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Abstract Background With the increasing risk of nuclear exposure, more attention has been paid to the prevention and treatment of acute radiation syndrome (ARS). Although amino acids are key nutrients involved in hematopoietic regulation, the impacts of amino acids on bone marrow hematopoiesis following irradiation and the associated mechanisms have not been fully elucidated. Hence, it is of paramount importance to study the changes in amino acid metabolism after irradiation and their effects on hematopoiesis as well as the related mechanisms. Methods The content of serum amino acids was analyzed using metabolomic sequencing. The survival rate and body weight of the irradiated mice were detected after altering the methionine content in the diet. Extracellular matrix (ECM) protein analysis was performed via proteomics analysis. Inflammatory factors were examined by enzyme-linked immunosorbent assay (ELISA). Flow cytometry, Western blotting, and immunofluorescence were employed to determine the mechanism by which S100 calcium-binding protein A4 (S100A4) regulates macrophage polarization. Results The survival time of irradiated mice was significantly associated with alterations in multiple amino acids, particularly methionine. A high methionine diet promoted irradiation tolerance, especially in the recovery of bone marrow hematopoiesis, yet with dose limitations. Folate metabolism could partially alleviate the dose bottleneck by reducing the accumulation of homocysteine. Mechanistically, high methionine levels maintained the abundance of ECM components, including collagens and glycoproteins, in the bone marrow post-irradiation, among which the level of S100A4 was significantly changed. S100A4 regulated macrophage polarization via the STAT3 pathway, inhibited bone marrow inflammation and facilitated the proliferation and differentiation of hematopoietic stem/progenitor cells. Conclusions We have demonstrated that an appropriate elevation in dietary methionine enhances irradiation tolerance in mice and explains the mechanism by which methionine regulates bone marrow hematopoiesis after irradiation.

BackgroundEarly detection of anxiety symptoms can support early intervention and may help reduce the burden of disease in later life in the elderly with abdominal obesity, thereby increasing the chances of healthy aging. The objective of this research is to formulate and validate a predictive model that forecasts the probability of developing anxiety symptoms in elderly Chinese individuals with abdominal obesity.MethodThis research’s model development and internal validation encompassed 2,427 participants from the 2017-2018 Study of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Forty-six variables were defined based on the Health Ecology Model (HEM) theoretical framework. Key variables were screened using LASSO regression, and the XGBoost (Extreme Gradient Boosting) model was further introduced to forecast the risk of developing anxiety symptoms in the elderly with abdominal obesity. SHapley Additive exPlanations (SHAP) was adopted to further interpret and show how the eigenvalues contributed to the model predictions.ResultsA total of 240 participants (9.89%) with anxiety symptoms out of 2,427 participants were included. LASSO regression identified nine key variables: looking on the bright side, self-reported economic status, self-reported quality of life, self-reported health status, watching TV or listening to the radio, feeling energetic, feeling ashamed/regretful/guilty, feeling angry, and fresh fruits. All the evaluation indicators of the XGBoost model showed good predictive efficacy. Based on the significance of the features identified by SHAP (Model Interpretation Methodology), the feature ‘looking on the bright side’ was the most important, and the feature ‘self-reported quality of life’ was the least important. The SHAP beeswarm plot illustrated the impacts of features affected by XGBoost.ConclusionUtilizing machine learning techniques, our predictive model can precisely evaluate the risk of anxiety symptoms among elderly individuals with abdominal obesity, facilitating the timely adoption of targeted intervention measures. The integration of XGBoost and SHAP offers transparent interpretations for customized risk forecasts.

Abstract Purpose The study was designed to investigate the occurrence and risk factors of malnutrition in diabetic foot ulcers (DFU) patients and examine the association between malnutrition and length of stay (LOS). Methods This observational study included DFU hospitalized patients in two campuses of a hospital from January 2021 to June 2023. The diagnosis standard of malnutrition was established by using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Patients were followed up to ascertain the length of hospitalization, and hospital stays longer than 17 days were considered as prolonged LOS. To explore the risk factors of malnutrition and the association between malnutrition and LOS, univariate and multivariate logistic regression analyses were performed. Results Overall 219 DFU patients were enrolled, malnutrition was identified in 38.36% of patients according to GLIM criteria, and 92 patients (42%) were recognized as prolonged LOS. Logistic regression analyses showed that BMI (P

