Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

d-type peptides based fluorescent probes for "turn on" sensing of heparin.

Developing "turn on" fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising "turn on" fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based "turn on" probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d-type peptide fluorescent probe XH-6 indicated that d-type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of "turn on" fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d-type peptides based fluorescent probes.

An integrated strategy of UPLC-Q-TOF/MS and HPTLC/PAD-DESI-MSI for the analysis of chemical variations: A case study of Tibetan medicine Tiebangchui.

Image 1.

Metal-Organic Frameworks Possessing Suitable Pores for Xe/Kr Separation.

Adsorption separation of the Xe/Kr mixture remains a tough issue since Xe and Kr have an inert nature and similar sizes. Here we present a chlorinated metal-organic framework (MOF) [JXNU-19(Cl)] and its nonchlorinated analogue (JXNU-19) for Xe/Kr separation. The two isostructural MOFs constructed from the heptanuclear cobalt-hydroxyl clusters bridged by organic ligands are three-dimensional structures. Detailed contrast of the Xe/Kr adsorption separation properties of the MOF shows that significantly enhanced Xe uptakes and Xe/Kr adsorption selectivity (17.1) are observed for JXNU-19 as compared to JXNU-19(Cl). The main binding sites for Xe in the MOF revealed by computational simulations are far away from the chlorine sites, suggesting that the introduction of the chlorine groups results in the unfavorable Xe adsorption for JXNU-19(Cl). The optimal pores, high surface area, and multiple strong Xe-framework interactions facilitate the effective Xe/Kr separation for JXNU-19.

Transglutaminase cross-linking ovalbumin-flaxseed oil emulsion gels: Properties, microstructure, and performance in oxidative stability.

This study prepared emulsion gels by modifying ovalbumin (OVA)-flaxseed oil (FSO) emulsions with transglutaminase (TGase) and investigated their properties, structure and oxidative stability under different enzyme reaction times. Here, we found prolonged reaction times led to the transformation of α-helix and ß-turn into ß-sheet and random coil. The elasticity, hardness and water retention of the emulsion gels increased significantly, but the water-holding capacity decreased when the reaction time exceeded 4 h. Confocal laser scanning microscope (CLSM) indicated extended enzyme reaction time fostered oil droplet aggregation with proteins. Emulsion gel reduced FSO oxidation, especially after 4 h of the enzyme reaction, the peroxide value (PV) of the emulsion gel was reduced by 29.16% compared to the control. In summary, the enzyme reaction time of 4 h resulted in the formation of a dense gel structure and enhanced oxidative stability. This study provides the potential applications in functional foods and biomedical fields.

SBCNet: Scale and Boundary Context Attention Dual-branch Network for Liver Tumor Segmentation.

Automated segmentation of liver tumors in CT scans is pivotal for diagnosing and treating liver cancer, offering a valuable alternative to labor-intensive manual processes and ensuring the provision of accurate and reliable clinical assessment. However, the inherent variability of liver tumors, coupled with the challenges posed by blurred boundaries in imaging characteristics, presents a substantial obstacle to achieving their precise segmentation. In this paper, we propose a novel dual-branch liver tumor segmentation model, SBCNet, to address these challenges effectively. Specifically, our proposed method introduces a contextual encoding module, which enables a better identification of tumor variability using an advanced multiscale adaptive kernel. Moreover, a boundary enhancement module is designed for the counterpart branch to enhance the perception of boundaries by incorporating contour learning with the Sobel operator. Finally, we propose a hybrid multi-task loss function, concurrently concerning tumors' scale and boundary features, to foster interaction across different tasks of dual branches, further improving tumor segmentation. Experimental validation on the publicly available LiTS dataset demonstrates the practical efficacy of each module, with SBCNet yielding competitive results compared to other state-of-the-art methods for liver tumor segmentation. The code can be available at https://github.com/gardnerzhou/SBCNet.

Effect of Infusion Set Replacement Intervals on Central Line-Associated Bloodstream Infection in the Intensive Care Unit: Study Protocol of the INSPIRATION Study.

