B-cell-specific signatures reveal novel immunophenotyping and therapeutic targets for hepatocellular carcinoma.

BACKGROUND: Immunotherapy presents both promises and challenges in treating hepatocellular carcinoma (HCC) due to its complex immunological microenvironment. The role of B cells, a key part of the immune system, remains uncertain in HCC. AIM: To identify B-cell-specific signatures and reveal novel immunophenotyping and therapeutic targets for HCC. METHODS: Using the Tumor Immune Single-cell Hub 2 database, we identified B-cell-related genes (BRGs) in HCC. Gene enrichment analysis was performed to explore the possible collaboration between B cells and T cells in HCC. We conducted univariate Cox regression analysis using The Cancer Genome Atlas liver HCC collection dataset to find BRGs linked to HCC prognosis. Subsequently, least absolute shrinkage and selection operator regression was utilized to develop a prognostic model with 11 BRGs. The model was validated using the International Cancer Genome Consortium dataset and GSE76427. RESULTS: The risk score derived from the prognostic model emerged as an independent prognostic factor for HCC. Analysis of the immune microenvironment and cell infiltration revealed the immune status of various risk groups, supporting the cooperation of B and T cells in suppressing HCC. The BRGs model identified new molecular subtypes of HCC, each with distinct immune characteristics. Drug sensitivity analysis identified targeted drugs effective for each HCC subtype, enabling precision therapy and guiding clinical decisions. CONCLUSION: We clarified the role of B cells in HCC and propose that the BRGs model offers promising targets for personalized immunotherapy.

An Aquatic Autonomic Nervous System.

Reproducing human nervous systems with endogenous mechanisms has attracted increasing attention, driven by its great potential in streamlining the neuro-electronic interfaces with bilateral signaling. Here, an artificial aquatic autonomic nervous system (ANS) with switchable excitatory/inhibitory characteristics and acetylcholine (ACh)-mediated plasticity is reported based on the newly emerged organic photoelectrochemical transistor (OPECT). Under the modulation of spatial light and ACh, the system exhibits an immediate switch between excitation and inhibition, and many pulse patterns as well as advanced ANS functions are mimicked. To demonstrate its potential usage, the artificial ANS is then utilized to control artificial pupils and muscles to emulate real biological responses during an emergency. In contrast to previous solid-state attempts, this ANS is aqueous compatible just like biological nervous systems, which are capable of real neurotransmitter mediation.

Dramatic droplet deformation through interfacial particles jamming.

Droplets of one fluid in a second, immiscible fluid are typically spherical in shape due to the interfacial tension between the two fluids. Shear forces can lead to droplet deformation when they are subjected to flow, and these effects can be further modified when the droplet is stabilized by a surfactant due to a flow-induced gradients in the surfactant concentration. An alternative method of stabilizing droplets is through the use of colloidal particles, whose stabilization behavior is intrinsically different from molecular surfactants. Under the same flow condition, a gradient of particle concentration can result in the jamming of particles in regions with a high packing density, making the interface solid-like, albeit only under compression and not tension. However, how this asymmetry in the surfactant properties alters the droplet shape under shear is unknown. Here, we show that shear of particle-stabilized droplets can lead to a remarkable array of shape deformations as the droplets flow through a constrained microchannel. The shear-induced migration of particles on the surface results in the formation of an elastic shell at the back of the droplet, which can wrinkle and invaginate, ultimately leading to a unique core-shell structure. The shapes depend on the Peclet number of the flow, reflecting the balance of shear forces that drive the particles and diffusion that randomizes them. These findings highlight the consequences of the asymmetry in the forces between the particles and provide a unique method to controllably create droplets with a vast array of different shapes.

Evaluation of cardiac remodeling in pediatric chronic kidney disease by cardiovascular magnetic resonance.

