N4BP1 mediates RAM domain-dependent notch signaling turnover during neocortical development.

Notch signaling pathway activity, particularly fluctuations in the biologically active effector fragment NICD, is required for rapid and efficient dynamic regulation of proper fate decisions in stem cells. In this study, we identified NEDD4-binding protein 1 (N4BP1), which is highly expressed in the developing mouse cerebral cortex, as a negative modulator of Notch signaling dynamics in neural progenitor cells. Intriguingly, N4BP1 regulated NICD stability specifically after Notch1 S3 cleavage through ubiquitin-mediated degradation that depended on its RAM domain, not its PEST domain, as had been extensively and previously described. The CoCUN domain in N4BP1, particularly the "Phe-Pro" motif (862/863 amino acid), was indispensable for mediating NICD degradation. The Ring family E3 ligase Trim21 was, in contrast to other NEDD4 family members, required for N4BP1-regulated NICD degradation. Overexpression of N4BP1 in cortical neural progenitors promoted neural stem cell differentiation, whereas neural progenitor cells lacking N4BP1 were sensitized to Notch signaling, resulting in the maintenance of stem-like properties in neural progenitor cells and lower production of cortical neurons.

Leveraging LD eigenvalue regression to improve the estimation of SNP heritability and confounding inflation.

Heritability is a fundamental concept in genetic studies, measuring the genetic contribution to complex traits and bringing insights about disease mechanisms. The advance of high-throughput technologies has provided many resources for heritability estimation. Linkage disequilibrium (LD) score regression (LDSC) estimates both heritability and confounding biases, such as cryptic relatedness and population stratification, among single-nucleotide polymorphisms (SNPs) by using only summary statistics released from genome-wide association studies. However, only partial information in the LD matrix is utilized in LDSC, leading to loss in precision. In this study, we propose LD eigenvalue regression (LDER), an extension of LDSC, by making full use of the LD information. Compared to state-of-the-art heritability estimating methods, LDER provides more accurate estimates of SNP heritability and better distinguishes the inflation caused by polygenicity and confounding effects. We demonstrate the advantages of LDER both theoretically and with extensive simulations. We applied LDER to 814 complex traits from UK Biobank, and LDER identified 363 significantly heritable phenotypes, among which 97 were not identified by LDSC.

Cofea: correlation-based feature selection for single-cell chromatin accessibility data.

Single-cell chromatin accessibility sequencing (scCAS) technologies have enabled characterizing the epigenomic heterogeneity of individual cells. However, the identification of features of scCAS data that are relevant to underlying biological processes remains a significant gap. Here, we introduce a novel method Cofea, to fill this gap. Through comprehensive experiments on 5 simulated and 54 real datasets, Cofea demonstrates its superiority in capturing cellular heterogeneity and facilitating downstream analysis. Applying this method to identification of cell type-specific peaks and candidate enhancers, as well as pathway enrichment analysis and partitioned heritability analysis, we illustrate the potential of Cofea to uncover functional biological process.

EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis.

Lenvatinib is a commonly used first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is limited due to the drug resistance. EVA1A was a newly identified tumor suppressor, nevertheless, the impact of EVA1A on resistance to lenvatinib treatment in HCC and the potential molecular mechanisms remain unknown. In this study, the expression of EVA1A in HCC lenvatinib-resistant cells is decreased and its low expression was associated with a poor prognosis of HCC. Overexpression of EVA1A reversed lenvatinib resistance in vitro and in vivo, as demonstrated by its ability to promote cell apoptosis and inhibit cell proliferation, invasion, migration, EMT, and tumor growth. Silencing EVA1A in lenvatinib-sensitive parental HCC cells exerted the opposite effect and induced resistance to lenvatinib. Mechanistically, upregulated EVA1A inhibited the PI3K/AKT/MDM2 signaling pathway, resulting in a reduced interaction between MDM2 and p53, thereby stabilizing p53 and enhancing its antitumor activity. In addition, upregulated EVA1A suppressed the PI3K/AKT/mTOR signaling pathway and promoted autophagy, leading to the degradation of mutant p53 and attenuating its oncogenic impact. On the contrary, loss of EVA1A activated the PI3K/AKT/MDM2 signaling pathway and inhibited autophagy, promoting p53 proteasomal degradation and mutant p53 accumulation respectively. These findings establish a crucial role of EVA1A loss in driving lenvatinib resistance involving a mechanism of modulating PI3K/AKT/p53 signaling axis and suggest that upregulating EVA1A is a promising therapeutic strategy for alleviating resistance to lenvatinib, thereby improving the efficacy of HCC treatment.

