The response of daytime nitrate formation to source emissions reduction based on chemical kinetic and thermodynamic model.

Particulate nitrate is an important component of particulate matter and poses a significant threat to the ecosystem and human health. The gas-phase formation pathway of nitrate is extremely important, which mainly comprises the NO2 oxidation process triggered by OH radicals and the nitrate partitioning process. The response of nitrate to source emission reduction during different pollution periods remains unclear. Here, we applied the chemical kinetic and thermodynamics model to explore the importance oxidation process and partitioning process during different pollution periods based on high-time resolution observation data. The result indicated that with the aggravation of pollution, the partitioning process gradually ceases to be a limiting step in the formation of nitrates. The results of the influencing factor analysis indicate that NO2 concentration and aerosol pH values play a more significant role in the formation of nitrates. Specifically, during the clean period, nitrate formation is sensitive to both NO2 concentration and pH values, but during the pollution period, it becomes sensitive only to NO2 concentration. By combining source apportionment, we explored the response of nitrate formation to source emission reduction, and the results showed that the control of vehicle exhaust emissions and coal combustion sources is more effective in mitigating nitrate pollution. Additionally, this study also emphasized the importance of early prevention and control of pollution sources. This research provides scientific evidence for the precise management and control of nitrates.

Primary care quality and provider disparities in China: a standardized-patient-based study.

Background: Primary health care is the foundation of high-performing health systems. Achieving an improved primary care system requires a thorough understanding of the current quality of care among various providers within the system. As the world's largest developing country, China has made significant investments in primary care over the past decade. This study evaluates the quality of primary care across different provider types in China, offering in-sights for enhancing China's primary care system. Methods: We merged data from four standardized patient (SP) research projects to compare the quality of five major primary care providers in China: rural clinics, county hospitals, migrant clinics, urban community health cen-ters (CHCs), and online platforms. We evaluated quality of care across process quality (e.g., checklist completion), diagnosis quality (e.g., diagnostic accuracy), and case management (e.g., correct medication), employing multiple regression analyses to explore quality differences by provider type, and their associations with physician characteristics. Findings: We document a poor quality of primary care in China, with no-table disparities across different providers. CHCs emerge as relatively reliable primary care providers in terms of process quality, diagnostic accuracy, and cor-rect medication prescriptions. Online platforms outpace rural clinics, county hospitals, and migrant clinics in many areas, showcasing their potential to en-hance access to quality healthcare resources in under-resourced rural regions. We observe a positive association between the qualifications of physicians and the quality of primary care, underscoring the necessity for a greater presence of more highly qualified practitioners. Interpretation: Primary care quality in China varies greatly among providers, reflecting inequalities in healthcare access. While online platforms indicate po-tential for improving care in under-resourced areas, their high referral rates suggest they cannot completely substitute traditional care. The findings em-phasize the need for more qualified practitioners and stringent regulation to enhance care quality and reduce unnecessary treatments. Funding: No founders had a role in the study design, data collection, data analysis, data interpretation, or writing of the report. We have acknowledged this in the revised manuscript.

Screening and identification of susceptibility genes for cervical cancer via bioinformatics analysis and the construction of an mitophagy-related genes diagnostic model.

PURPOSE: This study aims to utilize bioinformatics methods to systematically screen and identify susceptibility genes for cervical cancer, as well as to construct and validate an mitophagy-related genes (MRGs) diagnostic model. The objective is to increase the understanding of the disease's pathogenesis and improve early diagnosis and treatment. METHOD: We initially collected a large amount of genomic data, including gene expression profile and single nucleotide polymorphism (SNP) data, from the control group and Cervical cancer (CC) patients. Through bioinformatics analysis, which employs methods such as differential gene expression analysis and pathway enrichment analysis, we identified a set of candidate susceptibility genes associated with cervical cancer. RESULTS: MRGs were extracted from single-cell RNA sequencing data, and a network graph was constructed on the basis of intercellular interaction data. Furthermore, using machine learning algorithms, we constructed a clinical prognostic model and validated and optimized it via extensive clinical data. Through bioinformatics analysis, we successfully identified a group of genes whose expression significantly differed during the development of CC and revealed the biological pathways in which these genes are involved. Moreover, our constructed clinical prognostic model demonstrated excellent performance in the validation phase, accurately predicting the clinical prognosis of patients. CONCLUSION: This study delves into the susceptibility genes of cervical cancer through bioinformatics approaches and successfully builds a reliable clinical prognostic model. This study not only helps uncover potential pathogenic mechanisms of cervical cancer but also provides new directions for early diagnosis and treatment of the disease.