Abstract The continuous production of mature blood cell lineages is maintained by hematopoietic stem cells but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Thus, devising therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and patients receiving radiotherapy. Herein, we describe the preparation of an injectable hydrogel formulation based on Arg‐Gly‐Asp‐alginate (RGD‐Alg) and Laponite using a simple mixing method that ensured a slow and sustained release of interleukin‐12 (IL‐12) (RGD‐Alg/Laponite@IL‐12). The local administration of RGD‐Alg/Laponite@IL‐12 increased survival rates and promoted the hematopoietic recovery of mice who had received sublethal‐dose irradiation. Local intra‐bone marrow (intra‐BM) injection of RGD‐Alg/Laponite@IL‐12 hydrogel effectively stimulated IL12 receptor‐phosphoinositide 3‐kinase/protein kinase B (IL‐12R‐PI3K/AKT) signaling axis, which promoted proliferation and hematopoietic growth factors secretion of BM mesenchymal stem/stromal cells. This signaling axis facilitates the repair of the hematopoietic microenvironment and plays a pivotal role in hematopoietic reconstitution. In conclusion, we describe a biomaterial‐sustained release of IL‐12 for the treatment of irradiated hematopoietic injury and provide a new therapeutic strategy for hematopoietic ARS.

Abstract Objective Poor fetal and perinatal outcomes in fetuses associated with umbilical artery thrombosis (UAT), such as severe intrauterine growth restriction (IUGR) and intrauterine asphyxia have been reported by some case series. Its hemodynamic impact remains unclear. The aim of this study was to evaluate the hemodynamic changes and perinatal outcome in UAT fetuses with a relatively large sample. Methods We included singleton fetuses diagnosed with UAT and with at least one available Doppler evaluation before the end of pregnancy in our center from 2016 to 2023. Fetuses with structural abnormalities and with no follow-up results were excluded. Doppler waveforms from the Umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and uterine artery (UtA) were routinely evaluated according to ISUOG Practice Guidelines from diagnosis. The same sample of GA-matched normal fetuses with Doppler measurements during the same period were randomly selected as control group. Results Eighty-nine singleton fetuses with UAT with at least one Doppler evaluation before the end of pregnancy were identified, 13 fetuses with no follow-up results were excluded. After comprehensive prenatal counseling, 14 cases received urgent cesarean section, the remaining 55 cases received expectant management, the median day between GA at diagnosis and end of pregnancy was 13 (5–53) days (range, 2-159). 7 (7/76, 9.2%) cases occurred stillbirth, and the incidence of IUGR and Neonatal Intensive Care Unit (NICU) admission were 18.4% (14/76) and 13.2% (10/76) respectively. 49 fetuses (49/76, 64.5%) combined with Doppler abnormalities. UA abnormalities (35/76, 46.1%) and MCA abnormalities (34/76, 44.7%) were the most changes at presentation. Compared to control group, UA-EDV was significantly increased in UAT fetuses [21.84 (15.59–26.64) vs. 16.40 (12.43–20.70) cm/s, p

Employing the Complex Adaptive System (CAS) framework, we analyzed the evolution of digitally transformed financial networks, underscoring the pivotal role of adaptation and learning among network participants. Government funds supporting banks and platforms in digital transformation prove more effective than direct subsidies to SMEs. Achieving sustainable development requires an optimal balance between investment and efficiency due to the impact of digitalization costs on constructing digital financial networks. The study advocates for a long-term microcredit financing mode tailored to SMEs, aiding them in maintaining financial stability. Additionally, intermediary nodes within the network, such as credit rating companies, can facilitate information sharing, thereby fostering the growth of digital financial networks. This heightened information sharing enhances the payoff for each subject and reduces financing constraints. Furthermore, the study establishes that digital financial networks can alleviate the repercussions of unforeseen events, such as the COVID-19 pandemic. Finally, empirical analysis of the Beijing University Inclusive Finance Index data and financial records of Chinese SMEs listed on the New Third Board from 2016 to 2018 confirms that digital finance can alleviate the financing constraints of SMEs. In summary, the progression of digital financial networks is intricate, necessitating a thorough comprehension of diverse factors. The government is encouraged to guide the enhancement of relevant systems and regulations, bolstering supervision, and facilitating the high-quality development of digital finance networks.

