Gut microbiome and metabolites mediate the benefits of caloric restriction in mice after acute kidney injury.

The role of gut microbiome in acute kidney injury (AKI) is increasing recognized. Caloric restriction (CR) has been shown to enhance the resistance to ischemia/reperfusion injury to the kidneys in rodents. Nonetheless, it is unknown whether intestinal microbiota mediated CR protection against ischemic/reperfusion-induced injury (IRI) in the kidneys. Herein, we showed that CR ameliorated IRI-elicited renal dysfunction, oxidative stress, apoptosis, and inflammation, along with enhanced intestinal barrier function. In addition, gut microbiota depletion blocked the favorable effects of CR in AKI mice. 16S rRNA and metabolomics analysis showed that CR enriched the gut commensal Parabacteroides goldsteinii (P. goldsteinii) and upregulated the level of serum metabolite dodecafluorpentan. Intestinal colonization of P. goldsteinii and oral administration of dodecafluorpentan showed the similar beneficial effects as CR in AKI mice. RNA sequencing and experimental data revealed that dodecafluorpentan protected against AKI-induced renal injury by antagonizing oxidative burst and NFκB-induced NLRP3 inflammasome activation. In addition, we screened and found that Hamaudol improved renal insufficiency by boosting the growth of P. goldsteinii. Our results shed light on the role of intestinal microbiota P. goldsteinii and serum metabolites dodecafluorpentan in CR benefits to AKI.

Network pharmacology combined with experimental validation show that apigenin as the active ingredient of Campsis grandiflora flower against Parkinson's disease by inhibiting the PI3K/AKT/NF-κB pathway.

The exploration of novel natural products for Parkinson's disease (PD) is a focus of current research, as there are no definitive drugs to cure or stop the disease. Campsis grandiflora (Thunb.) K. Schum (Lingxiaohua) is a traditional Chinese medicine (TCM), and the exact active constituents and putative mechanisms for treating PD are unknown. Through data mining and network pharmacology, apigenin (APi) was identified as the main active ingredient of Lingxiaohua, and key targets (TNF, AKT1, INS, TP53, CASP3, JUN, BCL2, MMP9, FOS, and HIF1A) of Lingxiaohua for the treatment of PD were discovered. The primary routes implicated were identified as PI3K/AKT, Apoptosis, TNF, and NF-κB pathways. Subsequently, therapeutic potential of APi in PD and its underlying mechanism were experimentally evaluated. APi suppressed the release of mediators of inflammation and initiation of NF-κB pathways in MES23.5 cells induced by MPP+. APi suppressed caspase-3 activity and apoptosis and elevated p-AKT levels in MES23.5 cells. Pretreatment with LY294002, a PI3K inhibitor, resulted in APi treatment blocking the activation of NF-κB pathway and expression of inflammatory factors in MES23.5 cells by activating the PI3K/AKT pathway. In conclusion, APi protects dopaminergic neurons by controlling the PI3K/AKT/NF-κB pathway, giving novel insights into the pharmacological mechanism of Lingxiaohua in treating PD.

Nesfatin-1 enhances vascular smooth muscle calcification through facilitating BMP-2 osteogenic signaling.

Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.

Distribution, sources, and risk assessment of polycyclic aromatic hydrocarbons in surface soils and plants from industrial and agricultural areas, Junggar Basin, Xinjiang.

The contamination characteristics of Polycyclic Aromatic Hydrocarbons (PAHs) in different environmental functional areas are different. In this study, the contamination of PAHs in soils and common plants in typical mining and farmland areas in Xinjiang, China, was analyzed. The results showed that the contamination levels of PAHs in mining soils were significantly higher than those in farmland soils, and the mining soils were dominated by 4-5-ring PAHs and farmland soils by 3-4-ring PAHs. Analysis of their sources using a positive definite factor matrix model showed that PAHs in mining soils mainly originated from coal and natural gas combustion, and transportation processes; while farmland soils mainly came from biomass and coal combustion, and fossil fuel volatile spills. The cancer risk of PAHs in soils was evaluated using a combination of the Monte Carlo and the lifetime carcinogenic risk models, and the results showed that the overall level of cancer risk for mining soils was higher than that for farmland soils, and can put some people in high risk of cancer. For plant samples, except for individual crop samples, the contamination levels of mining plants and crops were similar, with 4-5-ring PAHs dominating in desert plants in mining areas and the highest proportion of 3-ring PAHs in crops in agricultural fields, and PAHs in both plants were mainly from biomass and coal combustion. The results of correlation analysis showed that 2-ring PAHs in crop roots were significantly positively correlated with it in corresponding soils, and some high-ring PAHs in crop leaves were significantly negatively correlated with it in corresponding soils. Therefore, there were significant differences in the pollution characteristics of PAHs in soils and common plants in mining and agricultural areas. Human health risks and ecological risks are mainly concentrated in mining areas, and appropriate intervention measures should be taken for pollution remediation.