BACKGROUND: Children with chronic kidney disease (CKD) are at high risk of cardiovascular disease. Cardiovascular magnetic resonance (CMR) is the reference method for assessing cardiac remodeling. To our knowledge, no study has reported a comprehensive analysis of left ventricular(LV) cardiac remodeling using CMR in different stages of pediatric CKD. This prospective case-control study aimed to investigate cardiac remodeling in pediatric CKD, using CMR, and determine its relationship with risk factors. METHOD: CMR was performed in 124 children with CKD and 50 controls. The cardiac remodeling parameters included left ventricular mass index (LVMI), LV remodeling index (LVRI), and LV wall thickness. Univariable and multivariable analyses were performed to assess the cardiac remodeling risk factors. RESULTS: Cardiac remodeling was observed in 35.5% (44/124) of children with CKD. The LVMI, LVRI, and LV wall thickness were higher in advanced stages of CKD (P < 0.05). In the CKD stage 1-2 group, a lower in the estimated glomerular filtration rate was an independent determinant of impaired LVMI (ß = -0.425, P = 0.019) and LVRI (ß = -0.319, P = 0.044). A higher protein to creatinine ratio(PCR) was independently associated with impaired LVRI (ß = 0.429, P = 0.022). In the CKD stage 3-5 group, higher in systolic blood pressure (SBP) (ß = 0.464, P = 0.005) and PCR (ß = 0.852, P = 0.031) were independent determinants of impaired LVMI. Additionally, higher SBP was positively correlated with impaired LVRI(r = 0.599, P < 0.001). There was a trend toward more abnormal cardiac remodeling in the CKD stage 3-5 group with hypertension than those without. CONCLUSION: Cardiac remodeling is prevalent in children with CKD, from an early stage. kidney markers are independently associated with cardiac remodeling. Hypertension increases the risk of cardiac remodeling in CKD stages 3-5. Strict BP control may help reverse or prevent remodeling.

Association between smoking status and the prognosis of brain metastasis in patients with non-small cell lung cancer.

Objective: This study aimed to explore the relationship between smoking status and the interval to brain metastasis in patients with non-small cell lung cancer (NSCLC) and its impact on survival time after brain metastasis. Methods: Data were collected from patients with NSCLC with brain metastases who were treated at our centre between January 2005 and December 2017. Clinical indices such as clinicopathological features and smoking status were recorded, and patients were followed up until 1 September 2022. Based on our inclusion and exclusion criteria, 461 patients were analysed and matched using 1:1 propensity score matching. Three balanced groups were formed: non-smoking (n = 113), smoking cessation (n = 113), and smoking (n = 113). The interval to brain metastasis and overall survival were compared between the groups. Results: There was a statistically significant difference in the interval to brain metastasis between the non-smoking and smoking cessation groups (p = 0.001), as well as between the non-smoking and smoking groups (p < 0.001). However, the difference between the smoking cessation and smoking groups was not statistically significant (p = 0.106). Multivariate and univariate analyses identified smoking status, clinical stage, lung cancer surgery, chemotherapy, and chest radiotherapy as independent predictors of the interval to brain metastasis. Additionally, the multivariate analysis showed that smoking status, driver gene mutations, and chest radiotherapy independently influenced survival after brain metastasis. Conclusion: Smoking status in patients with NSCLC affects the interval to brain metastasis and survival after brain metastasis.

Super-resolution microscopy unveils the nanoscale organization and self-limiting clustering of CD47 in human erythrocytes.

The transmembrane protein CD47, an innate immune checkpoint protein, plays a pivotal role in preventing healthy erythrocytes from immune clearance. Our study utilized stochastic optical-reconstruction microscopy (STORM) and single-molecule analysis to investigate the distribution of CD47 on the human erythrocyte membrane. Contrary to previous findings in mouse erythrocytes, we discovered that CD47 exists in randomly distributed monomers rather than in clusters across the human erythrocyte membrane. Using 2nd antibody-induced crosslinking, we found that CD47 aggregates into stable clusters within minutes. By comparing these STORM results with those of the fully mobile protein CD59 and the cytoskeleton-bound membrane protein glycophorin C under similar conditions, as well as devising two-color STORM co-labeling and co-clustering experiments, we further quantitatively revealed an intermediate, self-limiting clustering behavior of CD47, elucidating its fractional (∼14%) attachment to the cytoskeleton. Moreover, we report reductions in both the amount of CD47 and its clustering capability in aged erythrocytes, providing new insight into erythrocyte senescence. Together, the combination of STORM and 2nd antibody-based crosslinking unveils the unique self-limiting clustering behavior of CD47 due to its fractional cytoskeleton attachment.