With the development of ordnance technology, the survival and safety of individual combatants in high-tech warfare are under serious threat, and the Personal Protective Equipment (PPE), as an important guarantee to reduce casualties and maintain military combat effectiveness, is widely developed. This paper systematically reviewed various PPE based on individual combat through literature research and comprehensive discussion, and introduced in detail the latest application progress of PPE in terms of material and technology from three aspects: individual integrated protection system, traditional protection equipment, and intelligent protection equipment, respectively, and discussed in depth the functional improvement and optimization status brought by advanced technology for PPE, focusing on the achievements of individual equipment technology application. Finally, the problems and technical bottlenecks in the development of PPE were analyzed and summarized, and the development trend of PPE were pointed out. The results of the review will provide a forward-looking reference for the current development of individual PPE, and are important guidance for the design and technological innovation of advanced equipment based on the future technological battlefield.

Abstract Background Malnutrition remains a pervasive issue among older adults, a prevalence that is markedly higher among those diagnosed with diabetes. The primary objective of this study was to develop and validate a risk prediction model that can accurately identify instances of malnutrition among elderly hospitalized patients with type 2 diabetes mellitus (T2DM) within a Chinese demographic. Methods This cross-sectional study was conducted between August 2021 and August 2022, we enrolled T2DM patients aged 65 years and above from endocrinology wards. The creation of a nomogram for predicting malnutrition was based on risk factors identified through univariate and multivariate logistic regression analyses. The predictive accuracy of the model was evaluated by the receiver operating characteristic curve (ROC),the area under the ROC (AUC), the concordance index (C-index), and calibration curves. Results The study included a total of 248 older T2DM patients, with a recorded malnutrition prevalence of 26.21%. The identified critical risk factors for malnutrition in this cohort were body mass index, albumin, impairment in activities of daily living, dietary habits, and glycosylated hemoglobin. The AUC of the nomogram model reached 0.914 (95% CI: 0.877—0.951), with an optimal cutoff value of 0.392. The model demonstrated a sensitivity of 80.0% and a specificity of 88.5%. Bootstrap-based internal verification results revealed a C-index of 0.891, while the calibration curves indicated a strong correlation between the actual and predicted malnutrition risks. Conclusions This study underscores the critical need for early detection of malnutrition in older T2DM patients. The constructed nomogram represents a practical and reliable tool for the rapid identification of malnutrition among this vulnerable population.

High-speed impact threats and terrorist actions on the battlefield require the development of more effective protective materials and structures, and various protective structure is designed according their energy-absorbing characteristics. In this research, the deformation behavior, microscopic failure modes and energy absorption characteristics of re-entrant hexagonal structure, regular hexagonal structure and regular quadrilateral structure are studied under different strain rates impact. The re-entrant hexagonal structure forms a “X”-shaped deformation zone, the regular quadrilateral and regular hexagonal structure form an “I”-shaped deformation zone. The microscopic appearance of the section is a mixed fracture form. The effects of the topological shape, cell angle, and cell height on the impact behavior of the structure were evaluated. When the cell height is fixed and the cell angle is changed, the energy absorption of the structure increase and then decrease as the relative density increase. The mechanical properties of the structure are optimal when the relative density is about 18.6% and the cell angle is 22.5°. When the cell angle is fixed and the cell height is changed, as the relative density increases, the energy absorption of the structure gradually increases. The regular quadrilateral structure and the re-entrant hexagonal structure experienced clear strain rate effects under dynamic impact conditions; the regular hexagonal structure did not exhibit obvious strain rate effects. The results presented herein provide a basis for further rational design and selection of shock-resistant protective structures that perform well in high-speed impact environments.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Oxaliplatin-based chemotherapy is a standard treatment approach for colorectal cancer (CRC). However, oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe dose-limiting clinical problem that might lead to treatment interruption. This neuropathy may be reversible after treatment discontinuation. Its complicated mechanisms are related to DNA damage, dysfunction of voltage-gated ion channels, neuroinflammation, transporters, oxidative stress, and mitochondrial dysfunction, etc. Several strategies have been proposed to diminish OIPN without compromising the efficacy of adjuvant therapy, namely, combination with chemoprotectants (such as glutathione, Ca/Mg, ibudilast, duloxetine, etc.), chronomodulated infusion, dose reduction, reintroduction of oxaliplatin and topical administration [hepatic arterial infusion chemotherapy (HAIC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and hyperthermic intraperitoneal chemotherapy (HIPEC)]. This article provides recent updates related to the potential mechanisms, therapeutic strategies in treatment of OIPN, and pharmacokinetics of several methods of oxaliplatin administration in clinical trials.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Lichens are some of the most unique fungi and are naturally encountered as symbiotic biological organisms that usually consist of fungal partners (mycobionts) and photosynthetic organisms (green algae and cyanobacteria). Due to their distinctive growth environments, including hot deserts, rocky coasts, Arctic tundra, toxic slag piles, etc., they produce a variety of biologically meaningful and structurally novel secondary metabolites to resist external environmental stresses. The endofungi that live in and coevolve with lichens can also generate abundant secondary metabolites with novel structures, diverse skeletons, and intriguing bioactivities due to their mutualistic symbiosis with hosts, and they have been considered as strategically significant medicinal microresources for the discovery of pharmaceutical lead compounds in the medicinal industry. They are also of great importance in the fundamental research field of natural product chemistry. In this work, we conducted a comprehensive review and systematic evaluation of the secondary metabolites of endolichenic fungi regarding their origin, distribution, structural characteristics, and biological activity, as well as recent advances in their medicinal applications, by summarizing research achievements since 2015. Moreover, the current research status and future research trends regarding their chemical components are discussed and predicted. A systematic review covering the fundamental chemical research advances and pharmaceutical potential of the secondary metabolites from endolichenic fungi is urgently required to facilitate our better understanding, and this review could also serve as a critical reference to provide valuable insights for the future research and promotion of natural products from endolichenic fungi.

