Rhei Radix et Rhizoma and its anthraquinone derivatives: Potential candidates for pancreatitis treatment.

BACKGROUND: Pancreatitis is a common exocrine inflammatory disease of the pancreas and lacks specific medication currently. Rhei Radix et Rhizoma (RR) and its anthraquinone derivatives (AQs) have been successively reported for their pharmacological effects and molecular mechanisms in experimental and clinical pancreatitis. However, an overview of the anti-pancreatitis potential of RR and its AQs is limited. PURPOSE: To summarize and analyze the pharmacological effects of RR and its AQs on pancreatitis and the underlying mechanisms, and discuss their drug-like properties and future perspectives. METHODS: The articles related to RR and its AQs were collected from the Chinese National Knowledge Infrastructure, Wanfang data, PubMed, and the Web of Science using relevant keywords from the study's inception until April first, 2024. Studies involving RR or its AQs in cell or animal pancreatitis models as well as structure-activity relationship, pharmacokinetics, toxicology, and clinical trials were included. RESULTS: Most experimental studies are based on severe acute pancreatitis rat models and a few on chronic pancreatitis. Several bioactive anthraquinone derivatives of Rhei Radix et Rhizoma (RRAQs) exert local protective effects on the pancreas by maintaining pancreatic acinar cell homeostasis, inhibiting inflammatory signaling, and anti-fibrosis, and they improve systemic organ function by alleviating intestinal and lung injury. Pharmacokinetic and toxicity studies have revealed the low bioavailability and wide distribution of RRAQs, as well as hepatotoxicity and nephrotoxicity. However, there is insufficient research on the clinical application of RRAQs in pancreatitis. Furthermore, we propose effective strategies for subsequent improvement in terms of balancing effectiveness and safety. CONCLUSION: RRAQs can be developed as either candidate drugs or novel lead structures for pancreatitis treatment. The comprehensive review of RR and its AQs provides references for optimizing drugs, developing therapies, and conducting future studies on pancreatitis.

Quercetin Ameliorates Myocardial Injury in Diabetic Rats by Regulating Autophagy and Apoptosis through AMPK/mTOR Signaling Pathway.

A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet in vivo. Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group in vitro and in vivo. Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.

Single-Cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape.

Cell differentiation during organogenesis relies on precise epigenetic and transcriptional control. Disruptions to this regulation can result in developmental abnormalities and malignancies, yet the underlying mechanisms are not well understood. Wilms tumors, a type of embryonal tumor closely linked to disrupted organogenesis, harbor mutations in epigenetic regulators in 30-50% of cases. However, the role of these regulators in kidney development and pathogenesis remains unexplored. By integrating mouse modeling, histological characterizations, and single-cell transcriptomics and chromatin accessibility profiling, we show that a Wilms tumor-associated mutation in the chromatin reader protein ENL disrupts kidney development trajectory by rewiring the gene regulatory landscape. Specifically, the mutant ENL promotes the commitment of nephron progenitors while simultaneously restricting their differentiation by dysregulating key transcription factor regulons, particularly the HOX clusters. It also induces the emergence of abnormal progenitor cells that lose their chromatin identity associated with kidney specification. Furthermore, the mutant ENL might modulate stroma-nephron interactions via paracrine Wnt signaling. These multifaceted effects caused by the mutation result in severe developmental defects in the kidney and early postnatal mortality in mice. Notably, transient inhibition of the histone acetylation binding activity of mutant ENL with a small molecule displaces transcriptional condensates formed by mutant ENL from target genes, abolishes its gene activation function, and restores developmental defects in mice. This work provides new insights into how mutations in epigenetic regulators can alter the gene regulatory landscape to disrupt kidney developmental programs at single-cell resolution in vivo . It also offers a proof-of-concept for the use of epigenetics-targeted agents to rectify developmental defects.

Elucidation of the Molecular Mechanism of Compound Danshen Dripping Pills Against Angina Pectoris based on Network Pharmacology and Molecular Docking.