Limosilactobacillus-related 3-OMDP as a potential therapeutic target for depression.

OBJECTIVE: Gut microbiota was closely involved in the pathogenesis of depression, but the underlying molecular mechanisms in depression remained unclear. This study was conducted to investigate the relationship between neurotransmitters/inflammatory factors and gut microbiota in depressed mice. MATERIALS AND METHODS: A chronic social defeat stress (CSDS) depression model was established. Gut microbial composition was detected in faeces, neurotransmitters were detected in faeces, colon, blood and hippocampus, and inflammatory factors were detected in hippocampus. After a key neurotransmitter was identified, intervention experiment was conducted to explore whether it could improve depressive-like behaviours. RESULTS: Six differential genera in faeces, 14 differential neurotransmitters in gut-brain axis, and two differential inflammatory factors (interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6)) in hippocampus were identified in depressed mice. There were significant correlations among differential genera, differential neurotransmitters and IL-1ß/IL-6. Among these differential neurotransmitters, 3-O-Methyldopa (3-OMDP) was found to be consistently decreased in faeces, colon, blood and hippocampus, and 3-OMDP was significantly correlated to Limosilactobacillus and IL-1ß. After receiving 3-OMDP, the depressive-like behaviours in depressed mice were improved and the increased IL-1ß/IL-6 levels were reversed. CONCLUSIONS: These results indicated that gut microbiota might affect host's inflammation levels in brain through regulating neurotransmitters, eventually leading to the onset of depression. 'Limosilactobacillus-3-OMDP-IL-1ß/IL-6' might be a potential pathway in the crosstalk of gut and brain, and 3-OMDP held the promise as a therapeutic target for depression.

The decrease in Limosilactobacillus caused disturbances in peripheral and central 3-OMDP, which resulted in increased IL-6 and IL-1ß levels in brain, eventually leading to the onset of depression.3-OMDP could reverse the increased IL-6 and IL-1ß levels and improve the depressive-like behaviours in depressed mice.

N-Directed, Radical Relay Enantioconvergent Sulfinylation of Distal C(sp3)-H Bonds via Cobalt Catalysis.

Cobalt-catalyzed enantioconvergent cross-coupling of C(sp3)-H bonds with in situ-generated sulfenate anions is achieved to access chiral sulfoxides, which are found in the structures of many biologically active agents. The more challenging aliphatic C-H bonds as well as sterically hindered substrates containing tertiary C-H bonds could also be tolerated well. Mechanistic studies indicate that the transformation could undergo a CoIIS(O)R-mediated single-electron transfer with N-fluorocarboxamides, followed by a 1,5-hydrogen atom transfer and then a pivotal organocobalt(IV)-controlled enantioselective cross-coupling process. This novel asymmetric radical reaction for C-S bond construction could open a new door for the synthesis of sulfur-centered chiral compounds.

Propensity score matching analysis of early vs. delayed surgery for intertrochanteric fracture in older patients: a retrospective multicenter cohort study of 7414 patients with a mean 4-year follow up.