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log2 ratio| >1 and p-value

Abstract Background Left ventricular non-compaction cardiomyopathy (LVNC) is a rare congenital heart defect. Gene defections have been found in patients with LVNC and their family members; and MYH7 is the most frequent gene associated with LVNC. Methods We performed a complete prenatal ultrasound and echocardiographic examination on a fetus with cardiac abnormality and a parent–child trio whole-exome sequencing to identify the potential genetic causes. When the genetic abnormality in MYH7 was identified in the fetus, we performed echocardiography and genetic screening on its high-risk relatives. Results Second trimester ultrasound and echocardiography showed several malformations in the fetus: Ebstein’s anomaly (EA), heart dilatation, perimembranous ventricle septal defects, mild seroperitoneum, and single umbilical artery. Heterozygous genotyping of a splicing variant allele (NM_00025.3: c.732+G>A) was identified in this fetus and her mother, not her father, indicating a maternal inheritance. Subsequently, direct sequencing confirmed the presence of this splicing variant among her grandmother (mother of mother), mother, older sister, and herself in a heterozygous manner. No PCR products were amplified by qRT-PCR for the RNA samples extracted from peripheral blood cells. In addition to this proband who was diagnosed with EA, her older sister and grandmother (mother of mother) were diagnosed with isolated asymptomatic LVCN, but her mother was just a carrier with no marked clinical manifestations after family screening. Conclusion The presence of MYH7 splicing variant c.732+G>A can be inherited maternally, and its cardiac phenotypes are different from one carrier to another.

Background: Anxiety disorder (AD) is the most common mental disorder, which is closely related to atrial fibrillation (AF) and is considered to be a trigger of AF. Pinocembrin has been demonstrated to perform a variety of neurological and cardiac protective effects through its anti-inflammatory and antioxidant activities. The current research aims to explore the antiarrhythmic effect of pinocembrin in anxiety disorder rats and its underlying mechanisms.Methods: 60 male Sprague-Dawley rats were distributed into four groups: CTL group: control rats + saline; CTP group: control rats + pinocembrin; Anxiety disorder group: anxiety disorder rats + saline; ADP group: anxiety disorder rats + pinocembrin. Empty bottle stimulation was conducted to induce anxiety disorder in rats for 3 weeks, and pinocembrin was injected through the tail vein for the last 2 weeks. Behavioral measurements, in vitro electrophysiological studies, biochemical assays, ELISA, Western blot and histological studies were performed to assess the efficacy of pinocembrin. In addition, HL-1 atrial cells were cultured in vitro to further verify the potential mechanism of pinocembrin.Results: After 3 weeks of empty bottle stimulation, pinocembrin significantly improved the exploration behaviors in anxiety disorder rats. Pinocembrin alleviated electrophysiological remodeling in anxiety disorder rats, including shortening the action potential duration (APD), prolonging the effective refractory period (ERP), increasing the expression of Kv1.5, Kv4.2 and Kv4.3, decreasing the expression of Cav1.2, and ultimately reducing the AF susceptibility. These effects may be attributed to the amelioration of autonomic remodeling and structural remodeling by pinocembrin, as well as the inhibition of oxidative stress with upregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathway.Conclusion: Pinocembrin can reduce AF susceptibility in anxiety disorder rats induced by empty bottle stimulation, with the inhibition of autonomic remodeling, structural remodeling, and oxidative stress. Therefore, pinocembrin is a promising treatment for AF in patients with anxiety disorder.

