ß2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function.

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of ß2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.

ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation.

The nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a critical mediator of the innate immune response. How NLRP3 responds to stimuli and initiates the assembly of the NLRP3 inflammasome is not fully understood. Here, we found that a cellular metabolite, palmitate, facilitates NLRP3 activation by enhancing its S-palmitoylation, in synergy with lipopolysaccharide stimulation. NLRP3 is post-translationally palmitoylated by zinc-finger and aspartate-histidine-histidine-cysteine 5 (ZDHHC5) at the LRR domain, which promotes NLRP3 inflammasome assembly and activation. Silencing ZDHHC5 blocks NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation of caspase-1 activation, IL-1ß/18 release, and GSDMD cleavage, both in human cells and in mice. ABHD17A depalmitoylates NLRP3, and one human-heritable disease-associated mutation in NLRP3 was found to be associated with defective ABHD17A binding and hyper-palmitoylation. Furthermore, Zdhhc5-/- mice showed defective NLRP3 inflammasome activation in vivo. Taken together, our data reveal an endogenous mechanism of inflammasome assembly and activation and suggest NLRP3 palmitoylation as a potential target for the treatment of NLRP3 inflammasome-driven diseases.

Posttranscriptional regulation of de novo lipogenesis by glucose-induced O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.

Prediction of CAF-related genes in immunotherapy and drug sensitivity in hepatocellular carcinoma: a multi-database analysis.

This study aims to identify the cancer-associated fibroblasts (CAF)-related genes that can affect immunotherapy and drug sensitivity in hepatocellular carcinoma (HCC). Expression data and survival data associated with HCC were obtained in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted correlation network analysis (WGCNA) analysis was performed to obtain CAF-related genes. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for regression analysis and risk models. Subsequently, Gene Set Enrichment Analysis (GSEA) analysis, Gene Set Enrichment Analysis (ssGSEA) analysis, Tumor Immune Dysfunction and Exclusion (TIDE) analysis and drug sensitivity analysis were performed on the risk models. Survival analysis of CAF scores showed that the survival rate was lower in samples with high CAF scores than those with low scores. However, this difference was not significant, suggesting CAF may not directly influence the prognosis of HCC patients. Further screening of CAF-related genes yielded 33 CAF-related genes. Seven risk models constructed based on CDR2L, SPRED1, PFKP, ENG, KLF2, FSCN1 and VCAN, showed significant differences in immunotherapy and partial drug sensitivity in HCC. Seven CAF-related genes may have important roles in immunotherapy, drug sensitivity and prognostic survival in HCC patients.

Attentional control influence habituation through modulation of connectivity patterns within the prefrontal cortex: Insights from stereo-EEG.

Attentional control, guided by top-down processes, enables selective focus on pertinent information, while habituation, influenced by bottom-up factors and prior experiences, shapes cognitive responses by emphasizing stimulus relevance. These two fundamental processes collaborate to regulate cognitive behavior, with the prefrontal cortex and its subregions playing a pivotal role. Nevertheless, the intricate neural mechanisms underlying the interaction between attentional control and habituation are still a subject of ongoing exploration. To our knowledge, there is a dearth of comprehensive studies on the functional connectivity between subsystems within the prefrontal cortex during attentional control processes in both primates and humans. Utilizing stereo-electroencephalogram (SEEG) recordings during the Stroop task, we observed top-down dominance effects and corresponding connectivity patterns among the orbitofrontal cortex (OFC), the middle frontal gyrus (MFG), and the inferior frontal gyrus (IFG) during heightened attentional control. These findings highlighting the involvement of OFC in habituation through top-down attention. Our study unveils unique connectivity profiles, shedding light on the neural interplay between top-down and bottom-up attentional control processes, shaping goal-directed attention.

BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites.

Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1γ and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.

A Treg-related riskscore model may improve the prognosis evaluation of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) poses a significant health challenge. This study aims to investigate the prognostic value of a regulatory T cell (Treg)-related gene signature in CRC. METHODS: We extracted the gene expression and clinical data on CRC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The gene module related to Treg was identified by weighted gene co-expression network analysis (WGCNA). The genes in the significant module were filtered by univariate Cox, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis. A riskscore model was established in terms of the key Treg-related genes. The reliability of this riskscore model was validated using the external GEO dataset. The association of riskscore with clinical features, mutation patterns and signaling pathways was explored. RESULTS: Genes in the blue module showed the strongest association with Tregs. After a series of filtering cycles, seven Treg-related key genes, GDE1, GSR, HSPB1, AOC2, TBX19, TAMM41 and TIGD6, were selected to construct a riskscore model. This model performed well in evaluating the patients' survival in TCGA cohort, and was further affirmed by the GSE17536 validation cohort. For precise evaluation of the patients' survival, we established a nomogram in light of riskscore and clinical factors. Patients in different risk groups had distinct clinical features, mutation patterns and signaling pathway activities. The expression of five key genes was significantly associated with Treg infiltration in the CRC samples. CONCLUSION: We established a useful riskscore model in light of seven Treg-related genes. This model may contribute to the prognosis evaluation, direct tailored treatment, and hopefully improve clinical outcomes of the CRC patients.