BACKGROUND: The widespread acceptance of early surgery as a treatment for acute intertrochanteric fracture (ITF) has been accompanied by ongoing controversy due to conflicting conclusions presented in previous studies. This study aims to compare the occurrence of perioperative complications and mortality, as well as functional outcomes in older patients with ITF who underwent either early or delayed surgery. METHODS: A retrospective multicenter cohort study involving 7414 patients with ITF between Jan. 2017 and Dec. 2021 was conducted. After predefined participants selection inclusion and exclusion criteria, 2323 surgically treated ITF patients were included and analyzed utilizing propensity score matching (PSM) method. Their demographics, injury-related data, surgery-related data, and perioperative adverse outcomes during hospitalization were collected and compared between the early or delayed surgery groups by PSM with a 1:4 ratio. All participants received a minimum of two-year follow-up and perioperative outcomes, functional outcomes, and survival analyses were conducted and compared. RESULTS: After adjustment for potential confounders, there were no significant difference in surgery duration, intraoperative blood loss, transfusion rate, mortality rates, functional outcomes, and perioperative complications rates including severe complications, cardiac complications, pulmonary complications, and neurological complications regardless of whether the patient was treated with early or delayed surgery (all P > 0.05). Although length of hospital stay (mean, 11.5 versus 14.4 days, P < 0.001), total hospital costs (mean, 39305 versus 42048 yuan, P < 0.001), and minor complications rates including hematological complications (31.7% versus 41.2%, P = 0.007) and nutritional/metabolic complications (59.3% versus 66.4%, P = 0.039) were lower in the early surgery group, our result indicated patients with early surgery were more inclined to receive more blood transfusion (mean, 2.8 versus 2.2 units, P = 0.004). CONCLUSIONS: Our findings suggest that a 48-hour delay in surgical intervention for older patients with an ITF does not result in a higher mortality rate, worse functional outcomes, and increased incidence of major perioperative complications when compared to early surgery. While expedited surgery is undoubtedly necessary for suitable patients, a reasonable preoperative delay of 48 h may be justified and safe for those with severe conditions, rather than strictly adhering to the current guidelines.

Cross-omics strategies and personalised options for lung cancer immunotherapy.

Lung cancer is one of the most common malignant tumours worldwide and its high mortality rate makes it a leading cause of cancer-related deaths. To address this daunting challenge, we need a comprehensive understanding of the pathogenesis and progression of lung cancer in order to adopt more effective therapeutic strategies. In this regard, integrating multi-omics data of the lung provides a highly promising avenue. Multi-omics approaches such as genomics, transcriptomics, proteomics, and metabolomics have become key tools in the study of lung cancer. The application of these methods not only helps to resolve the immunotherapeutic mechanisms of lung cancer, but also provides a theoretical basis for the development of personalised treatment plans. By integrating multi-omics, we have gained a more comprehensive understanding of the process of lung cancer development and progression, and discovered potential immunotherapy targets. This review summarises the studies on multi-omics and immunology in lung cancer, and explores the application of these studies in early diagnosis, treatment selection and prognostic assessment of lung cancer, with the aim of providing more personalised and effective treatment options for lung cancer patients.

Development and validation of a prediction model for gastric cancer: a single-center prospective study.

OBJECTIVE: This study aimed to develop and validate a novel nomogram for diagnosing gastric cancer (GC). METHODS: In this prospective analysis, 146 patients of Wenzhou Central Hospital were recruited for a GC group and a benign lesion group and were divided into a training set and an internal validation set in a ratio of 7:3. Clinical and analytical characteristics were collected and analyzed by logistic regression analysis. The performance of the predictive model was evaluated using the receiver operating characteristic curve, calibration curve, and decision curve analysis. RESULTS: There were 5 variables, namely albumin, carcinoembryonic antigen, carbohydrate antigen 125, creatinine, and small proline-rich protein 2A, that were identified as the final parameters for the developed model. In the training and internal validation sets, the area under the curve of the model was 0.968 and 0.979, respectively, showing good diagnostic performance. CONCLUSION: This study developed and validated a new nomogram based on 5 parameters. This model shows good diagnostic performance in distinguishing GC from benign lesion groups and has certain significance in clinical application.

Revealing the association between East Asian oral microbiome and colorectal cancer through Mendelian randomization and multi-omics analysis.