Immunization status and factors influencing hepatitis B vaccination of preterm infants in three provinces of China, 2019 to 2021.

BACKGROUND: Premature infants have less physiologic reserve and often delayed vaccination compared to full-term infants. The birth dose of hepatitis B vaccine (HepB-BD) is an essential measure to achieve the goal of "zero infections" of hepatitis B virus in all newborns. However, there are few investigations of hepatitis B vaccination of preterm infants, leading to uncertainty of coverage and insufficient knowledge of factors influencing timely vaccination of this important population. METHODS: We obtained hepatitis B vaccine (HepB) vaccination histories of premature infants born during 2019-2021 in three provinces from the respective provincial immunization information systems. Extracted data included date of birth, sex, region, and dates of HepB administration. We conducted descriptive analyses that included basic characteristics of the study subjects, HepB-BD administration, and full-series HepB vaccination. Factors potentially influencing HepB-BD and full series vaccination were analyzed by logistic regression. RESULTS: There were 1623 premature infants included in the analytic data set. Overall HepB-BD coverage was 71.41%; coverage among premature infants born to mothers with unknown hepatitis B surface antigen (HBsAg) status was 69.57%; coverage was higher at county-level-and-above hospitals (72.02%) than hospitals below county level (61.11%). Full-series HepB coverage was 94.15%; full-series coverage among preterm infants weighing less than 2000 g at birth was 76.92%. Logistic regression showed that the HepB-BD vaccination rate was positively associated with being born to an HBsAg-positive mother and being preterm with high birth weight. Regression analysis for factors influencing full-series HepB coverage showed that being born prematurely was positively associated with full-series coverage and being premature with a very low birth weight was negatively associated with full-series coverage. CONCLUSIONS: HepB-BD coverage levels in three provinces of China were less than the target of 90%, especially among premature infants born to mothers with unknown HBsAg status and at hospitals below the county level. Screening of pregnant women should be a universal normal standard. Hepatitis B vaccination training should be strengthened in hospitals to improve the HepB-BD vaccination rate of premature infants and to effectively prevent mother-to-child transmission of hepatitis B virus.

The Circulating CDC42 Expression in Sepsis: Relation to Disease Susceptibility, Inflammation, Multiple Organ Dysfunctions and Mortality Risk.

OBJECTIVE: Cell division cycle 42 (CDC42) modulates inflammation and multiple organ dysfunction by regulating T-cell differentiation and macrophage polarization. This research intended to explore the association of blood CDC42 expression with septic risk, multi-organ dysfunctions, and mortality. METHODS: 145 sepsis patients and 50 health controls were recruited, then CDC42 expression in peripheral blood mononuclear cell (PBMC) from them was measured by RT-qPCR. RESULTS: CDC42 was decreased in sepsis patients versus health controls (P<0.001); meanwhile, the receiver operating characteristic (ROC) curve showed that CDC42 had a certain value to predict sepsis risk with an area under the curve (AUC) (95% confidence interval (CI): 0.797 (0.725-0.869). Furthermore, CDC42 was negatively correlated with C-reactive protein (P<0.001), tumor necrosis factor-alpha (P<0.001) and interleukin-17A (P<0.001) but less with interleukin-6 (P=0.056). Moreover, CDC42 was negatively related to the SOFA score (P<0.001) and its several subscales (respiratory system, liver, cardiovascular, and renal system) (P<0.05). Furthermore, CDC42 was lower in septic deaths versus survivors (P<0.001); meanwhile, the ROC curve exhibited a certain ability of CDC42 in estimating 28-day mortality with an AUC (95%CI) of 0.766 (0.676-0.855). CONCLUSION: Circulating CDC42 exhibits potency to be a prognostic biomarker reflecting multi-organ dysfunctions and higher mortality risk in sepsis.