Irisin links Claudin-5 preservation and Mfn2-mediated mitochondrial dynamics to resist doxorubicin-induced cardiac endothelial damage.

Irisin is protective in the cardiac microenvironment and can resist doxorubicin-induced cardiotoxicity. The purpose of this study was to investigate the connection between Irisin, endothelial cell integrity, and mitochondrial dynamics. Primary cardiac microvascular endothelial cells (CMECs) were used to explore the regulatory effects of Irisin on tight junction proteins, mitochondrial dynamics, ß-catenin expression, and transcriptional activity. Results showed that Irisin can suppress doxorubicin-induced upregulation of MMP2 and MMP9, thereby reducing the degradation of tight junction proteins (ZO-1 and Claudin-5) and VE-cadherin. The preservation of Claudin-5 contributes to maintaining Mfn2 expression, which in turn supports mitochondrial fusion. Although Irisin restores doxorubicin-induced downregulation of ß-catenin, it concurrently limits ß-catenin transcriptional activity via Mfn2-mediated sulfenylation. Therefore, this study revealed a novel mechanism linking the protective effects of Irisin on the tight junction proteins and mitochondrial dynamics upon doxorubicin exposure.

A crazy trio in Parkinson's disease: metabolism alteration, α-synuclein aggregation, and oxidative stress.

Parkinson's disease (PD) is an aging-associated neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies containing α-synuclein within these neurons. Oligomeric α-synuclein exerts neurotoxic effects through mitochondrial dysfunction, glial cell inflammatory response, lysosomal dysfunction and so on. α-synuclein aggregation, often accompanied by oxidative stress, is generally considered to be a key factor in PD pathology. At present, emerging evidences suggest that metabolism alteration is closely associated with α-synuclein aggregation and PD progression, and improvement of key molecules in metabolism might be potentially beneficial in PD treatment. In this review, we highlight the tripartite relationship among metabolic changes, α-synuclein aggregation, and oxidative stress in PD, and offer updated insights into the treatments of PD, aiming to deepen our understanding of PD pathogenesis and explore new therapeutic strategies for the disease.

Molybdate-Templated Luminescent Silver Alkynyl Nanoclusters: Total Structure Determination and Optical Property Analysis.

Two novel MoO42--templated luminescent silver alkynyl nanoclusters with 20-nuclearity ([(MoO42-)@Ag20(C≡CtBu)8(Ph2PO2)7(tfa)2]·(tfa-) (1)) and 18-nuclearity ([(MoO42-)@Ag18(C≡CtBu)8(Ph2PO2)7]·(OH) (2)) (tfa = trifluoroacetate) were synthesized with the green light maximum emissions at 507 and 516 nm, respectively. The nanoclusters were investigated and characterized by single-crystal X-ray crystallography, electrospray ionization mass spectrum (ESI-MS), X-ray photoelectron spectroscopy, thermogravimetry (TG), photoluminescence (PL), ultraviolet-visible (UV-vis) spectroscopy, and density functional theory calculations (DFT). The two nanoclusters differ in their structure by a supplementary [Ag2(tfa)2] organometallic surface motif, which significantly participates in the frontier molecular orbitals of 1, resulting in similar bonding patterns but different optical properties between the two clusters. Indeed, both nanoclusters show strong temperature-dependent photoluminescence properties, which make them potential candidates in the fields of optical devices for further applications.

Epidemiological and etiological characteristics of 1266 patients with severe acute respiratory infection in central China, 2018-2020: a retrospective survey.