Background: Colorectal cancer (CRC) poses a global health threat, with the oral microbiome increasingly implicated in its pathogenesis. This study leverages Mendelian Randomization (MR) to explore causal links between oral microbiota and CRC using data from the China National GeneBank and Biobank Japan. By integrating multi-omics approaches, we aim to uncover mechanisms by which the microbiome influences cellular metabolism and cancer development. Methods: We analyzed microbiome profiles from 2017 tongue and 1915 saliva samples, and GWAS data for 6692 CRC cases and 27178 controls. Significant bacterial taxa were identified via MR analysis. Single-cell RNA sequencing and enrichment analyses elucidated underlying pathways, and drug predictions identified potential therapeutics. Results: MR identified 19 bacterial taxa significantly associated with CRC. Protective effects were observed in taxa like RUG343 and Streptococcus_umgs_2425, while HOT-345_umgs_976 and W5053_sp000467935_mgs_712 increased CRC risk. Single-cell RNA sequencing revealed key pathways, including JAK-STAT signaling and tyrosine metabolism. Drug prediction highlighted potential therapeutics like Menadione Sodium Bisulfite and Raloxifene. Conclusion: This study establishes the critical role of the oral microbiome in colorectal cancer development, identifying specific microbial taxa linked to CRC risk. Single-cell RNA sequencing and drug prediction analyses further elucidate key pathways and potential therapeutics, providing novel insights and personalized treatment strategies for CRC.

HBI: a hierarchical Bayesian interaction model to estimate cell-type-specific methylation quantitative trait loci incorporating priors from cell-sorted bisulfite sequencing data.

Methylation quantitative trait loci (meQTLs) quantify the effects of genetic variants on DNA methylation levels. However, most published studies utilize bulk methylation datasets composed of different cell types and limit our understanding of cell-type-specific methylation regulation. We propose a hierarchical Bayesian interaction (HBI) model to infer cell-type-specific meQTLs, which integrates a large-scale bulk methylation data and a small-scale cell-type-specific methylation data. Through simulations, we show that HBI enhances the estimation of cell-type-specific meQTLs. In real data analyses, we demonstrate that HBI can further improve the functional annotation of genetic variants and identify biologically relevant cell types for complex traits.

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Parkinson's disease (PD) is a neurodegenerative disease commonly seen in middle-aged and elderly people. The incidence of PD is increasing year by year, which seriously affects the patients' quality of life. Oxidative stress (OS) is one of the pathogeneses of PD. In recent years, with the deepening of research, it has been found that OS is closely related to other PD-related pathogenesis, such as the susceptibility of substantia nigra, mitochondrial dysfunction, abnormal folding of α -synuclein (α -Syn), nitric oxide (NO) increasing, endoplasmic reticulum stress (ERS), decreased antioxidant capacity, etc., which is considered to be the central link of the complex convergence of various pathogenesis. A large number of studies also have shown that acupuncture has great potential in regulating OS and treatment of PD. In the present article, we reviewed the role of OS in PD pathology and the mechanism of acupuncture in the treatment of PD by improving OS in recent years： 1) acupuncture acts on Parkinson's disease by increasing antioxidant enzyme levels, 2) acupuncture works in Parkinson's disease by improving pathways related to OS (Nrf2/ARE, PI3K/Akt), 3) acupuncture acts on Parkinson's disease by improving OS-related neuroinflammation, and 4) acupuncture acts on Parkinson's disease by improving the cerebral-intestinal axis associated oxidative stress.

Prospective Cohort Investigation on Physical Activity of Osteoporosis Outcomes (PAOPO) in Jidong: Objectives, Study Design, and Baseline Characteristics.

Objective: The aim of this study was to investigate the prospective association between physical activity (PA), independently or in conjunction with other contributing factors, and osteoporosis (OP) outcomes. Methods: The Physical Activity in Osteoporosis Outcomes (PAOPO) study was a community-based cohort investigation. A structured questionnaire was used to gather the participants' sociodemographic characteristics. Bone mineral density (BMD) measurements were performed to assess OP outcomes, and the relationship between BMD and OP was evaluated within this cohort. Results: From 2013 to 2014, 8,471 participants aged 18 years and older were recruited from Tangshan, China's Jidong community. Based on their PA level, participants were categorized as inactive, moderately active, or very active. Men showed higher physical exercise levels than women across the activity groups. BMD was significantly higher in the very active group than in the moderately active and inactive groups. Individuals aged > 50 years are at a higher risk of developing OP and osteopenia. Conclusion: The PAOPO study offers promising insights into the relationship between PA and OP outcomes, encouraging the implementation of PA in preventing and managing OP.