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Causal relationships of grey matter structures in multiple sclerosis and neuromyelitis optica spectrum disorder: insights from Mendelian randomization.

Multiple sclerosis and neuromyelitis optica spectrum disorder are two debilitating inflammatory demyelinating diseases of the CNS. Although grey matter alterations have been linked to both multiple sclerosis and neuromyelitis optica spectrum disorder in observational studies, it is unclear whether these associations indicate causal relationships between these diseases and grey matter changes. Therefore, we conducted a bidirectional two-sample Mendelian randomization analysis to investigate the causal relationships between 202 grey matter imaging-derived phenotypes (33 224 individuals) and multiple sclerosis (47 429 cases and 68 374 controls) as well as neuromyelitis optica spectrum disorder (215 cases and 1244 controls). Our results suggested that genetically predicted multiple sclerosis was positively associated with the surface area of the left parahippocampal gyrus (ß = 0.018, P = 2.383 × 10-4) and negatively associated with the volumes of the bilateral caudate (left: ß = -0.020, P = 7.203 × 10-5; right: ß = -0.021, P = 3.274 × 10-5) and putamen nuclei (left: ß = -0.030, P = 2.175 × 10-8; right: ß = -0.024, P = 1.047 × 10-5). In addition, increased neuromyelitis optica spectrum disorder risk was associated with an increased surface area of the left paracentral gyrus (ß = 0.023, P = 1.025 × 10-4). Conversely, no evidence was found for the causal impact of grey matter imaging-derived phenotypes on disease risk in the opposite direction. We provide suggestive evidence that genetically predicted multiple sclerosis and neuromyelitis optica spectrum disorder are associated with increased cortical surface area and decreased subcortical volume in specific regions. Our findings shed light on the associations of grey matter alterations with the risk of multiple sclerosis and neuromyelitis optica spectrum disorder.

Encoding and display technologies for combinatorial libraries in drug discovery: The coming of age from biology to therapy.

Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies. Compared to traditional bioactivity-based screening methods, encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency, throughput, and resource minimization. This review systematically summarizes the development history, typology, and prospective applications of encoding and displayed technologies, including phage display, ribosomal display, mRNA display, yeast cell display, one-bead one-compound, DNA-encoded, peptide nucleic acid-encoded, and new peptide-encoded technologies, and examples of preclinical and clinical translation. We discuss the progress of novel targeted therapeutic agents, covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear, monocyclic, and bicyclic peptides, in addition to antibodies. We also address the pending challenges and future prospects of drug discovery, including the size of screening libraries, advantages and disadvantages of the technology, clinical translational potential, and market space. This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.

Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

Unleashing the potential of Li-O2 batteries with electronic modulation and lattice strain in pre-lithiated electrocatalysts.

Efficient catalysts are indispensable for overcoming the sluggish reaction kinetics and high overpotentials inherent in Li-O2 batteries. However, the lack of precise control over catalyst structures at the atomic level and limited understanding of the underlying catalytic mechanisms pose significant challenges to advancing catalyst technology. In this study, we propose the concept of precisely controlled pre-lithiated electrocatalysts, drawing inspiration from lithium electrochemistry. Our results demonstrate that Li+ intercalation induces lattice strain in RuO2 and modulates its electronic structure. These modifications promote electron transfer between catalysts and reaction intermediates, optimizing the adsorption behavior of Li-O intermediates. As a result, Li-O2 batteries employing Li0.52RuO2 exhibit ultrahigh energy efficiency, long lifespan, high discharge capacity, and excellent rate performance. This research offers valuable insights for the design and optimization of efficient electrocatalysts at the atomic level, paving the way for further advancements in Li-O2 battery technology.