[Remediation Mechanism of Chitosan-modified Biochar on Cd-contaminated Farmland Soil and Its Effect on Bacterial Community].

To explore the remediation mechanism of chitosan-modified biochar （passivator） on Cd-contaminated farmland soil, pot experiments were conducted to determine the effects of passivator on soil physical and chemical properties, ryegrass biomass, enzyme activity, and the response of soil bacterial diversity and structure. The results showed that when the amount of passivating agent was increased from 0.5% to 3%, the content of available Cd in soil was significantly decreased compared with that in the control, and the above-ground and subsurface biomass of ryegrass was increased by 1.08-1.56 times and 1.00-1.68 times, respectively. The enrichment and running coefficients were reduced by 6.15%-30.00% and 10.42%-31.25%, respectively. The correlation analysis results showed that soil pH, CEC, SOM, AN, AP, and AK were significantly negatively correlated with DTPA-Cd, indicating that the application of a passivating agent promoted the passivation of Cd in soil by changing the physical and chemical properties of soil. High-throughput sequencing results showed that the application of the inactivation agent changed the structure and diversity of the soil bacterial community, which was manifested as a significant decrease in α diversity, significant isolation of bacteria between different treatment groups, and an increase in the relative abundance of beneficial bacteria such as Sphingomonas and Blastococcus. Moreover, the activities of soil urease and cellulase increased, whereas the activities of sucrase and catalase decreased with the addition of a passivator. This study provides a theoretical basis and technical reference for the application of modified biochar in the remediation of Cd-contaminated farmland soil.

Comparative assessment of acute neurotoxicity of real-world ultra-fine black carbon emitted from residential solid fuel combustion.

Incomplete combustion of residential solid fuel is one of the main anthropogenic sources for black carbon (BC). Fresh BC, mainly enriched in ultra-fine fraction of particles, can directly cross blood-brain barrier and are reported to be associated with neurodegenerative diseases. Because of the difficulties in collection and purification of BC from ambient particles, there are still significant knowledge gaps in understanding neurotoxicity caused by real-world BC. The purpose of this study is to compare the neurotoxic effects caused by BCs emitted from combustion of six residential solid fuels, and try to reveal associated biological mechanisms in SH-SY5Y cells. Two straw BC (Wheat-BC and Corn-BC) showed highest neurotoxic effects followed by wood BC (Pine-BC and Aspen-BC) and coal BC (Xvzhou and Longkou Coal), as indicated by viability, lactic dehydrogenase, malondialdehyde, adenosine triphosphate and acetylcholine levels. Coal BC caused nearly no toxicity in human neuroblastoma (SH-SY5Y) cells within highest dose of 200 µg/mL. RNA sequence and bioinformatics analysis were applied to effectively identify differential genes and signaling pathways. Based on Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Protein Protein Interaction network (PPI network) construction, we found biomass BC affected mitochondrial function, interfered with cellular metabolic processes, disturbed redox homeostasis, and finally resulted in cellular damages. Coal-BC mainly caused cytokine/chemokine related inflammatory responses. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting methods were further applied to find out related signaling pathways. Biomass BC activated IL6R/JAK3/STAT3 and JAK3/STAT6 pathways leading to oxidative stress and inflammatory responses. Coal BC activated JAK3/STAT3 pathway leading to chemokine related responses. This study revealed the heterogeneity in neurotoxicity of BCs from different combustion sources and provided important data for health risk assessment. BC-related neurotoxicity should be considered when making air pollution emission control strategies, with residential biomass receiving more policy attention.

Analysis of genomic and characterization features of Luteolibacter soli sp. nov., isolated from soil.