The proportion of tumour stroma predicts response to treatment of immune checkpoint inhibitor in combination with chemotherapy in patients with stage IIIB-IV non-small cell lung cancer.

AIMS: Immunotherapy has brought a new era to cancer treatment, yet we lack dependable predictors for its effectiveness. This study explores the predictive significance of intratumour stroma proportion (iTSP) for treatment success and prognosis in non-small cell lung cancer (NSCLC) patients undergoing treatment with immune check-point inhibitors (ICIs) together with chemotherapy. METHODS AND RESULTS: We retrospectively collected data from patients with unresectable stage IIIB-IV NSCLC who were treated with first-line ICIs and chemotherapy. Each patient received a confirmed pathological diagnosis, and the pathologist evaluated the iTSP on haematoxylin and eosin (H&E)-stained sections of diagnostic tissue slides. Among the 102 H&E-stained biopsy samples, 61 (59.8%) were categorised as stroma-L (less than 50% iTSP), while 41 (40.2%) were classified as stroma-H (more than 50% iTSP). We observed that the stroma-L group exhibited a significantly better objective response rate (ORR) (72.1 versus 51.2%, P = 0.031) and deeper response depth (DpR) (-50.49 ± 28.79% versus -35.83 ± 29.91%, P = 0.015) compared to the stroma-H group. Furthermore, the stroma-L group showed longer median progression-free survival (PFS) (9.6 versus 6.0 months, P = 0.011) and overall survival (OS) (24.0 versus 12.2 months, P = 0.001) compared to the stroma-H group. Multivariate Cox proportional hazards regression analysis indicated that iTSP was a highly significant prognostic factor for both PFS [hazard ratio (HR) = 1.713; P = 0.030] and OS (HR = 2.225; P = 0.003). CONCLUSION: Our findings indicate that a lower iTSP corresponds to improved clinical outcomes and greater DpR in individuals with stage IIIB-IV NSCLC treated with first-line ICIs and chemotherapy. The iTSP could potentially serve as a predictive biomarker for ICIs therapy response.

Deep ultraviolet laser at 223.8†nm with adjustable repetition rate and narrow pulse width.

We presented the first, to our knowledge, demonstration of an ultraviolet (UV) laser at 223.8 nm by six-harmonic generation of an electro-optic Q-switched cavity dumping 1342 nm Nd:YVO4 laser. It offers high power, constant short pulse duration, and adjustable pulse repetition rate. The pulse duration is independent of the pump power and repetition rate compared to classical Q-switched oscillators. The output efficiency of the UV laser is optimized by adjusting the focusing lens. With the incident pump power of 30 W, an maximum average output power of 249 mW was obtained at 13 kHz. The pulse width maintained 3.4-3.5 ns from 5 to 20 kHz. The maximum pulse energy of 28.1 µJ was obtained at 5 kHz, and the corresponding peak power was up to 8.1 kW.

CircMTA1 promotes glioblastoma angiogenesis by encoding MTA1-134aa.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with rapid angiogenesis. How to inhibit GBM angiogenesis is a key problem to be solved. To explore the targets of inhibiting GBM angiogenesis, this study confirmed that the expression of circMTA1 (hsa_circ_0033614) was significantly upregulated in human brain microvascular endothelial cells exposed to glioma cell-conditioned medium (GECs). The expression of circMTA1 in the cytoplasm was significantly higher than that in the nucleus. Upregulated circMTA1 in GECs can promote cell proliferation, migration, and tube formation. Further exploration of the circularization mechanism of circMTA1 confirmed that KHDRBS1 protein can bind to the upstream and downstream flanking sequences of circMTA1 and promote circMTA1 biogenesis by coordinating Alu element pairing. KHDRBS1 upregulated the proliferation, migration, and tube formation of GECs by promoting the biogenesis of circMTA1. CircMTA1 can encode the protein MTA1-134aa by internal ribosome entry site sequence-mediated translation mechanism, and promote the proliferation, migration, and tube formation of GECs through the encoded MTA1-134aa. This study provides a new target for inhibiting angiogenesis in brain GBM and a new strategy for improving the therapeutic efficacy of GBM.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Developmental validation of the STRSeqTyper122 kit for massively parallel sequencing of forensic STRs.