Unraveling the contribution of melamine tableware for human internal exposure to melamine and its derivatives: Insights from crossover and biomonitoring studies.

Melamine tableware can release melamine in daily-use; however, currently there is insufficient evidence to support whether the amount released could pose human exposure risk. We therefore conducted two studies, one is 8-day randomized crossover trial involving 27 volunteers who used melamine and stainless-steel tableware in turn (n = 648) and the other is cross-sectional study including 113 college students and 200 residents (n = 313) to further provide population-based evidence. The crossover study results showed that using melamine tableware could promote urinary concentrations of melamine, cyanuric acid (CYA), and ammelide by 42.1 %, 66.9 %, and 36.2 %, respectively. In the biomonitoring survey, students who are more accessible to melamine tableware in the canteen had 1.47-fold higher median urinary concentrations of melamine-related compounds than that of common residents (393 vs 267 nmol/L, p < 0.01). Additionally, positive associations between exposure to melamine and an oxidative stress indicator, 8-oxo-7,8-dihydroguanine (ß = 1.13, 95 % CI: 0.32, 1.94), and CYA and 8-hydroxy-2'-deoxyguanosine (ß = 0.87, 95 % CI: 0.22, 1.53) were observed in students (p < 0.01), indicating long-term chronic exposure to these chemicals may induce molecular damage to nucleic acids. Our findings provide compelling evidence that frequent use of melamine tableware continues to be a potential threat to human health.

Outcomes of melphalan 140 mg/m2 followed by autologous stem cell transplantation in multiple myeloma patients with co-morbidities: Single-centre experience.

High-dose melphalan followed by stem cell rescue is the standard consolidative therapy for transplant-eligible patients with multiple myeloma (MM) in the United Kingdom. A melphalan dose of 200 mg/m2 (Mel200) is considered the "gold standard" for autologous stem cell transplant (ASCT) conditioning for fit patients ≤70 years old; however, with a peak diagnosis incidence at 80-89 years old in the UK dose adjustments will be inevitable to limit toxicities. In this single-centre UK-based retrospective analysis, data was collected from patients with plasma cell dyscrasias who underwent a first reduced-intensity, Mel140, ASCT from 2006 to 2019, a total of 81 patients. We found that the procedure was overall safe with seven (9%) of patients requiring ITU admission and a single transplant-related death within the initial autograft admission. The progression-free survival (PFS) and overall survival were comparable with those previously reported in the literature with median PFS for our cohort of 31 months. Univariate analysis of our data showed an inferior PFS for patients aged ≥70 years. In conclusion, although this is a retrospective analysis, it demonstrates that dose-reduced melphalan conditioning is safe and effective in patients deemed unfit for standard-intensity conditioning.

High-performance deep-blue electroluminescence from multi-resonance TADF emitters with a spirofluorene-fused double boron framework.

The development of multi-resonance thermally activated delayed fluorescence (MR-TADF) materials in the deep-blue region is highly desirable. A usual approach involves constructing an extended MR-TADF framework; however, it may also intensify aggregate-caused quenching issues and thereby reduce device efficiency. In this study, we develop a molecular design strategy that fuses the MR-TADF skeleton with 9,9'-spirobifluorene (SF) units to create advanced deep-blue emitters. The SF moiety facilitates high-yield one-shot bora-Friedel-Crafts reaction towards an extended skeleton and mitigates interchromophore interactions as a steric group. Our findings reveal that orbital interactions at the fusion site significantly influence the electronic structure, and optimizing the fusion mode allows for the development of emitters with extended conjugation length while maintaining non-bonding character. The proof-of-concept emitter exhibits narrowband emission in the deep-blue region, a near-unity photoluminescence quantum yield, and a fast k RISC of 2.4 × 105 s-1. These exceptional properties enable the corresponding sensitizer-free OLED to achieve a maximum external quantum efficiency (EQEmax) of 39.0% and Commission Internationale de l'Eclairage (CIE) coordinates of (0.13, 0.09). Furthermore, the hyperfluorescence device realizes an EQEmax of 40.4% with very low efficiency roll-off.