OGG1: An emerging multifunctional therapeutic target for the treatment of diseases caused by oxidative DNA damage.

Oxidative DNA damage-related diseases, such as incurable inflammation, malignant tumors, and age-related disorders, present significant challenges in modern medicine due to their complex molecular mechanisms and limitations in identifying effective treatment targets. Recently, 8-oxoguanine DNA glycosylase 1 (OGG1) has emerged as a promising multifunctional therapeutic target for the treatment of these challenging diseases. In this review, we systematically summarize the multiple functions and mechanisms of OGG1, including pro-inflammatory, tumorigenic, and aging regulatory mechanisms. We also highlight the potential of OGG1 inhibitors and activators as potent therapeutic agents for the aforementioned life-limiting diseases. We conclude that OGG1 serves as a multifunctional hub; the inhibition of OGG1 may provide a novel approach for preventing and treating inflammation and cancer, and the activation of OGG1 could be a strategy for preventing age-related disorders. Furthermore, we provide an extensive overview of successful applications of OGG1 regulation in treating inflammatory, cancerous, and aging-related diseases. Finally, we discuss the current challenges and future directions of OGG1 as an emerging multifunctional therapeutic marker for the aforementioned challenging diseases. The aim of this review is to provide a robust reference for scientific researchers and clinical drug developers in the development of novel clinical targeted drugs for life-limiting diseases, especially for incurable inflammation, malignant tumors, and age-related disorders.

A retrospective survey on the effectiveness of vaccines administered to individuals in China with regard to inactivated COVID-19 vaccines, Ad5-nCoV and/or aerosolized Ad5-nCoV.

We administered a questionnaire to participants who received different vaccination regimens to evaluate the effectiveness of Ad5-vectored COVID-19 vaccines. The results showed that administration of intramuscular Ad5-nCoV provided 21.32% more protection against SARS-CoV-2 infection than that of the inactivated COVID-19 vaccine in people who had received only one type of COVID-19 vaccine. Furthermore, aerosolized Ad5-nCoV exhibited good protection, whether it was administered as a homologous booster to people vaccinated with the intramuscular Ad5-nCoV or as a heterologous booster to people vaccinated with inactivated COVID-19 vaccines. Our research indicates that Ad5-nCoV is an effective booster. This finding supports the future selection of COVID-19 immunization strategies.

Effect of Immune Thrombocytopenic Purpura Medications on Depression Risk: An Analysis of NHANES Data.

BACKGROUND: Immune thrombocytopenic purpura (ITP) in adults typically develops slowly and insidiously. The ITP medications might be linked to psychological disorders, but the connection is not well-understood. OBJECTIVE: This study aimed to examine the association between ITP medication use and the risk of depression among participants in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. METHODS: Using data from 70 190 NHANES participants, we conducted a cross-sectional study, excluding individuals under 18 years, with hypertension, HIV, hepatitis C, and various comorbidities. A total of 17 299 individuals were included in the analysis of this study. We identified 2 populations within this study: those using ITP medications, including prednisone, dexamethasone, and rituximab and those not using ITP drugs. Depression status was assessed using the Patient Health Questionnaire-9 (PHQ-9), and the relationship between ITP medication use and depression was analyzed through multivariate logistic regression. RESULTS: There was no significant association between ITP medication use and an increased risk of depression after adjusting for demographic and health-related variables. Notably, among the study participants, 1.8% of the non-depressed population were on ITP medication compared with 0.3% in the depressed population. The analysis revealed varying depression risks associated with different sociodemographic factors. For instance, the correlation between ITP medication and depression risk was influenced by a combination of age, race, income, and smoking status. CONCLUSION AND RELEVANCE: The study suggests that ITP medication use does not independently increase the risk of depression. This finding is crucial for guiding clinical decisions and managing patient expectations regarding ITP treatment and its psychological impacts.