Massively parallel sequencing allows for integrated genotyping of different types of forensic markers, which reduces DNA consumption, simplifies experimental processes, and provides additional sequence-based genetic information. The STRseqTyper122 kit genotypes 63 autosomal STRs, 16 X-STRs, 42 Y-STRs, and the Amelogenin locus. Amplicon sizes of 117 loci were below 300 bp. In this study, MiSeq FGx sequencing metrics for STRseqTyper122 were presented. The genotyping accuracy of this kit was examined by comparing to certified genotypes of NIST standard reference materials and results from five capillary electrophoresis-based kits. The sensitivity of STRseqTyper122 reached 125 pg, and > 80% of the loci were correctly called with 62.5 pg and 31.25 pg input genomic DNA. Repeatability, species specificity, and tolerance for DNA degradation and PCR inhibitors of this kit were also evaluated. STRseqTyper122 demonstrated reliable performance with routine case-work samples and provided a powerful tool for forensic applications.

Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Effect of azilsartan on myocardial remodeling after acute myocardial infarction.

PURPOSE: To investigate the effect of azilsartan on myocardial remodeling after acute myocardial infarction (AMI). METHODS: A total of 200 AMI patients under percutaneous coronary intervention (PCI) were selected from the Affiliated Huaian No.1 People's Hospital of Nanjing Medical University from Jan 2021 to Dec 2021. The subjects were randomly divided to take either azilsartan or benazepril. Serum C1q tumor necrosis factor-associated protein 1 (CTRP1) levels were detected in all subjects after admission, and the indices of left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF) were measured by using echocardiography. At the follow-up of 6 months and 1 year after PCI, the differences in CTRP1 and echocardiogram indices between the two groups were compared, and the influencing factors of myocardial remodeling after acute myocardial infarction were analyzed. RESULTS: The levels of LVEDV and CTRP1 in all subjects at 6 months and 1 year after PCI were lower than those before discharge, and the LVEDV in the azilsartan group at 6 months and 1 year after PCI was lower than that in the benazepril group. An improvement in myocardial remodeling was obviously observed within 6 months after PCI, but the effect declined over time. CONCLUSIONS: Azilsartan can improve myocardial remodeling after acute myocardial infarction. CTRP1 may become an effective target for the prevention and treatment of myocardial remodeling after acute myocardial infarction.

Family adjustment and resilience after a parental cancer diagnosis.

PURPOSE: To explore the resources, parents with cancer and their partners draw upon to sustain their family resilience through the cancer experience. METHODS: Fifteen participants who were parents of children aged 8 to 25 years completed phone, audio-recorded, and semi-structured interviews. Of these participants, 11 were parents diagnosed with cancer, and four were partners of a parent diagnosed with cancer. Interview questions aimed to increase understanding about how families communicate, connect, and face challenges from the cancer experience. Interview data was analysed using inductive thematic analysis to provide scope to generate themes from parent's experiences rather than to test pre-existing frameworks. RESULTS: The thematic analysis of interview transcripts generated three key themes related to family resilience: (1) adaptability to changes in roles and routines, (2) open communication within the family, and (3) accepting support from others. CONCLUSION: This study found that parents' ability to use personal resources when faced with significant challenges helped to improve the resilience of parents' family system. Further research is needed to understand the factors that influence family resilience when a parent is diagnosed with cancer. Implications for the development of targeted interventions that provide support to not only the patient, but their whole family system will be discussed.

Exploring the interplay of depression, sleep quality, and hearing in tinnitus-related handicap: insights from polysomnography and pure-tone audiometry.