BACKGROUND: Severe acute respiratory infection (SARI), a significant global health concern, imposes a substantial disease burden. In China, there is inadequate data concerning the monitoring of respiratory pathogens, particularly bacteria, among patients with SARI. Therefore, this study aims to delineate the demographic, epidemiological, and aetiological characteristics of hospitalised SARI patients in Central China between 2018 and 2020. METHODS: Eligible patients with SARI admitted to the First Affiliated Hospital of Zhengzhou University between 1 January 2018 and 31 December 2020 were included in this retrospective study. Within the first 24 h of admission, respiratory (including sputum, nasal/throat swabs, bronchoalveolar lavage fluid, thoracocentesis fluid, etc.), urine, and peripheral blood specimens were collected for viral and bacterial testing. A multiplex real-time polymerase chain reaction (PCR) diagnostic approach was used to identify human influenza virus, respiratory syncytial virus, parainfluenza virus, adenovirus, human bocavirus, human coronavirus, human metapneumovirus, and rhinovirus. Bacterial cultures of respiratory specimens were performed with a particular focus on pathogenic microorganisms, including S. pneumoniae, S. aureus, K. pneumoniae, P. aeruginosa, Strep A, H. influenzae, A. baumannii, and E. coli. In cases where bacterial culture results were negative, nucleic acid extraction was performed for PCR to assay for the above-mentioned eight bacteria, as well as L. pneumophila and M. pneumoniae. Additionally, urine specimens were exclusively used to detect Legionella antigens. Furthermore, epidemiological, demographic, and clinical data were obtained from electronic medical records. RESULTS: The study encompassed 1266 patients, with a mean age of 54 years, among whom 61.6% (780/1266) were males, 61.4% (778/1266) were farmers, and 88.8% (1124/1266) sought medical treatment in 2020. Moreover, 80.3% (1017/1266) were housed in general wards. The most common respiratory symptoms included fever (86.8%, 1122/1266) and cough (77.8%, 986/1266). Chest imaging anomalies were detected in 62.6% (792/1266) of cases, and 58.1% (736/1266) exhibited at least one respiratory pathogen, with 28.5% (361/1266) having multiple infections. Additionally, 95.7% (1212/1266) of the patients were from Henan Province, with the highest proportion (38.3%, 486/1266) falling in the 61-80 years age bracket, predominantly (79.8%, 1010/1266) seeking medical aid in summer and autumn. Bacterial detection rate (39.0%, 495/1266) was higher than viral detection rate (36.9%, 468/1266), with the primary pathogens being influenza virus (13.8%, 175/1266), K. pneumoniae (10.0%, 127/1266), S. pneumoniae (10.0%, 127/1266), adenovirus (8.2%, 105/1266), P. aeruginosa (8.2%, 105/1266), M. pneumoniae (7.8%, 100/1266), and respiratory syncytial virus (7.7%, 98/1266). During spring and winter, there was a significant prevalence of influenza virus and human coronavirus, contrasting with the dominance of parainfluenza viruses in summer and autumn. Respiratory syncytial virus and rhinovirus exhibited higher prevalence across spring, summer, and winter. P. aeruginosa, K. pneumoniae, and M. pneumoniae were identified at similar rates throughout all seasons without distinct spikes in prevalence. However, S. pneumoniae showed a distinctive pattern with a prevalence that doubled during summer and winter. Moreover, the positive detection rates of various other viruses and bacteria were lower, displaying a comparatively erratic prevalence trend. Among patients admitted to the intensive care unit, the predominant nosocomial bacteria were K. pneumoniae (17.2%, 43/249), A. baumannii (13.6%, 34/249), and P. aeruginosa (12.4%, 31/249). Conversely, in patients from general wards, predominant pathogens included influenza virus (14.8%, 151/1017), S. pneumoniae (10.4%, 106/1017), and adenovirus (9.3%, 95/1017). Additionally, paediatric patients exhibited significantly higher positive detection rates for influenza virus (23.9%, 11/46) and M. pneumoniae (32.6%, 15/46) compared to adults and the elderly. Furthermore, adenovirus (10.0%, 67/669) and rhinovirus (6.4%, 43/669) were the primary pathogens in adults, while K. pneumoniae (11.8%, 65/551) and A. baumannii (7.1%, 39/551) prevailed among the elderly, indicating significant differences among the three age groups. DISCUSSION: In Central China, among patients with SARI, the prevailing viruses included influenza virus, adenovirus, and respiratory syncytial virus. Among bacteria, K. pneumoniae, S. pneumoniae, P. aeruginosa, and M. pneumoniae were frequently identified, with multiple infections being very common. Additionally, there were substantial variations in the pathogen spectrum compositions concerning wards and age groups among patients. Consequently, this study holds promise in offering insights to the government for developing strategies aimed at preventing and managing respiratory infectious diseases effectively.