The strain designated as Y139T is a novel Gram-stain-negative, aerobic, and non-motile bacterium, was isolated from a soil sample in McClain County, Oklahoma, United States. The cells of strain Y139T were a rod-shaped, with the width of 0.4-0.7 µm and the length of 1.5-2.0 µm . Growth occurred at 20-37°C (optimum, 30°C), pH 5.5-9.5 (optimum, pH 7.0), and 0-1.0% NaCl (w/v) (optimum, 0%). The polar lipid profiles included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidyldimethylethanolamine, and an unidentified lipid. The major fatty acids included C16:0, iso-C14:0, and C16:1 ω9c. Menaquinone-9 (MK-9) was recognized as the only respiratory quinone. Strain Y139T showed the highest 16S rRNA gene sequence similarity to Luteolibacter flavescens MCCC 1K03193T (98.3%). Phylogenetic analysis positioned it within the genus Luteolibacter. The draft genome of strain Y139T consisted of 7,106,054 bp, and contained 5,715 open reading frames (ORFs), including 5,656 coding sequences (CDSs) and 59 RNA genes. The genomic DNA G + C content was found to be 62.5%. Comparing strain Y139T with L. flavescens MCCC 1K03193T and Luteolibacter arcticus CCTCC AB 2014275T, the average nucleotide identity (ANI) values were 80.6 and 82.1%, respectively. Following phylogenetic, physiological, biochemical, and chemotaxonomic analyses, a novel species within the genus Luteolibacter, designated as Luteolibacter soli sp. nov., was proposed for strain Y139T, which was also assigned as the type strain (=KCTC 92644T = MCCC 1H01451T). Further analysis of core genes across 9 Luteolibacter species uncovered significant genomic divergence, particularly in those related to cofactor, vitamin, and energy metabolism. Analysis of biogeographic distribution suggested that lake and soil were the main habitats for the genus Luteolibacter. Additionally, the genus Luteolibacter was sensitive to climate warming and precipitation.

Corrigendum: Modified Si Miao powder granules alleviates osteoarthritis progression by regulating M1/M2 polarization of macrophage through NF-κB signaling pathway.

[This corrects the article DOI: 10.3389/fphar.2024.1361561.].

Leptin reduces LPS-induced A1 reactive astrocyte activation and inflammation via inhibiting p38-MAPK signaling pathway.

Neurotoxic A1 reactive astrocytes are induced by inflammatory stimuli. Leptin has been confirmed to have neuroprotective properties. However, its effect on the activation of A1 astrocytes in infectious inflammation is unclear. In the current study, astrocytes cultured from postnatal day 1 Sprague-Dawley rats were stimulated with lipopolysaccharide (LPS) to induce an acute in vitro inflammatory response. Leptin was applied 6 h later to observe its protective effects. The viability of the astrocytes was assessed. A1 astrocyte activation was determined by analyzing the gene expression of C3, H2-D1, H2-T23, and Serping 1 and secretion of pro-inflammatory cytokines IL-6 and TNF-α. The levels of phospho-p38 (pp38) and nuclear factor-κB (NF-κB) phosphor-p65 (pp65) were measured to explore the possible signaling pathways. Additionally, an LPS-induced inflammatory animal model was established to investigate the in vivo effects of leptin on A1 astrocytic activation. Results showed that in the in vitro culture system, LPS stimulation caused elevated expression of A1 astrocyte-specific genes and the secretion of pro-inflammatory cytokines, indicating the activation of A1 astrocytes. Leptin treatment significantly reversed the LPS induced upregulation in a dose-dependent manner. Similarly, LPS upregulated pp38, NF-κB pp65 protein and inflammatory cytokines were successfully reduced by leptin. In the LPS-induced animal model, the amelioratory effect of leptin on A1 astrocyte activation and inflammation was further confirmed, showed by the reduced sickness behaviors, A1 astrocyte genesis and inflammatory cytokines in vivo. Our results demonstrate that leptin efficiently inhibits LPS-induced neurotoxic activation of A1 astrocytes and neuroinflammation by suppressing p38-MAPK signaling pathway.

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in Spinal Cord Injury.

Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction, with a high rate of disability and mortality. Due to the complicated pathological process of SCI, there is no effective clinical treatment strategy at present. Although mesenchymal stem cells (MSCs) are effective in the treatment of SCI, their application is limited by factors such as low survival rate, cell dedifferentiation, tumorigenesis, blood-brain barrier, and immune rejection. Fortunately, there is growing evidence that most of the biological and therapeutic effects of MSCs may be mediated by the release of paracrine factors, which are extracellular vesicles called exosomes. Exosomes are small endosomal vesicles with bilaminar membranes that have recently been recognized as key mediators for communication between cells and tissues through the transfer of proteins, lipids, nucleic acids, cytokines, and growth factors. Mesenchymal stem cell-derived exosomes (MSC-exos) play a critical role in SCI repair by promoting angiogenesis and axonal growth, regulating inflammation and immune response, inhibiting apoptosis, and maintaining the integrity of the blood-spinal cord barrier. Furthermore, they can be used to transport genetic material or drugs to target cells, and their relatively small size allows them to permeate the blood-brain barrier. Studies have demonstrated that some exosomal miRNAs derived from MSCs play a significant role in the treatment of SCI. In this review, we summarize recent research advances in MSC-exos and exosomal miRNAs in SCI therapy to better understand this emerging cell-free therapeutic strategy and discuss the advantages and challenges of MSC-exos in future clinical applications.

Alzheimer's Disease Related Biomarkers Were Associated with Amnestic Cognitive Impairment in Parkinson's Disease: A Cross-Sectional Cohort Study.

BACKGROUND: Cognitive impairment is common in patients with Parkinson's disease (PD) and occurs through multiple mechanisms, including Alzheimer's disease (AD) pathology and the involvement of α-synucleinopathies. We aimed to investigate the pathological biomarkers of both PD and AD in plasma and neuronal extracellular vesicles (EVs) and their association with different types of cognitive impairment in PD patients. METHODS: A total of 122 patients with PD and 30 healthy controls were included in this cross-sectional cohort study between March 2021 and July 2023. Non-dementia PD patients were divided into amnestic and non-amnestic groups according to the memory domain of a neuropsychological assessment. Plasma and neuronal EV biomarkers, including α-synuclein (α-syn), beta-amyloid (Aß), total tau (T-tau), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP), were measured using a single-molecule array and a chemiluminescence immunoassay, respectively. RESULTS: Neuronal EV but not plasma α-syn levels, were significantly increased in PD as compared to healthy controls, and they were positively associated with UPDRS part III scores and the severity of cognitive impairment. A lower plasma Aß42 level and higher neuronal EV T-tau level were found in the amnestic PD group compared to the non-amnestic PD group. CONCLUSIONS: The results of the current study demonstrate that neuronal EV α-syn levels can be a sensitive biomarker for assisting in the diagnosis and disease severity prediction of PD. Both AD and PD pathologies are important factors in cognitive impairment associated with PD, and AD pathologies are more involved in amnestic memory deficit in PD.

Status of the oral environment in patients with digestive system tumors during the perioperative period.

BACKGROUND: Surgery is an important treatment modality for patients with digestive system tumors, and perioperative management is crucial for the patients' recovery and quality of life. During the perioperative period, significant changes can occur in the oral environment of patients, such as dry mouth, mucosal ulceration, and oral infections. These issues not only cause discomfort to the patients but may also affect postoperative recovery and treatment outcomes. Therefore, it is essential to investigate and analyze the oral environment during the perioperative period in patients with digestive system tumors. AIM: This study aims to investigate the oral health status in patients with digestive system tumors during the perioperative period and analyze the influencing factors. METHODS: In this retrospective study, a total of 242 patients with digestive system tumors admitted to The Seventh Affiliated Hospital, Xinjiang Medical University from September 2021 to June 2023 were selected as the study population (patient group). During the same period, 245 healthy volunteers who received oral examinations were selected as the healthy group. The study compared the oral hygiene environment of the two groups, including the Dental Plaque Index (DI), Calculus Index (CI), and Periodontal Disease Index (PDI). Measurements were taken at admission (T0), 1 hour before surgery (T1), and 3 days after surgery (T2). Based on the PDI index, the patient group was divided into a periodontal disease group (PDI ≥ 3, n = 196) and a periodontal healthy group (PDI < 3, n = 46). The risk factors for the development of periodontal disease in digestive system tumor patients were analyzed, considering variables such as gender, age, BMI, smoking status, alcohol consumption frequency, monthly income, tumor type, oral self-care habits, low-grade inflammation, and nutritional status. RESULTS: The DI, CI and PDI indexes in patient group were higher than those in healthy group (3.23±0.64 vs 1.46±0.43, 1.92±0.46 vs 1.21±0.41, 3.83±0.79 vs 2.65±0.69, all P < 0.05). DI index, CI index and PDI index at T1 and T2 were significantly lower than those at T0 (P < 0.05), and these indices at T2 were slightly higher than T1, but the difference was not statistically significant (all P > 0.05). Multivariate analyses identified high levels of high-sensitivity C-Reactive Protein [OR: 15.070 (1.611-140.951)], low levels of hemoglobin [OR: 0.239 (0.058-0.981)], and presence of dental caries [OR: 246.737 (1.160-52464.597)] as risk factors associated with periodontal disease in patients with digestive system tumors. CONCLUSION: It is important to enhance the attention and management of the oral environment during the perioperative period for patients with digestive system tumors.