BACKGROUND: Compound Danshen dripping pills (CDDP), a traditional Chinese medicine, has had an extensive application in the treatment of angina pectoris (AP) in China. However, research on the bioactive ingredients and underlying mechanisms of CDDP in AP remains unclear. OBJECTIVE: In the present study, we explored the major chemical components and potential molecular mechanisms linked to the anti-angina effects of CDDP through the application of network pharmacology and molecular docking. METHODS: The potential targets of active ingredients in CDDP were sourced from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and the Swiss Target Prediction Database (STPD). Additionally, targets related to angina pectoris (AP) were retrieved from various databases, including Gene Cards, DisGeNET, Dis Genet, the Drug Bank database (DBD), and the Therapeutic Target Database (TDD). Protein- protein interaction [1] networks were also established, and core targets were identified based on their topological significance. GO enrichment analysis and KEGG pathway analysis were conducted using the R software. Interactions between active ingredients and potential targets selected through the above process were investigated through molecular docking. RESULTS: Seventy-six active ingredients were selected with the following criteria: OB ≥ 30%, DL ≥ 0.18. 383 targets of CDDP and 1488 targets on AP were gathered, respectively. Afterwards, 194 common targets of CDDP and anti-AP targets were defined, of which 12 were core targets. GO enrichment analysis indicated that CDDP acted on AP by response to lipopolysaccharide, regulating the reactive oxygen species and metal ion metabolism, and epithelial cell proliferation. In addition, KEGG enrichment analysis indicated that the signaling pathways were notably enriched in lipid and atherosclerosis, fluid shear stress and atherosclerosis, IL-17 signaling pathway, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt signaling pathway, and TNF signaling pathway. Moreover, the molecular docking manifested excellent binding capacity between the active ingredients and targets on AP. CONCLUSION: This study comprehensively illustrated the bioactive, potential targets, and molecular mechanisms of CDDP against AP, offering fresh perspectives into the molecular mechanisms of CDDP in preventing and treating AP.

Cognitive trajectories in older adults and the role of depressive symptoms: A 7-year follow-up study.

OBJECTIVES: To examine different trajectories of cognitive changes in elderly adults and explore the mediating role of depressive symptoms. DESIGN: A 7-year, community-based, prospective cohort study. SETTING: The downtown neighborhood of Shanghai, China. PARTICIPANTS: A cohort of 394 older adults, with an average age of 71.8 years, was recruited in 2015 and has been reassessed every two years until 2021. METHODS: Latent Class Growth Analysis was used to model aging trajectories and Linear Mixed-Effect Models for Repeated Measures were used to estimate the least squares mean changes of cognition between subjects with depression (DEP+) and without (DEP-) across all visits. RESULTS: Three cognitive trajectories were identified: the "successful aging" (SA) trajectory had the best and most consistent performance (n=229, 55.9%); the "normal aging" (NA) trajectory showed lower but stable cognition (n=141, 37.3%); while the "cognitive decline" (CD) trajectory displayed poor and declining cognition (n=24, 6.8%). Depressive symptoms were found to be influential across all trajectories. In the CD trajectory, the MoCA scores of the DEP+ group increased in within-group comparisons and were significantly higher than those of the DEP- group at visits 1 and 3 in between-group comparisons. A similar trend was observed in the NA trajectory, though it did not reach statistical significance. CONCLUSIONS: Our research suggests that mild and decreasing depressive symptoms can be a reversible factor that might slow down the irreversible cognitive decline in the elderly. Therefore, we suggest that even mild depressive symptoms in the elderly should be monitored and detected.

[Analysis of the Jumping Characteristics and Influencing Factors of Ozone Pollution in Beijing].