Capturing the electron-electron cusp with the coupling-constant averaged exchange-correlation hole: A case study for Hooke's atoms.

In density-functional theory, the exchange-correlation (XC) energy can be defined exactly through the coupling-constant (λ) averaged XC hole n̄xc(r,r'), representing the probability depletion of finding an electron at r' due to an electron at r. Accurate knowledge of n̄xc(r,r') has been crucial for developing XC energy density-functional approximations and understanding their performance for molecules and materials. However, there are very few systems for which accurate XC holes have been calculated since this requires evaluating the one- and two-particle reduced density matrices for a reference wave function over a range of λ while the electron density remains fixed at the physical (λ = 1) density. Although the coupled-cluster singles and doubles (CCSD) method can yield exact results for a two-electron system in the complete basis set limit, it cannot capture the electron-electron cusp using finite basis sets. Focusing on Hooke's atom as a two-electron model system for which certain analytic solutions are known, we examine the effect of this cusp error on the XC hole calculated using CCSD. The Lieb functional is calculated at a range of coupling constants to determine the λ-integrated XC hole. Our results indicate that, for Hooke's atoms, the error introduced by the description of the electron-electron cusp using Gaussian basis sets at the CCSD level is negligible compared to the basis set incompleteness error. The system-, angle-, and coupling-constant-averaged XC holes are also calculated and provide a benchmark against which the Perdew-Burke-Ernzerhof and local density approximation XC hole models are assessed.

Challenges for density functional theory in simulating metal-metal singlet bonding: A case study of dimerized VO2.

VO2 is renowned for its electric transition from an insulating monoclinic (M1) phase, characterized by V-V dimerized structures, to a metallic rutile (R) phase above 340 K. This transition is accompanied by a magnetic change: the M1 phase exhibits a non-magnetic spin-singlet state, while the R phase exhibits a state with local magnetic moments. Simultaneous simulation of the structural, electric, and magnetic properties of this compound is of fundamental importance, but the M1 phase alone has posed a significant challenge to the density functional theory (DFT). In this study, we show none of the commonly used DFT functionals, including those combined with on-site Hubbard U to treat 3d electrons better, can accurately predict the V-V dimer length. The spin-restricted method tends to overestimate the strength of the V-V bonds, resulting in a small V-V bond length. Conversely, the spin-symmetry-breaking method exhibits the opposite trends. Each of these two bond-calculation methods underscores one of the two contentious mechanisms, i.e., Peierls lattice distortion or Mott localization due to electron-electron repulsion, involved in the metal-insulator transition in VO2. To elucidate the challenges encountered in DFT, we also employ an effective Hamiltonian that integrates one-dimensional magnetic sites, thereby revealing the inherent difficulties linked with the DFT computations.

Genetically engineered membrane-based nanoengagers for immunotherapy of pancreatic cancer.

Modulating macrophages presents a promising avenue in tumor immunotherapy. However, tumor cells have evolved mechanisms to evade macrophage activation and phagocytosis. Herein, we introduced a bispecific antibody-based nanoengager to facilitate the recognition and phagocytosis of tumor cells by macrophages. Specifically, we genetically engineered two single chain variable fragments (scFv) onto cell membrane: anti-CD40 scFv for engaging with macrophages and anti-Claudin18.2 (CLDN18.2) scFv for interacting with tumor cells. These nanoengagers were further constructed by coating scFv-anchored membrane into PLGA nanoparticle core. Our developed nanoengagers significantly boosted immune responses, including increased recognition and phagocytosis of tumor cells by macrophages, enhanced activation and antigen presentation, and elevated cytotoxic T lymphocyte activity. These combined benefits resulted in enhancing antitumor efficacy against highly aggressive "cold" pancreatic cancer. Overall, this study offers a versatile nanoengager design for immunotherapy, achieved through genetically engineering to incorporate antibody-anchored membrane.