BackgroundThe prevalence and associated factors of dysphagia in Parkinson's disease (PD) are different in studies conducted in different countries. The purpose of our systematic review and meta-analysis was to evaluate the prevalence of dysphagia in PD and to clarify its associated factors.MethodsTwo researchers systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang Database, SinoMed and VIP databases and manually searched references in the retrieved articles to identify potential research subjects. The last search was conducted on June 28, 2022. Finally, a total of 58 studies including 60 observations with 20,530 PD patients were included in our meta-analysis.ResultsThe meta-analysis estimated that the pooled prevalence rate of dysphagia in PD was 36.9% (95% CI: 30.7–43.6%) and instrumental examination showed a higher prevalence (57.3%, 95% CI: 44.3–69.1%). Oceania showed the highest prevalence of dysphagia in PD (56.3%) compared to Africa (39.5%), Asia (38.6%), Europe (36.1%) and America (28.9%). Dysphagia in PD was associated with older age, lower body mass index, longer disease duration, higher Hoehn and Yahr stage and levodopa equivalent daily dose, PIGD subtype, severe motor symptoms, drooling and higher levels of depression, and lower quality of life.ConclusionsIn conclusion, our meta-analysis showed that dysphagia occurs in more than one-third of PD patients and was associated with several demographic characteristics and PD-related characteristics, motor symptoms, non-motor symptoms, as well as decreased quality of life. It deserves early screening, diagnosis, and treatment in clinical practice to prevent serious complications from dysphagia.

Nanomedicines are considered one of the promising strategies for anticancer therapy; however, the low targeting efficiency of nanomedicines in vivo is a great obstacle to their clinical applications. Camouflaging nanomedicines with either platelet membrane (PM) or platelet would significantly prolong the retention time of nanomedicines in the bloodstream, enhance the targeting ability of nanomedicines to tumor cells, and reduce the off-target effect of nanomedicines in major organs during the anticancer treatment. In the current review, the advantages of using PM or platelet as smart carriers for delivering nanomedicines to inhibit tumor growth, metastasis, and recurrence were summarized. The opportunities and challenges of this camouflaging strategy for anticancer treatment were also discussed.

Sustaining proliferative signaling and enabling replicative immortality are two important hallmarks of cancer. The complex of cyclin-dependent kinase (CDK) and its cyclin plays a decisive role in the transformation of the cell cycle and is also critical in the initiation and progression of cancer. CRIF1, a multifunctional factor, plays a pivotal role in a series of cell biological progresses such as cell cycle, cell proliferation, and energy metabolism. CRIF1 is best known as a negative regulator of the cell cycle, on account of directly binding to Gadd45 family proteins or CDK2. In addition, CRIF1 acts as a regulator of several transcription factors such as Nur77 and STAT3 and partly determines the proliferation of cancer cells. Many studies showed that the expression of CRIF1 is significantly altered in cancers and potentially regarded as a tumor suppressor. This suggests that targeting CRIF1 would enhance the selectivity and sensitivity of cancer treatment. Moreover, CRIF1 might be an indispensable part of mitoribosome and is involved in the regulation of OXPHOS capacity. Further, CRIF1 is thought to be a novel target for the underlying mechanism of diseases with mitochondrial dysfunctions. In summary, this review would conclude the latest aspects of studies about CRIF1 in cancers and mitochondria-related diseases, shed new light on targeted therapy, and provide a more comprehensive holistic view.