INTRODUCTION: The replacement intervals for infusion sets may differ among healthcare institutions, which may have an impact on the occurrence of central line-associated bloodstream infections (CLABSI). Nevertheless, there exists a limited amount of high-quality evidence available to assist clinicians in determining the most suitable replacement intervals for infusion sets. Therefore, the objective of this trial is to compare the efficacy of 24-h and 96-h replacement intervals for infusion sets on CLABSI among critically ill adults who have central venous access devices. METHODS: This is a multicenter, parallel-group randomized controlled trial that will investigate the effect of infusion set replacement intervals on CLABSI in adult patients admitted to intensive care units (ICUs). The study will enroll 1240 participants who meet the inclusion criteria, which includes being 18 years or older, expected to stay in the ICU for longer than 96 h, and in need of central venous access. Participants will be randomly assigned to either a control group receiving a 96-h replacement interval or a treatment group receiving a 24-h replacement interval. PLANNED OUTCOME: The primary outcome of this trial is the rate of CLABSI within 28 days after randomization. CONCLUSION: This is the first randomized controlled trial to investigate the effects of infusion set replacement at 24-h and 96-h intervals on CLABSI in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05359601.

A Novel Food Bore Protein Hydrogel with Silver Ions for Promoting Burn Wound Healing.

Hydrogels have emerged as a promising option for treating local scald wounds due to their unique physical and chemical properties. This study aims to evaluate the efficacy of ovalbumin/gelatin composite hydrogels in repairing deep II-degree scald wounds using a mouse dorsal skin model. Trauma tissues collected at various time points are analyzed for total protein content, hydroxyproline content, histological features, and expression of relevant markers. The results reveal that the hydrogel accelerates the healing process of scalded wounds, which is 17.27% higher than the control group. The hydrogel treatment also effectively prevents wound enlargement and redness of the edges caused by infection during the initial stage of scalding. The total protein and hydroxyproline content of the treated wounds are significantly elevated. Additionally, the hydrogel up-regulates the expression of VEGF (a crucial angiogenic factor) and down-regulates CD68 (a macrophage marker). In summary, this study provides valuable insights into the potential of multifunctional protein-based hydrogels in wound healing.

21-gene recurrence score in predicting the outcome of postoperative radiotherapy in T1-2N1 luminal breast cancer after breast-conserving surgery.

BACKGROUND: In those with one to three positive lymph nodes (N1) breast cancer (BC), the 21-gene recurrence score (RS) classification can be referred for decision-making on adjuvant chemotherapy. This study aimed to investigate the effect of RS in predicting the survival benefit of postoperative radiotherapy (PORT) in T1-2N1 BC with estrogen receptor-positive and human epidermal growth factor receptor 2-negative disease after breast-conserving surgery (BCS). METHODS: We included patients with BC and available RS data from the Surveillance, Epidemiology, and End Results Oncotype DX database. The chi-square test, Kaplan-Meier method, propensity score matching (PSM) as well as multivariable Cox proportional hazard analyses were used for statistical analyses. RESULTS: We included 6509 patients in the analysis. Of these patients, 5302 (85.5%) were treated with BCS + PORT, and 207 (15.5%) had BCS alone. There were 1419 (21.8%), 4319 (66.4%), and 771 (11.8%) patients being low-, intermediate-, and high-risk RS, respectively. After PSM, PORT was significantly associated with a 5-year overall survival (OS) advantage (95.1% vs. 90.5%, P < 0.001) compared to those without PORT, which similar breast cancer-specific survival (BCSS) was found between the treatment arms (P = 0.126). The sensitivity analyses showed that PORT was not associated with a better BCSS (P = 0.472) and OS (P = 0.650) than those without PORT in the low-risk RS cohort. However, PORT was associated with a better BCSS (P = 0.031) and OS (P < 0.001) compared to those without PORT in the intermediate/high-risk RS cohorts. CONCLUSIONS: Our study highlights the possible role of the RS in predicting the outcome of PORT in T1-2N1 luminal BC patients undergoing BCS.

Decoding acute myocarditis in patients with COVID-19: Early detection through machine learning and hematological indices.