Identification and characterization of multipotential stem cells in immortalized normal ovarian surface epithelial cells.

The ovarian surface epithelium (OSE) is a single layer of squamous-to-cuboidal epithelial cells that experience repetitive ovulatory rupture and subsequent repair. However, the characteristics of human immortalized ovarian surface epithelial cells (IOSE80) remain elusive. This study aims to determine whether IOSE80 cells have the characteristics of stem cell proliferation and multilineage differentiation and their application in regenerative medicine. IOSE80 cells are sequenced by high-throughput transcriptome analysis, and 5 sets of public data are used to compare the differences between IOSE80 cells and bone marrow mesenchymal stem cells, pluripotent stem cells, and oocytes in transcriptome profiling. The IOSE80 cells present a cobblestone-like monolayer and express the epithelial cell marker KRT18; the stem cell markers IFITM3, ALDH1A1, and VIM; lowly express stem cell marker LGR5 and germ cell markers DDX4 and DAZL. In addition, the GO terms "regulation of stem cell proliferation", "epithelial cell proliferation", etc., are significantly enriched ( P<0.05). IOSE80 cells have the potential to act as mesenchymal stem cells to differentiate into adipocytes with lipid droplets, osteoblasts, and chondroblasts in vitro. IOSE80 cells express pluripotent stem cell markers, including OCT4, SSEA4, TRA-1-60, and TRA-1-81, and they can be induced into three germ layers in vitro. IOSE80 cells also form oocyte-like cells in vitro and in vivo. In addition, IOSE80 cells exhibit robust proliferation, migration, and ovarian repair functions after in vivo transplantation. This study demonstrates that IOSE80 cells have the characteristics of pluripotent/multipotent stem cells, indicating their important role in tissue engineering and regenerative medicine.

Comparing the effects of argon plasma coagulation and interferon therapy in patients with vaginal intraepithelial neoplasia: a single-center retrospective study.

PURPOSE: This study aimed to evaluate the clinical efficacy and safety of argon plasma coagulation (APC) therapy and interferon therapy in patients with grade I and II vaginal intraepithelial neoplasia (VaIN). METHODS: A total of 112 patients with VaIN were diagnosed via colposcopy-induced biopsy and classified into the APC group (n = 77) and interferon group (n = 35). Clinical data including age, grade, symptoms, historical or concomitant neoplasia of the lower genital tract, indications for hysterectomy, pregnancy history, cytology, human papillomavirus (HPV) subtype, treatment modalities, and clinical outcomes were analyzed, retrospectively. Complications and clinical outcomes were assessed at 6- and 12-month follow-ups. RESULTS: There was no significant difference in the HPV clearance rate between the APC (53.42%) and interferon (33.33%) groups at 6 months after treatment. However, the 12-month follow-up of the APC group showed a significantly higher HPV clearance rate as compared to the interferon group (87.67% vs. 51.52%, P < 0.05). The APC group exhibited a significantly higher cure rate (79.22% vs. 40.0%) and lower persistence rate (12.99% vs. 37.14%) than the interferon group (P < 0.05). Adverse reaction analysis revealed that the primary reaction in the APC group was vaginal drainage, in contrast to the increased vaginal discharge in the interferon group; though the difference was significant (68.83% vs. 28.57%, P < 0.05), no serious complications were observed. CONCLUSIONS: Treatment with APC is a safe and more effective procedure against VaIN I and II, compared to interferon. APC may serve as a viable alternative to other physiotherapies.

Regulator of Ribosome Synthesis 1 (RRS1) Stabilizes GRP78 and Promotes Breast Cancer Progression.