Cancer is still a leading cause of death worldwide and liquid biopsy is a powerful tool that can be applied to different stages of cancer screening and treatment. However, as the second most abundant cell type in the bloodstream, platelets are isolated through well-established and fast methods in clinic but their value as a BioSource of cancer biomarkers is relatively recent. Many studies demonstrated the bidirectional interaction between cancer cells and platelets. Platelets transfer various proteins (e.g., growth factors, cytokine, chemokines) and RNAs (e.g., mRNA, lncRNA, miRNA, circRNA) into the tumor cells and microenvironment, leading the stimulation of tumor growth and metastasis. In turn, the platelet clinical characteristics (e.g., count and volume) and contents (e.g., RNA and protein) are altered by the interactions with cancer cells and this enables the early cancer detection using these features of platelets. In addition, platelet-derived microparticles also demonstrate the prediction power of being cancer biomarkers. In this review, we focus on the clinical applications of platelet detection using the platelet count, mean platelet volume, platelet RNA and protein profiles for human cancers and discuss the gap in bringing these implementations into the clinic.

ObjectiveTo investigate the instant impact of hemodialysis (HD) on the cerebral morphological measurements of patients with end-stage renal disease (ESRD).Materials and methodsTwenty-five patients undergoing maintenance HD and twenty-eight age-, sex-, and education-matched healthy control (HC) were included. The HD group and HC group had 3D high-resolution structural magnetic resonance imaging (MRI) scans twice and once, respectively. Both groups underwent neuropsychologic tests. The morphological measurements of structural MRI were measured using CAT12 and these measures were compared among three groups. The relationship between morphological measures and clinical parameters and neuropsychological tests were investigated through multiple regression analysis.ResultsCompared to the HC group, the cortical thickness before HD significantly decreased in the bilateral temporal lobe and significantly decreased in the left superior temporal gyrus after HD. The cortical thickness significantly increased in the bilateral temporal lobe, frontal lobe and occipital lobe after HD compared to before HD. The sulcus depth in the bilateral insula, frontal lobe, and parietal lobe after HD significantly increased compared to before HD. No significant differences in sulcus depth between HD and HC were detected. After HD, the cortical thickness of the right parsopercularis was positively correlated with the number connection test-A. Cortical thickness in multiple regions were positively correlated with blood flow velocity and cortical thickness in the left parahippocampal gyrus was negatively correlated with ultrafiltration volume. Patients showed better performance in the digit symbol test and line tracing test after HD compared to before HD, but there were no significant differences in the comparison of neuropsychologic tests between patients and HC.ConclusionThe instant morphological changes were captured during a single hemodialysis in HD patients. There was an association between these instant changes in the brain and clinical parameters and neuropsychologic tests. This work implied the instant impact of a single hemodialysis impact on the brain in HD patients.

Multi-objective combinatorial optimization problems (MOCOPs) are designed to identify solution sets that optimally balance multiple competing objectives. Addressing the challenges inherent in applying deep reinforcement learning (DRL) to solve MOCOPs, such as model non-convergence, lengthy training periods, and insufficient diversity of solutions, this study introduces a novel multi-objective combinatorial optimization algorithm based on DRL. The proposed algorithm employs a uniform weight decomposition method to simplify complex multi-objective scenarios into single-objective problems and uses asynchronous advantage actor–critic (A3C) instead of conventional REINFORCE methods for model training. This approach effectively reduces variance and prevents the entrapment in local optima. Furthermore, the algorithm incorporates an architecture based on graph transformer networks (GTNs), which extends to edge feature representations, thus accurately capturing the topological features of graph structures and the latent inter-node relationships. By integrating a weight vector layer at the encoding stage, the algorithm can flexibly manage issues involving arbitrary weights. Experimental evaluations on the bi-objective traveling salesman problem demonstrate that this algorithm significantly outperforms recent similar efforts in terms of training efficiency and solution diversity. [ABSTRACT FROM AUTHOR]