Based on environmental monitoring data and meteorological observation data from 2016 to 2022 in Beijing, combined with backward trajectory clustering and potential source area contribution analysis, the characteristics, meteorological impacts, and potential source areas of ozone (O3) pollution were analyzed. The results showed that there was a total of 41 O3 pollution processes with jumping characteristics in Beijing from 2016 to 2022, with an average of 5.9 times a year. The occurrence time was concentrated in May to July, and the day of the jump (OJD2) was higher than the day before the jump (OJD1). The average value of ρ(O3-8h) was 78.3% higher, and the peak concentration was 78.9% higher. The high O3 concentration zone in the OJD2 region exhibited a characteristic of advancing from south to north. The main reasons for the occurrence of jumped O3 pollution in Beijing could be summarized as local accumulation caused by unfavorable meteorological conditions and regional transmission impact. The occurrence of jump-type ozone pollution was characterized by an increase in southerly wind frequency, temperature rise, pressure decrease, and precipitation decrease. The increase in southerly wind frequency provided conditions for the transport of O3 and its precursors, and rapid photochemical reactions occurred under local high temperatures, with less superimposed precipitation, comprehensively pushing up the ozone concentration level of OJD2. Six air mass transporting pathways were identified through clustering analysis; the air mass from the direction north of OJD2 decreased by 11.2%, whereas the air mass from the south and east directions increased by 6.7% and 4.4%, respectively, with the air masses mainly transmitting over short distances. The ozone concentration corresponding to the south and east directions was relatively high, making a significant contribution to Beijing's pollution. The analysis of potential source areas revealed that the main potential source areas of OJD2 ozone pollution were the central, southern, and eastern parts of Beijing-Tianjin-Hebei, which contributed 82.6% to the pollution trajectory. There was a significant contribution of regional transport during jump-type ozone pollution, and it is necessary to strengthen joint prevention and control in the Beijing-Tianjin-Hebei Region.

MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons.

Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer's disease (AD). The spreading of misfolded tau "seeds" along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the "ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein" (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.

A reactive compatibilization with the compound containing four epoxy groups for polylactic acid/poly(butylene adipate-co-terephthalate)/thermoplastic starch ternary bio-composites.

How to effectively improve the poor interfacial adhesion between polylactic acid/poly(butylene adipate-co-terephthalate) (PLA/PBAT) matrix and thermoplastic starch (TPS) is still a challenge. Therefore, this work aims to introduce a convenient method to enhance the performance of PLA/PBAT/TPS blend by melt reactive extrusion. Here, using 4,4'-methylene-bis(N,N-diglycidyl-aniline) (MBDG) containing four epoxy groups as a reactive compatibilizer, and respectively using 1-methylimidazole (MI) or triethylenediamine (TD) as a catalyzer, serial PLA/PBAT/TPS ternary bio-composites are successfully prepared via melt reactive extrusion. The results showed that, under the catalysis of organic base, especially MI, the epoxy groups of MBDG can effectively react with hydroxyl and carboxyl groups of PLA/PBAT and hydroxyl groups in TPS to form chain-expanded and cross-linked structures. The tensile strength of the composites is increased by 20.0 % from 21.1 MPa, and the elongation at break is increased by 182.4 % from 17.6 % owing to the chain extension and the forming of cross-linked structures. The molecular weight, thermal stability, crystallinity, and surface hydrophobicity of the materials are gradually improved with the increase of MBDG content. The melt fluidity of the composites is also improved due to the enhancement of compatibility. The obtained PLA/PBAT/TPS materials have the potential to be green plastic products with good properties.

Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory.

Regulation of histones occurs through multiple mechanisms including exchange with histone variants. Unlike canonical histones, variants are replication-independent and therefore accumulate in post-mitotic cells such as neurons. While recent findings link variants to neurological and neuropsychiatric disorders, few are well studied in the context of the brain. H2BE is the single H2B variant found outside germline tissues, yet its expression and effects on chromatin remained unclear. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad H2BE expression in the brain and its role in regulating chromatin structure, neuronal transcription, and mouse behavior. H2BE is enriched at promoters and enhances chromatin accessibility. We further identify a single amino acid driving these accessibility changes. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation and neuronal function underlying memory.