Regulator of ribosome synthesis 1 (RRS1), a crucial regulatory factor in ribosome biogenesis, exerts a remarkable impact on the progression of breast cancer (BC). However, the exact mechanisms and pathways have not yet been fully elucidated. To investigate the impact of RRS1 on BC growth and metastasis, along with its underlying mechanisms. We discovered that RRS1 is overexpressed in BC tissues and cell lines. This study aims to regulate the level of RRS1 through lentiviral transfection technology to explore its potential function in BC cells. Knockdown of RRS1 resulted in the inhibition of cell proliferation, invasion, and migration, whereas overexpression had the opposite effects. We firstly identified the interaction between RRS1 and Glucose-Regulated Protein 78 (GRP78) using Co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis, providing evidences of co-localization and positive regulation between RRS1 and GRP78. We observed that RRS1 inhibited the degradation of GRP78 through the ubiquitin-proteasome pathway, resulting in the stabilization of GRP78. In addition, our findings suggested that RRS1 promoted BC progression by activating the GRP78-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. In conclusion, this newly discovered RRS1/GRP78 signaling axis provides a molecular and theoretical basis for further exploring the mechanisms of breast cancer invasion and metastasis.

[Association of pregnancy factors with cow's milk protein allergy in infants].

OBJECTIVE: To preliminarily explore the association of pregnancy factors with cow's milk protein allergy in infants. METHODS: This study was based on data from a subcohort of a study called genetic susceptibility to cow's milk allergy in Chinese children, including infants born in Peking University People's Hospital between March 1, 2020, and December 31, 2020. The infants were divided into a cow's milk protein allergy (CMPA) group and a control group according to whether they had developed cow's milk protein allergy at the age of 1 year. We retrospectively collected the clinical data of infants and their mothers before and during pregnancy, and analyzed the association of multiple factors during pregnancy with cow's milk protein allergy in infants. RESULTS: A total of 278 infants were enrolled in this study, including 52 infants with CMPA and 226 infants without CMPA. Among them, there were 143 boys and 135 girls. The proportion of male infants in the CMPA group (69.2%) was higher than that in the control group (47.3%), and the difference was statistically significant (P=0.004). There were no significant differences in the distribution of birth weight, gestational age at birth, low-birth-weight infants, premature, umbilical cord entangle neck, and neonatal asphyxia between the CMPA group and the control group (P>0.05). The proportion of mothers complicated with autoimmune diseases, anemia or antibiotics exposure during pregnancy in the CMPA group was higher than that in the control group, and there were statistical differences between the two groups (P < 0.05). There was no significant difference in the distribution of other pregnancy complications between the two groups (P>0.05), such as eclampsia/preeclampsia, chronic hypertension/gestational hypertension, diabetes/gestational diabetes, thyroid diseases, and so on. There was no significant difference in the overall distribution of some blood routine indexes during pregnancy between the CMPA group and the control group (P>0.05). Multivariate Logistic regression analysis showed that male infant, mothers complicated with autoimmune diseases or anemia, antibiotic exposure during pregnancy were independent risk factors for cow's milk protein allergy. CONCLUSION: Male infant, mothers complicated with autoimmune diseases or anemia, antibiotic exposure during pregnancy were independent risk factors for cow's milk protein allergy.

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OBJECTIVES: To explore the risk factors associated with cow's milk protein allergy (CMPA) in infants. METHODS: This study was a multicenter prospective nested case-control study conducted in seven medical centers in Beijing, China. Infants aged 0-12 months were included, with 200 cases of CMPA infants and 799 control infants without CMPA. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for the occurrence of CMPA. RESULTS: Univariate logistic regression analysis showed that preterm birth, low birth weight, birth from the first pregnancy, firstborn, spring birth, summer birth, mixed/artificial feeding, and parental history of allergic diseases were associated with an increased risk of CMPA in infants (P<0.05). Multivariate logistic regression analysis revealed that firstborn (OR=1.89, 95%CI: 1.14-3.13), spring birth (OR=3.42, 95%CI: 1.70-6.58), summer birth (OR=2.29, 95%CI: 1.22-4.27), mixed/artificial feeding (OR=1.57, 95%CI: 1.10-2.26), parental history of allergies (OR=2.13, 95%CI: 1.51-3.02), and both parents having allergies (OR=3.15, 95%CI: 1.78-5.56) were risk factors for CMPA in infants (P<0.05). CONCLUSIONS: Firstborn, spring birth, summer birth, mixed/artificial feeding, and a family history of allergies are associated with an increased risk of CMPA in infants.

Adenovirus-mediated Overexpression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis.

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs.