Analysis of post-marketing requirements for oncology drug conditional approvals in the United States and China.

Background: Conditional approvals, also known as accelerated approvals, have been introduced by many pharmaceutical regulators around the world, allowing innovative drugs to enter the market earlier on the basis of limited evidence. This research aims to systematically analyze and compare the post-marketing requirements for conditional approvals of oncology drugs in China and the United States. By collecting and categorizing different types of post-marketing requirements, this study seeks to elucidate how these requirements are proposed and discern the underlying logic and patterns. Methods: This study delved into oncology drug approvals, encompassing FDA accelerated approvals (up to December 31, 2022) and NMPA conditional approvals (from 2017 to December 31, 2022). Leveraging review documents from FDA and NMPA, comprehensive data on product characteristics, all post-marketing commitments and requirements, and especially those related to confirmatory requirements were extracted. The analysis incorporated descriptive statistics, visualizations such as Upset plots, and thorough examination of confirmatory requirement timeframes. Findings: This study examined 168 FDA accelerated approvals and 41 NMPA conditional approvals for oncology indications. Post-marketing requirements displayed diversity: FDA emphasized confirmatory studies, clinical pharmacology studies, and more, while NMPA predominantly focused on confirmatory studies. Confirmatory requirement timeframes indicated higher FDA-required completion times for new confirmatory trials compared to continued completion of original pivotal trials. In contrast, NMPA's requirement patterns were comparatively singular, with relatively fixed timeframes. FDA's evolving trend showed decreasing timeframes over time, suggesting an increasing demand for timely confirmatory data. Interpretation: Conditional approvals offer a unique approach to bring potentially life-saving drugs to the market faster, despite limited supporting evidence. Our analysis of oncology drug conditional approvals in the U.S. and China reveals diverse post-marketing requirement patterns. This study provides valuable insights for regulatory decision-making in a dynamic pharmaceutical landscape. Balancing the risks and rewards of conditional approvals is crucial in ensuring both patient safety and timely access to innovative treatments.

Vaccination coverage of hepatitis B and associated factors among health care workers in Gansu province.

The investigation was conducted to describe the status of coverage of HBV vaccination among the health care workers in Gansu province and to explore the associated factors of HBV vaccination in this study. A cross-sectional study was conducted among 1544 health care workers from 64 hospitals in Gansu province. A self-designed questionnaire was used to interview the health care workers about HBV vaccination coverage. A multivariate logistic regression model explored the associated factors with HBV vaccination. The vaccination coverage was 89.17% for health care workers, nurses (90.40%) had the highest rate, followed by administration staff (89.38%) and medical technicians (89.30%). The full-dose HBV vaccination coverage was 64.25% for health care workers, and administration staff (65.04%) had the highest rate, followed by nurses (65.00%). This study found that the associated factors with HBV vaccination and full-dose vaccination were the history of training and the detection of serological indicators. The coverage of HBV vaccination among health care workers in Gansu province was high, but full-dose HBV vaccination coverage was low. It is necessary to strengthen the HBV knowledge and training in HBV prevention and treatment among health care workers in Gansu Province.