Soluble Gd6Cu24 clusters: effective molecular electrocatalysts for water oxidation.

The water oxidation half reaction in water splitting for hydrogen production is extremely rate-limiting. This study reports the synthesis of two heterometallic clusters (Gd6Cu24-IM and Gd6Cu24-AC) for application as efficient water oxidation catalysts. Interestingly, the maximum turnover frequency of Gd6Cu24-IM in an NaAc solution of a weak acid (pH 6) was 319 s-1. The trimetallic catalytic site, H2O-GdIIICuII2-H2O, underwent two consecutive two-electron two-proton coupled transfer processes to form high-valent GdIII-O-O-CuIII2 intermediates. Furthermore, the O-O bond was formed via intramolecular interactions between the CuIII and GdIII centers. The results of this study revealed that synergistic catalytic water oxidation between polymetallic sites can be an effective strategy for regulating O-O bond formation.

Theoretical and experimental study on stable oscillation of dual-frequency signals in an optoelectronic oscillator.

Due to the gain competition effect, it is hard to simultaneously maintain oscillation at two frequencies in an optoelectronic oscillator (OEO) loop. In this paper, a study of the gain competition effect in a dual-frequency OEO is theoretically and experimentally demonstrated. The steady-state conditions in the dual-frequency OEO are theoretically analyzed by deriving dynamic equations. A nonlinear time-varying model, as well as its calculation methods, is carried out to design and study the dynamic process of the dual-frequency OEO. Thanks to this model, the waveform, spectrum, and amplitude evaluation of generated signals, as well as the gain variation in the OEO loop, are numerically simulated. Based on the theoretical analysis and numerical simulation results, three schemes that can suppress the gain competition effect are proposed, and the one based on wavelength division multiplexing (WDM) technology is experimentally realized. The experimental results show that the novel independently tunable dual-frequency OEO, to the best of our knowledge, can generate two-tone RF signals in a range from 1.8 to 18.6 and 1.5 to 18.3 GHz, respectively.

Diagnosing and grading gastric atrophy and intestinal metaplasia using semi-supervised deep learning on pathological images: development and validation study.

OBJECTIVE: Patients with gastric atrophy and intestinal metaplasia (IM) were at risk for gastric cancer, necessitating an accurate risk assessment. We aimed to establish and validate a diagnostic approach for gastric biopsy specimens using deep learning and OLGA/OLGIM for individual gastric cancer risk classification. METHODS: In this study, we prospectively enrolled 545 patients suspected of atrophic gastritis during endoscopy from 13 tertiary hospitals between December 22, 2017, to September 25, 2020, with a total of 2725 whole-slide images (WSIs). Patients were randomly divided into a training set (n = 349), an internal validation set (n = 87), and an external validation set (n = 109). Sixty patients from the external validation set were randomly selected and divided into two groups for an observer study, one with the assistance of algorithm results and the other without. We proposed a semi-supervised deep learning algorithm to diagnose and grade IM and atrophy, and we compared it with the assessments of 10 pathologists. The model's performance was evaluated based on the area under the curve (AUC), sensitivity, specificity, and weighted kappa value. RESULTS: The algorithm, named GasMIL, was established and demonstrated encouraging performance in diagnosing IM (AUC 0.884, 95% CI 0.862-0.902) and atrophy (AUC 0.877, 95% CI 0.855-0.897) in the external test set. In the observer study, GasMIL achieved an 80% sensitivity, 85% specificity, a weighted kappa value of 0.61, and an AUC of 0.953, surpassing the performance of all ten pathologists in diagnosing atrophy. Among the 10 pathologists, GasMIL's AUC ranked second in OLGA (0.729, 95% CI 0.625-0.833) and fifth in OLGIM (0.792, 95% CI 0.688-0.896). With the assistance of GasMIL, pathologists demonstrated improved AUC (p = 0.013), sensitivity (p = 0.014), and weighted kappa (p = 0.016) in diagnosing IM, and improved specificity (p = 0.007) in diagnosing atrophy compared to pathologists working alone. CONCLUSION: GasMIL shows the best overall performance in diagnosing IM and atrophy when compared to pathologists, significantly enhancing their diagnostic capabilities.