The Impact of Multimorbidity on Labor Force Participation among the Middle-aged and Older Working Population in the United States.

OBJECTIVE: Multimorbidity, known as multiple chronic conditions (MCCs), is the co-existence of two or more chronic health conditions (CHC). The near-retirement-age population with MCC is more likely to experience discontinued labor force participation (LFP). Our objective was to evaluate the impact of MCC on LFP among adults aged 50-64 and to explore heterogeneous effects between self-employed and non-self-employed workers. METHOD: We constructed our sample using the Health and Retirement Study (HRS) from 1996 to 2018. We adopted an individual fixed-effect (F.E.) model and Propensity Score Matching (PSM) to measure the impact of MCC on the probability of being employed and changes in annual work hours. RESULTS: 50.5% of respondents have MCC. Individuals with MCC exhibit a predicted probability of being employed that is 9.3 percentage points (P<0.01, 95% CI: -0.109, -0.078) lower than those without MCC. Compared with non-CHC, MCC significantly reduced annual working hours by 6.1% (P<0.01, 95% CI: -0.091, -0.036) in the F.E. model and by 4.9% (P<0.01, CI: -0.064, -0.033) in PSM estimation. The effect is more pronounced for the self-employed with MCC, who have 13.0% (P<0.05, CI: -0.233, -0.026) fewer annual work hours than non-CHCs based on the FE model and 13.4% (P<0.01, CI: -0.197, -0.070) in PSM estimation. DISCUSSION: MCC significantly reduces LFP compared with non-MCC. MCC has a heterogeneous impact across occupational types. It is important to support the near-retirement-age working population with multimorbidity through effective clinical interventions and workplace wellness policies to help manage health conditions and remain active in the labor market.

Hippocampal PACAP signaling activation triggers a rapid antidepressant response.

BACKGROUND: The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. METHODS: The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus. RESULTS: Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine's rapid antidepressant response. CONCLUSIONS: Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling.

Collaborative Optimization of Curie Temperature and Piezoelectricity in Ternary BiFeO3-BiScO3-PbTiO3.

The enhancement of piezoelectricity without compromising the Curie temperature of a piezoelectric is challenging due to phenomenological incompatibility. In the present work, the phase diagram of (0.68-x)BiFeO3-xBiScO3-0.32PbTiO3, with varied addition of BiScO3 (x = 0, 0.05, 0.10, 0.15, and 0.20), was constructed through systematic studies of the dielectric, ferroelectric, and piezoelectric properties. A rhombohedral-tetragonal phase boundary was observed near x = 0.10 BiScO3 addition, of which the piezoelectricity was found to be seven times larger than that without BiScO3 (∼208 pm/V vs ∼38 pm/V). Most importantly, a high Curie temperature of 430 °C is successfully inherited from binary 0.68BiFeO3-0.32PbTiO3. This is explained by optimized Bi compensation, which is observed critical regulating Curie temperature in BFO-based binary and ternary systems. These results open up a paradigm for collaboratively optimizing the Curie temperature and piezoelectric response for a number of ferroelectrics and provide a promising BiFeO3-BiScO3-PbTiO3 film with integrated prominent performance for potential applications at elevated temperatures.

Bufadienolide-Fatty Acid Conjugates from the Fertilized Eggs of Toad Bufo gargarizans: Isolation, Characterization, Toxicity, and Antiproliferative Evaluation.