Role of endogenous T1ρ and its dispersion imaging in differential diagnosis of cardiac amyloidosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) has demonstrated excellent performance in the diagnosis of cardiac amyloidosis (CA). However, misdiagnosis occasionally occurs because the morphological and functional features of CA are non-specific. This study was performed to determine the value of non-contrast CMR T1ρ in the diagnosis of CA. METHODS: This prospective study included 45 patients with CA, 30 patients with hypertrophic cardiomyopathy (HCM), and 10 healthy controls (HCs). All participants underwent cine (whole heart), T1ρ mapping, pre- and post-contrast T1 mapping imaging (three slices), and late gadolinium enhancement using a 3T whole-body magnetic resonance imaging system. All participants underwent T1ρ at two spin-locking frequencies: 0 and 298 Hz. Extracellular volume (ECV) maps were obtained using pre- and post-contrast T1 maps. The myocardial T1ρ dispersion map, termed myocardial dispersion index (MDI), was also calculated. All parameters were measured in the left ventricular myocardial wall. Participants in the HC group were scanned twice on different days to assess the reproducibility of T1ρ measurements. RESULTS: Excellent reproducibility was observed upon evaluation of the coefficient of variation between two scans (T1ρ [298 Hz]: 3.1%; T1ρ [0 Hz], 2.5%). The ECV (HC: 27.4 ± 2.8% vs HCM: 32.6 ± 5.8% vs CA: 46 ± 8.9%; p < 0.0001), T1ρ [0 Hz] (HC: 35.8 ± 1.7 ms vs HCM: 40.0 ± 4.5 ms vs CA: 51.4 ± 4.4 ms; p < 0.0001) and T1ρ [298 Hz] (HC: 41.9 ± 1.6 ms vs HCM: 48.8 ± 6.2 ms vs CA: 54.4 ± 5.2 ms; p < 0.0001) progressively increased from the HC group to the HCM group, and then the CA group. The MDI progressively decreased from the HCM group to the HC group, and then the CA group (HCM: 8.8 ± 2.8 ms vs HC: 6.1 ± 0.9 ms vs CA: 3.4 ± 2.1 ms; p < 0.0001). For differential diagnosis, the combination of MDI and T1ρ [298 Hz] showed the greatest sensitivity (98.3%) and specificity (95.5%) between CA and HCM, compared with the native T1 and ECV. CONCLUSION: The T1ρ and MDI approaches can be used as non-contrast CMR imaging biomarkers to improve the differential diagnosis of patients with CA.

Genetic-epigenetic interplay in the determination of plant 3D genome organization.

The 3D chromatin organization plays a major role in the control of gene expression. However, our comprehension of the governing principles behind nuclear organization remains incomplete. Particularly, the spatial segregation of loci with similar repressive transcriptional states in plants poses a significant yet poorly understood puzzle. In this study, employing a combination of genetics and advanced 3D genomics approaches, we demonstrated that a redistribution of facultative heterochromatin marks in regions usually occupied by constitutive heterochromatin marks disrupts the 3D genome compartmentalisation. This disturbance, in turn, triggers novel chromatin interactions between genic and transposable element (TE) regions. Interestingly, our results imply that epigenetic features, constrained by genetic factors, intricately mold the landscape of 3D genome organisation. This study sheds light on the profound genetic-epigenetic interplay that underlies the regulation of gene expression within the intricate framework of the 3D genome. Our findings highlight the complexity of the relationships between genetic determinants and epigenetic features in shaping the dynamic configuration of the 3D genome.

An atlas of the tomato epigenome reveals that KRYPTONITE shapes TAD-like boundaries through the control of H3K9ac distribution.

In recent years, the exploration of genome three-dimensional (3D) conformation has yielded profound insights into the regulation of gene expression and cellular functions in both animals and plants. While animals exhibit a characteristic genome topology defined by topologically associating domains (TADs), plants display similar features with a more diverse conformation across species. Employing advanced high-throughput sequencing and microscopy techniques, we investigated the landscape of 26 histone modifications and RNA polymerase II distribution in tomato (Solanum lycopersicum). Our study unveiled a rich and nuanced epigenetic landscape, shedding light on distinct chromatin states associated with heterochromatin formation and gene silencing. Moreover, we elucidated the intricate interplay between these chromatin states and the overall topology of the genome. Employing a genetic approach, we delved into the role of the histone modification H3K9ac in genome topology. Notably, our investigation revealed that the ectopic deposition of this chromatin mark triggered a reorganization of the 3D chromatin structure, defining different TAD-like borders. Our work emphasizes the critical role of H3K9ac in shaping the topology of the tomato genome, providing valuable insights into the epigenetic landscape of this agriculturally significant crop species.