Iron-doped carbon nanotubes with magnetic enhanced Fe(VI) degradation of arsanilic acid and inorganic arsenic: Role of intermediate iron species and electron transfer.

Arsanilic acid (p-AsA), a prevalently used feed additive, is frequently detected in environment posing a great threat to humans. Potassium ferrate (Fe(VI)) was an efficient way to tackle arsenic contamination under acid and neutral conditions. However, Fe(VI) showed a noneffective removal of p-AsA under alkaline conditions due to its oxidation capacity attenuation. Herein, a magnetic iron-doped carbon nanotubes (F-CNT) was successfully prepared and further catalyzed Fe(VI) to remove p-AsA and total As species. The Fe(VI)/F-CNT system showed an excellent capability to oxidize p-AsA and adsorb total As species over an environment-related pH range of 6-9. The high-valent iron intermediates Fe(V)/Fe(IV) and the mediated electron-transfer played a significant part in the degradation of p-AsA according to the probes/scavengers experiments and galvanic oxidation process. Moreover, the situ formed iron hydroxide oxide and F-CNT significantly improved the adsorption capacity for total As species. The electron-donating groups (semiquinone and hydroquinone) and high graphitization of F-CNT were responsible for activating Fe(VI) based on the analysis of X-ray photoelectron spectroscopy (XPS). Density functional theory calculations and the detected degradation products both indicated that the amino group and the C-As bond of p-AsA were main reactive sites. Notably, Fe(VI)/F-CNT system was resistant to the interference from Cl-, SO42-, and HCO3-, and could effectively remove p-AsA and total As species even in the presence of complex water matrix. In summary, this work proposed an efficient method to use Fe(VI) for degrading pollutants under alkaline conditions and explore a new technology for livestock wastewater advanced treatment.

Characterization the prognosis role and effects of snoRNAs in melanoma patients.

Melanoma is a melanocyte-derived malignant cancer and is known for its early metastasis and high mortality rates. It is a highly cutaneous tumour disease that could be related to the abnormal immune microenvironment, and the identification of reliable diagnostic and prognostic markers is crucial for improving patient outcomes. In the search for biomarkers, various types of RNAs have been discovered and recognized as reliable prognostic markers. Among these, small nucleolar RNAs (snoRNAs) have emerged as a promising avenue for studying early diagnosis and prognostic markers in tumours due to their widespread presence in tissues, tumour specificity and stability. In our study, we analysed snoRNAs data from melanoma samples in the TCGA-SKCM cohort and developed a prognostic model comprising 12 snoRNAs (SNORD9, SNORA31, SNORD14E, SNORA14A, SNORA5A, SNORD83A, SNORA75, AL096855, AC007684, SNORD14A, SNORA65 and AC004839). This model exhibited unique prognostic accuracy and demonstrated a significant correlation with the immune infiltration tumour microenvironment. Additionally, analysis of the GSE213145 dataset, which explored the sensitivity and resistance of immune checkpoint inhibitors, further supported the potential of snoRNAs as prognostic markers for immunotherapy. Overall, our study contributes reliable prognostic and immune-related biomarkers for melanoma patients. These findings can offer valuable insights for the future discovery of novel melanoma treatment strategies and hold promise for improving clinical outcomes in melanoma patients.

Combination of omalizumab with allergen immunotherapy versus immunotherapy alone for allergic diseases: A meta-analysis of randomized controlled trials.