During the persistent COVID-19 pandemic, the swift progression of acute myocarditis has emerged as a profound concern due to its augmented mortality, underscoring the urgency of prompt diagnosis. This study analyzed blood samples from 5,230 COVID-19 individuals, identifying key blood and myocardial markers that illuminate the relationship between COVID-19 severity and myocarditis. A predictive model, applying Bayesian and random forest methodologies, was constructed for myocarditis' early identification, unveiling a balanced gender distribution in myocarditis cases contrary to a male predominance in COVID-19 occurrences. Particularly, older men exhibited heightened vulnerability to severe COVID-19 strains. The analysis revealed myocarditis was notably prevalent in younger demographics, and two subvariants COVID-19 progression paths were identified, characterized by symptom intensity and specific blood indicators. The enhanced myocardial marker model displayed remarkable diagnostic accuracy, advocating its valuable application in future myocarditis detection and treatment strategies amidst the COVID-19 crisis.

Nucleoporin Seh1 controls murine neocortical development via transcriptional repression of p21 in neural stem cells.

Mutations or dysregulation of nucleoporins (Nups) are strongly associated with neural developmental diseases, yet the underlying mechanisms remain poorly understood. Here, we show that depletion of Nup Seh1 in radial glial progenitors results in defective neural progenitor proliferation and differentiation that ultimately manifests in impaired neurogenesis and microcephaly. This loss of stem cell proliferation is not associated with defects in the nucleocytoplasmic transport. Rather, transcriptome analysis showed that ablation of Seh1 in neural stem cells derepresses the expression of p21, and knockdown of p21 partially restored self-renewal capacity. Mechanistically, Seh1 cooperates with the NuRD transcription repressor complex at the nuclear periphery to regulate p21 expression. Together, these findings identified that Nups regulate brain development by exerting a chromatin-associated role and affecting neural stem cell proliferation.

The power and the promise of CAR-mediated cell immunotherapy for clinical application in pancreatic cancer.

BACKGROUND: Pancreatic cancer, referred to as the "monarch of malignancies," is a neoplastic growth mostly arising from the epithelial cells of the pancreatic duct and acinar cells. This particular neoplasm has a highly unfavorable prognosis due to its marked malignancy, inconspicuous initial manifestation, challenging early detection, rapid advancement, and limited survival duration. Cellular immunotherapy is the ex vivo culture and expansion of immune effector cells, granting them the capacity to selectively target malignant cells using specialized techniques. Subsequently, these modified cells are reintroduced into the patient's organism with the purpose of eradicating tumor cells and providing therapeutic intervention for cancer. PRESENT SITUATION: Presently, the primary cellular therapeutic modalities employed in the treatment of pancreatic cancer encompass CAR T-cell therapy, TCR T-cell therapy, NK-cell therapy, and CAR NK-cell therapy. AIM OF REVIEW: This review provides a concise overview of the mechanisms and primary targets associated with various cell therapies. Additionally, we will explore the prospective outlook of cell therapy in the context of treating pancreatic cancer.

KLK10/LIPH/PARD6B/SLC52A3 are promising molecular biomarkers for the prognosis of pancreatic cancer through a ceRNA network.

Pancreatic adenocarcinoma (PAAD) remains challenging to diagnose and treat clinically due to its difficult early diagnosis, low surgical resection rate, and high risk of postoperative recurrence and metastasis. SMAD4 is a classical mutated gene in pancreatic cancer and is lost in up to 60%-90 % of PAAD patients, and its mutation often predicts a poor prognosis and treatment resistance. In this study, based on the expression profile data in The Cancer Genome Atlas database, we identified a ceRNA network composed of 2 lncRNAs, 1 miRNA, and 4 mRNAs through differential expression analysis and survival prognosis analysis. Among them, high expression of KLK10/LIPH/PARD6B/SLC52A3 influenced the prognosis and overall survival of PAAD patients. We confirmed the high expression of these target genes in pancreatic tissue of pancreatic-specific SMAD4-deficient mice. In addition, immune infiltration analysis showed that the high expression of these target genes affects the tumor immune environment and contributes to the progression of PAAD. Abnormal overexpression of these target genes may be caused by hypermethylation. In conclusion, we found that KLK10/LIPH/PARD6B/SLC52A3 is a potential prognostic marker for PAAD based on a competing endogenous RNA-mediated mechanism and revealed the potential pathogenic mechanism by which deficient expression of SMAD4 promotes pancreatic cancer progression, which provides a new pathway and theoretical basis for targeted therapy or improved prognosis of pancreatic cancer. These data will help reveal potential therapeutic targets for pancreatic cancer and improve the prognosis of pancreatic cancer patients.