Bufadienolides (BDs) are a class of naturally occurring toxins present in amphibian toads. Serving as the chemical weapons, they exist not only in the adult toads but also in toad eggs. Guided by mass spectrometry (MS)-based component analysis and feature-based molecular networking (FBMN), 30 bufadienolide-fatty acid conjugates (BDFs) were isolated from the fertilized eggs of toad Bufo gargrizans, including 25 previously undescribed compounds (1-25). Their chemical structures were elucidated by extensive spectroscopic analysis, chemical methods, and GC-MS. The toxicities of all BDFs and their corresponding free BDs were assessed using the zebrafish model. The structure-toxicity relationship analysis showed that the modification of BDs by hydroxy fatty acids can cause a significant increase of the toxicity. Furthermore, all the isolated compounds were evaluated for their antiproliferative activities in pancreatic cancer cell lines ASPC-1 and PANC10.05. The structure-activity relationship (SAR) analysis revealed that BDFs with hellebrigenin as the bufogenin moiety (6 and 7) exhibited the most potent antiproliferative effect. Further investigation into their functional mechanism demonstrated that 6 and 7 induced apoptosis in pancreatic cancer cells PANC10.05 and significantly suppressed the expression of the apoptosis-related gene c-MYC. In addition, 6 and 7 effectively inhibited the expression of the PI3K/Akt/mTOR pathway in PANC10.05. Moreover, we assessed the efficacy of 6 and 7 on cancer cells from various tissues and observed their broad-spectrum antiproliferative activity.

Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.

Background: There have been conflicting reports about the proarrhythmic risk of p-synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs. Aim: This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN. Materials and methods: We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective ß1, ß2 and ß3 adrenergic blockers. Results: Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 µM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 µM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 µM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 µM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. ß1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither ß2 nor ß3 blockers had a complete inhibitory effect. Conclusion: The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating ß1 receptor.

GenBase: A Nucleotide Sequence Database.

The rapid advancement of sequencing technologies poses challenges in managing the large volume and exponential growth of sequence data efficiently and on time. To address this issue, we present GenBase (https://ngdc.cncb.ac.cn/genbase), an open-access data repository that follows the International Nucleotide Sequence Database Collaboration (INSDC) data standards and structures, for efficient nucleotide sequence archiving, searching, and sharing. As a core resource within the National Genomics Data Center (NGDC), of the China National Center for Bioinformation (CNCB; https://ngdc.cncb.ac.cn), GenBase offers bilingual submission pipeline and services, as well as local submission assistance in China. GenBase also provides a unique Excel format for metadata description and feature annotation of nucleotide sequences, along with a real-time data validation system to streamline sequence submissions. As of April 23, 2024, GenBase received 68,251 nucleotide sequences and 689,574 annotated protein sequences across 414 species from 2319 submissions. Out of these, 63,614 (93%) nucleotide sequences and 620,640 (90%) annotated protein sequences have been released and are publicly accessible through GenBase's web search system, File Transfer Protocol (FTP), and Application Programming Interface (API). Additionally, in collaboration with INSDC, GenBase has constructed an effective data exchange mechanism with GenBank and started sharing released nucleotide sequences. Furthermore, GenBase integrates all sequences from GenBank with daily updates, demonstrating its commitment to actively contributing to global sequence data management and sharing.

Multi-scale analysis of the chemical and physical pollution evolution process from pre-co-pollution day to PM2.5 and O3 co-pollution day.

PM2.5 and O3 are two of the main air pollutants that have adverse impacts on climate and human health. The evolution process of PM2.5 and O3 co-pollution are of concern because of the increased frequency of PM2.5 and O3 co-pollution days. Here, we examined the chemical coupling and revealed the driving factors of the PM2.5 and O3 co-pollution evolution process from cleaning day, PM2.5 pollution day, or O3 pollution day, applied by theoretical analysis and model calculation methods. The results demonstrate that PM2.5 and O3 co-pollution day frequently occurred with high concentrations of gaseous precursors and higher sulfur oxidation ratio (SOR) and nitrogen oxidation ratio (NOR), which we attribute to the enhancement of atmospheric oxidation capacity (AOC). The AOC is positively correlated with O3 and weakly correlated with PM2.5. In addition, we found that the correlation coefficients of PM2.5-NO2 (0.62) were higher than that of PM2.5-SO2 (0.32), highlighting the priority of NOx controlling to mitigate PM2.5 pollution. Overall, our discovery can provide scientific evidence to design feasible solutions for the controlling PM2.5 and O3 co-pollution process.