BACKGROUND: Allergen immunotherapy (AIT)-associated adverse events (AEs) limit its usage in the management of allergic diseases. The monoclonal anti-IgE antibody (omalizumab) and AIT have complementary actions. However, no consensus has been reached on whether their combination could exert superior efficacy and safety. OBJECTIVE: To evaluate whether the combination of AIT with omalizumab is superior to AIT alone in treating allergic diseases. METHODS: The MEDLINE/PubMed, Embase, Scopus and Cochrane Library databases were searched to identify randomized control trials (RCTs) reporting the outcomes of omalizumab combined with AIT (omalizumab + AIT) versus AIT alone. A random-effect model was established to estimate outcomes with a 95% confidence interval (CI). RESULTS: A total of 11 eligible RCTs (involving 901 patients) were screened out for the meta-analysis. According to a pooled analysis, omalizumab + AIT significantly increased the number of patients achieving the target maintenance dose (TMD) and sustained unresponsiveness (SU) to allergens (odds ratio [OR] = 2.43; 95% CI: 1.33-4.44; p = 0.004; I2 = 35%, and OR = 6.77; 95% CI: 2.10-21.80; p = 0.001; I2 = 36%, respectively). Similarly, individuals receiving the combination therapy reported significantly fewer episodes of severe systemic AEs than AIT alone (OR = 0.32; 95% CI: 0.18-0.59; p = 0.0003; I2 = 0%). Meanwhile, the improvements in symptom severity score (mean difference [MD] = -0.26), rescue medication daily means score (MD = -0.14), and number of patients consuming epinephrine in AIT (OR = 0.20) were all more evident than those in AIT alone. CONCLUSION: Omalizumab + AIT can significantly enhance the efficacy and safety of AIT by increasing TMD and SU to allergens, while decreasing severe systemic AEs.

Sweat gland development requires an eccrine dermal niche and couples two epidermal programs.

Eccrine sweat glands are indispensable for human thermoregulation and, similar to other mammalian skin appendages, form from multipotent epidermal progenitors. Limited understanding of how epidermal progenitors specialize to form these vital organs has precluded therapeutic efforts toward their regeneration. Herein, we applied single-nucleus transcriptomics to compare the expression content of wild-type, eccrine-forming mouse skin to that of mice harboring a skin-specific disruption of Engrailed 1 (En1), a transcription factor that promotes eccrine gland formation in humans and mice. We identify two concurrent but disproportionate epidermal transcriptomes in the early eccrine anlagen: one that is shared with hair follicles and one that is En1 dependent and eccrine specific. We demonstrate that eccrine development requires the induction of a dermal niche proximal to each developing gland in humans and mice. Our study defines the signatures of eccrine identity and uncovers the eccrine dermal niche, setting the stage for targeted regeneration and comprehensive skin repair.

Antibodies to S2 domain of SARS-CoV-2 spike protein in Moderna mRNA vaccinated subjects sustain antibody-dependent NK cell-mediated cell cytotoxicity against Omicron BA.1.

Vaccination with the primary two-dose series of SARS-CoV-2 mRNA protects against infection with the ancestral strain, and limits the presentation of severe disease after re-infection by multiple variants of concern (VOC), including Omicron, despite the lack of a strong neutralizing response to these variants. We compared antibody responses in serum samples collected from mRNA-1273 (Moderna) vaccinated subjects to identify mechanisms of immune escape and cross-protection. Using pseudovirus constructs containing domain-specific amino acid changes representative of Omicron BA.1, combined with domain competition and RBD-antibody depletion, we showed that RBD antibodies were primarily responsible for virus neutralization and variant escape. Antibodies to NTD played a less significant role in antibody neutralization but acted along with RBD to enhance neutralization. S2 of Omicron BA.1 had no impact on neutralization escape, suggesting it is a less critical domain for antibody neutralization; however, it was as capable as S1 at eliciting IgG3 responses and NK-cell mediated, antibody-dependent cell cytotoxicity (ADCC). Antibody neutralization and ADCC activities to RBD, NTD, and S1 were all prone to BA.1 escape. In contrast, ADCC activities to S2 resisted BA.1 escape. In conclusion, S2 antibodies showed potent ADCC function and resisted Omicron BA.1 escape, suggesting that S2 contributes to cross-protection against Omicron BA.1. In line with its conserved nature, S2 may hold promise as a vaccine target against future variants of SARS-CoV-2.