Exploring the oxidative rancidity mechanism and changes in volatile flavors of watermelon seed kernels based on lipidomics.

Watermelon seed kernels (WSK) are prone to oxidative rancidity, while their evaluation biomarkers and changes in volatile flavor are still unknown. The research tracked the changes in volatile compounds and lipid components before and after rancidity using HS-SPME-GC-O-MS and lipidomic techniques. The results showed the flavor of watermelon seed kernels changed significantly before and after rancidity, from mild aroma to rancidity. A total of 42 volatile compounds were detected via GC-O-MS, and a total of 220 lipid molecules were detected via lipidomic technology. 55 lipids with significant differences were screened via multivariate statistical analysis. Combining the above analysis, it found that glycerol phospholipid and glyceride pathways were the most important metabolic pathways and 1-Pentanol and styrene could be used as potential biomarkers to judge the rancidity process of watermelon seed kernels. The research could provide powerful technical support for the storage, transportation and freshness preservation of watermelon seed kernels.

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315.

Oncolytic peptides represent promising novel candidates for anticancer treatments. In our efforts to develop oncolytic peptides possessing both high protease stability and durable anticancer efficiency, three rounds of optimization were conducted on the first-in-class oncolytic peptide LTX-315. The robust synthetic method, in vitro and in vivo anticancer activity, and anticancer mechanism were investigated. The D-type peptides represented by FXY-12 possessed significantly improved proteolytic stability and sustained anticancer efficiency. Strikingly, the novel hybrid peptide FXY-30, containing one FXY-12 and two camptothecin moieties, exhibited the most potent in vitro and in vivo anticancer activities. The mechanism explorations indicated that FXY-30 exhibited rapid membranolytic effects and induced severe DNA double-strand breaks to trigger cell apoptosis. Collectively, this study not only established robust strategies to improve the stability and anticancer potential of oncolytic peptides but also provided valuable references for the future development of D-type peptides-based hybrid anticancer chemotherapeutics.

Chitin nanofibers prepared by enzymatic hydrolysis: Characterization and application for Pickering emulsions.

Chitin nanofibers (ChNFs) have a wide range of applications in numerous fields owing to their exceptional material properties and biological functionality. This research focused on producing ChNFs with diameters of 20-70 nm using chitinase and ultrasound from crayfish shells. The impact of enzymatic duration on ChNF yield and performance was investigated. Results revealed ChNFs forming a high aspect ratio network structure. Chitinase hydrolysis enhanced ChNF dispersion and yield while improving crystallinity and thermal stability without significantly altering their chemical structure. Enzymatically modified ChNF suspensions also exhibited stable rheological properties. Moreover, ChNFs showed good emulsification and emulsion stability in Pickering emulsion. The mechanism may be the effective adsorption of ChNFs at the oil-water interface, and the formation of a ChNF network in the continuous phase that prevents droplet coalescence. This study highlights that the potential of chitinase and ultrasound for the production of ChNFs and the utilization of crayfish shell waste.

Effect of transglutaminase on ovalbumin emulsion gels as carriers of encapsulated probiotic bacteria.

BACKGROUND: The use of emulsion gels to protect and deliver probiotics has become an important topic in the food industry. This study used transglutaminase (TGase) to regulate ovalbumin (OVA) to prepare a novel emulsion gel. The effects of OVA concentration and the addition of TGase on the microstructure, rheological properties, water-holding capacity, and stability of the emulsion gels were investigated. RESULTS: With the addition of TGase and the increasing OVA, the particle size of the emulsion gels decreased significantly (P < 0.05). The gels with TGase exhibited greater water holding, hardness, and chewiness to some extent by forming a more uniform and stable system. After simulated digestion, the survival rate of Bifidobacterium lactis embedded in OVA emulsion gels improved significantly in comparison with the oil-water mixture as a result of the protective effect of the emulsion gel encapsulation. CONCLUSION: By increasing the OVA content and adding TGase, the rheological characteristics, stability, and encapsulation capability of the OVA emulsion gel could be enhanced, providing a theoretical basis for the use of emulsion gels to construct probiotic delivery systems. © 2023 Society of Chemical Industry.