BACKGROUND: Tinnitus affects approximately 740 million adults globally, involving hearing, emotion, and sleep systems. However, studies using polysomnography and pure-tone audiometry (PTA) are limited. We aimed to assess the correlation between tinnitus and hearing, sleep quality, characteristics, and depression using polysomnography and PTA. METHODS: In this cross-sectional study, we divided participants into tinnitus and non-tinnitus groups. We included 100 outpatients (65 with tinnitus, 35 without) from a medical center in Taiwan, who underwent polysomnography and completed rating scales including the Patient Health Questionnaire-9 (PHQ-9), Chinese version of the Pittsburgh Sleep Quality Index (PSQI), and Chinese-Mandarin version of the Tinnitus Handicap Inventory (THI-CM). We analyzed correlations, conducted group comparisons, assessed factors related to THI-CM scores, constructed ROC curves to predict depression in the tinnitus group, and performed multinomial and logistic regression to explore associations. RESULTS: Descriptive statistics identified a cohort with mean age 53.9 ± 12.80 years, 63% exhibited PHQ-9 scores ≥ 10, and 66% had Apnea-Hypopnea Index (AHI) > 5. The ratio of rapid eye movement and deep sleep to stage 1 + 2 sleep was relatively low and non-significant. Likewise, leg movements was higher in the tinnitus group but not statistically significant. In the tinnitus group, 63.08% had depression, and 81.54% had AHI > 5. Univariate logistic regression linked tinnitus to AHI > 5 (Odds ratio (OR) 2.67, p = 0.026) and male sex (OR 2.49, p = 0.034). A moderate positive correlation was found between the THI-CM score and PHQ-9 score (rs = 0.50, p < 0.001). Further adjustment for obstructive sleep apnea showed associations between PHQ-9 (total score) or depression and THI-CM Grade 3-5 (OR = 1.28; OR = 8.68). Single- and multifactor regression analyses highlighted significant associations of PSQI scores > 13 (OR 7.06, p = 0.018) and THI-CM scores > 47 (OR 7.43, p = 0.002) with depression. CONCLUSIONS: Our study recruited tinnitus participants with slight or mild hearing loss and mild tinnitus handicap. Depression was identified as a predominant factor in tinnitus-related handicap. The mild tinnitus handicap in tinnitus participants may explain the lack of significant differences in depression, sleep quality, and polysomnographic sleep characteristics between tinnitus and non-tinnitus groups. Further extensive and prospective studies are needed to elucidate the complex links among depression, sleep, and tinnitus.

Efficient exact exchange using Wannier functions and other related developments in planewave-pseudopotential implementation of RT-TDDFT.

The plane-wave pseudopotential (PW-PP) formalism is widely used for the first-principles electronic structure calculation of extended periodic systems. The PW-PP approach has also been adapted for real-time time-dependent density functional theory (RT-TDDFT) to investigate time-dependent electronic dynamical phenomena. In this work, we detail recent advances in the PW-PP formalism for RT-TDDFT, particularly how maximally localized Wannier functions (MLWFs) are used to accelerate simulations using the exact exchange. We also discuss several related developments, including an anti-Hermitian correction for the time-dependent MLWFs (TD-MLWFs) when a time-dependent electric field is applied, the refinement procedure for TD-MLWFs, comparison of the velocity and length gauge approaches for applying an electric field, and elimination of long-range electrostatic interaction, as well as usage of a complex absorbing potential for modeling isolated systems when using the PW-PP formalism.

Efficient all-electron hybrid density functionals for atomistic simulations beyond 10 000 atoms.

Hybrid density functional approximations (DFAs) offer compelling accuracy for ab initio electronic-structure simulations of molecules, nanosystems, and bulk materials, addressing some deficiencies of computationally cheaper, frequently used semilocal DFAs. However, the computational bottleneck of hybrid DFAs is the evaluation of the non-local exact exchange contribution, which is the limiting factor for the application of the method for large-scale simulations. In this work, we present a drastically optimized resolution-of-identity-based real-space implementation of the exact exchange evaluation for both non-periodic and periodic boundary conditions in the all-electron code FHI-aims, targeting high-performance central processing unit (CPU) compute clusters. The introduction of several new refined message passing interface (MPI) parallelization layers and shared memory arrays according to the MPI-3 standard were the key components of the optimization. We demonstrate significant improvements of memory and performance efficiency, scalability, and workload distribution, extending the reach of hybrid DFAs to simulation sizes beyond ten thousand atoms. In addition, we also compare the runtime performance of the PBE, HSE06, and PBE0 functionals. As a necessary byproduct of this work, other code parts in FHI-aims have been optimized as well, e.g., the computation of the Hartree potential and the evaluation of the force and stress components. We benchmark the performance and scaling of the hybrid DFA-based simulations for a broad range of chemical systems, including hybrid organic-inorganic perovskites, organic crystals, and ice crystals with up to 30 576 atoms (101 920 electrons described by 244 608 basis functions).

Baicalin nanodelivery system based on functionalized metal-organic framework for targeted therapy of osteoarthritis by modulating macrophage polarization.

Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.

FOXK2 affects cancer cell response to chemotherapy by promoting nucleotide de novo synthesis.

AIMS: Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance. METHODS: By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma. RESULTS: FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients. CONCLUSION: Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance.