug interactions (DDIs) can compromise efficacy and pose serious health hazards. Integrating pharmacokinetics (PK) and pharmacodynamics (PD) models into DDIs research provides a reliable method for evaluating and optimizing drug regimens. With advancements in our comprehension of both individual drug mechanisms and DDIs, conventional models have begun to evolve towards more detailed and precise directions, especially in terms of the simulation and analysis of physiological mechanisms. Selecting appropriate models is crucial for an accurate assessment of DDIs. This review details the theoretical frameworks and quantitative benchmarks of PK and PD modeling in DDI evaluation, highlighting the establishment of PK/PD modeling against a backdrop of complex DDIs and physiological conditions, and further showcases the potential of quantitative systems pharmacology (QSP) in this field. Furthermore, it explores the current advancements and challenges in DDI evaluation based on models, emphasizing the role of emerging in vitro detection systems, high-throughput screening technologies, and advanced computational resources in improving prediction accuracy.

High recallability of memory B cells requires ZFP318-dependent transcriptional regulation of mitochondrial function.

Expression of the transcriptional regulator ZFP318 is induced in germinal center (GC)-exiting memory B cell precursors and memory B cells (MBCs). Using a conditional ZFP318 fluorescence reporter that also enables ablation of ZFP318-expressing cells, we found that ZFP318-expressing MBCs were highly enriched with GC-derived cells. Although ZFP318-expressing MBCs constituted only a minority of the antigen-specific MBC compartment, their ablation severely impaired recall responses. Deletion of Zfp318 did not alter the magnitude of primary responses but markedly reduced MBC participation in recall. CD40 ligation promoted Zfp318 expression, whereas B cell receptor (BCR) signaling was inhibitory. Enforced ZFP318 expression enhanced recall performance of MBCs that otherwise responded poorly. ZFP318-deficient MBCs expressed less mitochondrial genes, had structurally compromised mitochondria, and were susceptible to reactivation-induced cell death. The abundance of ZFP318-expressing MBCs, instead of the number of antigen-specific MBCs, correlated with the potency of prime-boost vaccination. Therefore, ZFP318 controls the MBC recallability and represents a quality checkpoint of humoral immune memory.