Personalized radiomics signature to screen for KIT-11 mutation genotypes among patients with gastrointestinal stromal tumors: a retrospective multicenter study.

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS: Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS: The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS: CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.

The romantic history of signaling pathway discovery in cell death: an updated review.

Cell death is a fundamental physiological process in all living organisms. Processes such as embryonic development, organ formation, tissue growth, organismal immunity, and drug response are accompanied by cell death. In recent years with the development of electron microscopy as well as biological techniques, especially the discovery of novel death modes such as ferroptosis, cuprotosis, alkaliptosis, oxeiptosis, and disulfidptosis, researchers have been promoted to have a deeper understanding of cell death modes. In this systematic review, we examined the current understanding of modes of cell death, including the recently discovered novel death modes. Our analysis highlights the common and unique pathways of these death modes, as well as their impact on surrounding cells and the organism as a whole. Our aim was to provide a comprehensive overview of the current state of research on cell death, with a focus on identifying gaps in our knowledge and opportunities for future investigation. We also presented a new insight for macroscopic intracellular survival patterns, namely that intracellular molecular homeostasis is central to the balance of different cell death modes, and this viewpoint can be well justified by the signaling crosstalk of different death modes. These concepts can facilitate the future research about cell death in clinical diagnosis, drug development, and therapeutic modalities.

5-hydroxymethylcytosines regulate gene expression as a passive DNA demethylation resisting epigenetic mark in proliferative somatic cells.

Enzymatic erasure of DNA methylation in mammals involves iterative 5-methylcytosine (5mC) oxidation by the ten-eleven translocation (TET) family of DNA dioxygenase proteins. As the most abundant form of oxidized 5mC, the prevailing model considers 5-hydroxymethylcytosine (5hmC) as a key nexus in active DNA demethylation that can either indirectly facilitate replication-dependent depletion of 5mC by inhibiting maintenance DNA methylation machinery (UHRF1/DNMT1), or directly be iteratively oxidized to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC) and restored to cytosine (C) through thymine DNA glycosylase (TDG)-mediated 5fC/5caC excision repair. In proliferative somatic cells, to what extent TET-dependent removal of 5mC entails indirect DNA demethylation via 5hmC-induced replication-dependent dilution or direct iterative conversion of 5hmC to 5fC/5caC is unclear. Here we leverage a catalytic processivity stalling variant of human TET1 (TET1.var: T1662E) to decouple the stepwise generation of 5hmC from subsequent 5fC/5caC generation, excision and repair. By using a CRISPR/dCas9-based epigenome-editing platform, we demonstrate that 5fC/5caC excision repair (by wild-type TET1, TET1.wt), but not 5hmC generation alone (by TET1.var), is requisite for robust restoration of unmodified cytosines and reversal of somatic silencing of the methylation-sensitive, germline-specific RHOXF2B gene promoter. Furthermore, integrated whole-genome multi-modal epigenetic sequencing reveals that hemi-hydroxymethylated CpG dyads predominantly resist replication-dependent depletion of 5mC on the opposing strand in TET1.var-expressing cells. Notably, TET1.var-mediated 5hmC generation is sufficient to induce similar levels of differential gene expression (compared to TET1.wt) without inducing major changes in unmodified cytosine profiles across the genome. Our study suggests 5hmC alone plays a limited role in driving replication-dependent DNA demethylation in the presence of functional DNMT1/UHRF1 mechanisms, but can regulate gene expression as a bona fide epigenetic mark in proliferative somatic cells.