Carbon Vacancy-Enhanced Activity of Fe-N-C Single Atom Catalysts toward Luminol Chemiluminescence in the Absence of H2O2.

The classic luminol-H2O2 chemiluminescence (CL) systems suffer from easy self-decomposition of H2O2 at room temperature, hindering the practical applications of the luminol-H2O2 CL system. In this work, unexpectedly, we found that the carbon vacancy-modified Fe-N-C single atom catalysts (VC-Fe-N-C SACs) can directly trigger a luminol solution to generate strong CL emission in the absence of H2O2. The Fe-based SACs were prepared through the conventional pyrolysis of zeolitic imidazolate frameworks. The massive carbon vacancies were readily introduced into Fe-N-C SACs through a tannic acid-etching process. Carbon vacancy significantly enhanced the catalytic activity of Fe-N-C SACs on the CL reaction of luminol-dissolved oxygen. The VC-Fe-N-C SACs performed a 13.4-fold CL enhancement compared with the classic luminol-Fe2+ system. It was found that the introduction of a carbon vacancy could efficiently promote dissolved oxygen to convert to reactive oxygen species. As a proof of concept, the developed CL system was applied to detect alkaline phosphatase with a linear range of 0.005-1 U/L as well as a detection limit of 0.003 U/L. This work demonstrated that VC-Fe-N-C SAC is a highly efficient CL catalyst that can promote the analytic application of the luminol CL system.

A data-adaptive Bayesian regression approach for polygenic risk prediction.

MOTIVATION: Polygenic risk score (PRS) has been widely exploited for genetic risk prediction due to its accuracy and conceptual simplicity. We introduce a unified Bayesian regression framework, NeuPred, for PRS construction, which accommodates varying genetic architectures and improves overall prediction accuracy for complex diseases by allowing for a wide class of prior choices. To take full advantage of the framework, we propose a summary-statistics-based cross-validation strategy to automatically select suitable chromosome-level priors, which demonstrates a striking variability of the prior preference of each chromosome, for the same complex disease, and further significantly improves the prediction accuracy. RESULTS: Simulation studies and real data applications with seven disease datasets from the Wellcome Trust Case Control Consortium cohort and eight groups of large-scale genome-wide association studies demonstrate that NeuPred achieves substantial and consistent improvements in terms of predictive r2 over existing methods. In addition, NeuPred has similar or advantageous computational efficiency compared with the state-of-the-art Bayesian methods. AVAILABILITY AND IMPLEMENTATION: The R package implementing NeuPred is available at https://github.com/shuangsong0110/NeuPred. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

CITEdb: a manually curated database of cell-cell interactions in human.

MOTIVATION: The interactions among various types of cells play critical roles in cell functions and the maintenance of the entire organism. While cell-cell interactions are traditionally revealed from experimental studies, recent developments in single-cell technologies combined with data mining methods have enabled computational prediction of cell-cell interactions, which have broadened our understanding of how cells work together, and have important implications in therapeutic interventions targeting cell-cell interactions for cancers and other diseases. Despite the importance, to our knowledge, there is no database for systematic documentation of high-quality cell-cell interactions at the cell type level, which hinders the development of computational approaches to identify cell-cell interactions. RESULTS: We develop a publicly accessible database, CITEdb (Cell-cell InTEraction database, https://citedb.cn/), which not only facilitates interactive exploration of cell-cell interactions in specific physiological contexts (e.g. a disease or an organ) but also provides a benchmark dataset to interpret and evaluate computationally derived cell-cell interactions from different tools. CITEdb contains 728 pairs of cell-cell interactions in human that are manually curated. Each interaction is equipped with structured annotations including the physiological context, the ligand-receptor pairs that mediate the interaction, etc. Our database provides a web interface to search, visualize and download cell-cell interactions. Users can search for cell-cell interactions by selecting the physiological context of interest or specific cell types involved. CITEdb is the first attempt to catalogue cell-cell interactions at the cell type level, which is beneficial to both experimental, computational and clinical studies of cell-cell interactions. AVAILABILITY AND IMPLEMENTATION: CITEdb is freely available at https://citedb.cn/ and the R package implementing benchmark is available at https://github.com/shanny01/benchmark. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.