Abelmoschus manihot (L.) medik. seeds alleviate rheumatoid arthritis by modulating JAK2/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Abelmoschus manihot (L.) Medik. Seeds (AMS, སོ་མ་ར་ཛ།), a Tibetan classical herbal in China, are rich in flavonoids and phenolic glycosides compounds, such as quercetin and its derivatives. Moreover, it has been found to possess anti-rheumatoid arthritis (RA) effects. Nonetheless, its anti-RA mechanism is yet unknown. AIM OF THE STUDY: This research aimed to examine the active ingredients of AMS as well as potential pharmacological mechanisms in AMS on RA. MATERIALS AND METHODS: The ultra-performance liquid chromatography-electrospray ionization-tandem multistage mass spectrometry (UPLC-ESI-IT-MSn) technique was used to determine the primary chemical components of AMS that were responsible for the therapeutic effects on RA. In addition, 36 male Wistar rats weighing between 200 and 220 g were classified at random into six groups [normal control group, collagen-induced arthritis (CIA) group, methotrexate group (positive control, 1.05 mg/kg), AMS group (157.5 mg/kg, 315 mg/kg, 630 mg/kg)]. CIA rats were given AMS extract by intragastric administration for 28 days, and their ankles were photographed to observe the degree of swelling. Further, the arthritis score, paws swelling, and body weight changes of CIA rats were determined to observe whether AMS has any effect on RA, and synovial and cartilage tissue injuries were identified by histopathology. Besides, the levels of IL-10, TNF-α, IL-1ß, INF-γ, etc. in serum were estimated by ELISA. Western blot experiments were implemented to identify the expression levels of protein involved in the JAK2/STAT3 signaling pathway in the CIA rats' synovial tissues. Moreover, the mechanisms and targets of active ingredient therapy of AMS for RA were predicted using network pharmacology and then verified using molecular docking. RESULT: In the present study, 12 compounds were detected by UPLC-ESI-IT-MSn, such as quercetin and its derivative which could be potential active ingredients that contribute to the anti-RA properties of AMS. Our in vivo studies on CIA rats revealed that an AMS-H dose of 630 mg/kg significantly improved joint damage while decreasing the arthritic index and paw swelling. Furthermore, AMS inhibited the INF-γ, IL-6, IL-17, IL-1ß, and TNF-α, levels while upregulating the expression of anti-inflammatory cytokines IL-10 and IL-4 in serum. Besides, AMS inhibited the protein Bcl-2/Bax, STAT3, and JAK2 levels, and promoted the expression of Caspase3, SOCS1, and SOCS3 in the JAK2/STAT3 pathway. Additionally, the JAK/STAT signaling pathway was found to perform a remarkable function in the AMS therapy of RA as evidenced by enrichment in GO terms and KEGG pathways. Meanwhile, data from molecular docking experiments indicated that the core targets of PIK3CA, JAK2, and SRC bound stably to the active ingredients of mimuone, 4'-methoxy-bavachromanol, and quercetin. CONCLUSION: According to these findings, the AMS could improve joint inflammation in CIA rats, and its underlying mechanism could be linked to the regulation of the JAK2/STAT3 pathway. Therefore, AMS might become a promising agent for alleviating inflammation in RA patients.

Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway.

Neurodegenerative diseases (NDs) constitute a group of disorders characterized by the progressive deterioration of nervous system functionality. Currently, the precise etiological factors responsible for NDs remain incompletely elucidated, although it is probable that a combination of aging, genetic predisposition, and environmental stressors participate in this process. Accumulating evidence indicates that viral infections, especially neurotropic viruses, can contribute to the onset and progression of NDs. In this review, emerging evidence supporting the association between viral infection and NDs is summarized, and how the autophagy pathway mediated by viral infection can cause pathological aggregation of cellular proteins associated with various NDs is discussed. Furthermore, autophagy-related genes (ARGs) involved in Herpes simplex virus (HSV-1) infection and NDs are analyzed, and whether these genes could link HSV-1 infection to NDs is discussed. Elucidating the mechanisms underlying NDs is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of NDs.