BackgroundDepression is often comorbid with cardiovascular diseases and contributes to the development and maintenance of atrial fibrillation (AF). Ample research demonstrated that pinocembrin had protective effects on the neuropsychiatric and cardiovascular systems via its pharmacological properties. However, whether pinocembrin protects from AF in depression models is not known. The present research investigated antiarrhythmic effects of pinocembrin and the underlying mechanisms in depressed rats.MethodsOne hundred and ten male Sprague Dawley rats were randomly divided into six groups: the CTL group (the normal rats administered saline), the CTP group (the normal rats administered pinocembrin), the MDD group (the depressed rats administered saline), the MDP group (the depressed rats administered pinocembrin), the MDA group (the depressed rats administered apocynin), and the MPA group (the depressed rats administered both pinocembrin and apocynin). Chronic unpredictable mild stress (CUMS) was performed for 28 days to establish the depression model. Pinocembrin was administered via gavage from Day 8 to Day 28, and apocynin was administered via intraperitoneal injection from Day 1 to Day 28. The effects were evaluated using behavioral measurements, in vitro electrophysiological studies, whole-cell patch-clamp recordings, biochemical detection, Western blot, and histological studies.ResultsPinocembrin treatment significantly attenuated the abnormality of heart rate variability (HRV), the prolongation of action potential duration (APD), the shortening of the effective refractory period (ERP), the reduction of transient outward potassium current (Ito), and the increase in L-type calcium current (ICa–L), which increase susceptibility to AF in a rat model of depression. Compared to the depressed rats, pinocembrin also increased the content of Kv4.2, Kv4.3, and atrial gap junction channel Cx40 and decreased the expression level of Cav1.2, which ameliorated oxidative stress and inhibited the ROS/p-p38MAPK pro-apoptotic pathway and the ROS/TGF-β1 pro-fibrotic pathway.ConclusionPinocembrin is a therapeutic strategy with great promise for the treatment of AF in depressed patients by reducing oxidative stress.

Abstract Introduction Graph metrics have been proposed as potential biomarkers for diagnosis in clinical work. However, before it can be applied in a clinical setting, their reproducibility should be evaluated. Methods This study systematically investigated the effect of two denoising pipelines and different whole‐brain network constructions on reproducibility of subject‐specific graph measures. We used the multi‐session fMRI dataset from the Brain Genomics Superstruct Project consisting of 69 healthy young adults. Results In binary networks, the test–retest variability for global measures was large at low density irrespective of the denoising strategy or the type of correlation. Weighted networks showed very low test–retest values (and thus a good reproducibility) for global graph measures irrespective of the strategy used. Comparing the test–retest values for different strategies, there were significant main effects of the type of correlation (Pearson correlation vs. partial correlation), the (partial) correlation value (absolute vs. positive vs. negative), and weight calculation (based on the raw (partial) correlation values vs. based on transformed Z‐values). There was also a significant interaction effect between type of correlation and weight calculation. Similarly as for the binary networks, there was no main effect of the denoising pipeline. Conclusion Our results demonstrated that normalized global graph measures based on a weighted network using the absolute (partial) correlation as weight were reproducible. The denoising pipeline and the granularity of the whole‐brain parcellation used to define the nodes were not critical for the reproducibility of normalized graph measures.

PurposeRepairing the irradiation-induced osteogenic differentiation injury of bone marrow mesenchymal stem cells (BM-MSCs) is beneficial to recovering haematopoiesis injury in radiotherapy; however, its mechanism is elusive. Our study aimed to help meet the needs of understanding the effects of radiotherapy on BM-MSC osteogenic potential.Methods and MaterialsBalb/c mice and the BM-MSCs were used to evaluate the irradiation-induced osteogenic differentiation injury in vivo. The cellular and molecular characterization were applied to determine the mechanism for recovery of irradiation-derived haematopoiesis injuries.ResultsWe report a functional role of IL-12 in acute irradiation hematopoietic injury recovery and intend to dissect the possible mechanisms through BM-MSC, other than the direct effect of IL-12 on hematopoietic stem and progenitor cells (HSPCs). Specifically, we show that early use of IL-12 enhanced the osteogenic differentiation of BM-MSCs through IL-12Rβ1/TYK2/STAT3 signaling; furthermore, IL-12 induced osteogenesis facilitated bone formation and irradiation hematopoiesis recovery when transplanted BM-MSCs in the femur of Balb/c mice. For the mechanism of action, we found that IL-12 receptor beta 1 (IL-12Rβ1) expression of irradiated BM-MSCs was upregulated rapidly, coincidentally consistent with early use of IL-12 induced osteogenic differentiation enhancement. IL-12Rβ1 and tyrosine kinase 2 gene (Tyk2) silencing experiments and phosphotyrosine of signal transducer and activator of transcription 3 (p-STAT3) suppression experiments indicated the IL-12Rβ1/TYK2/STAT3 signaling was essential in IL-12-induced osteogenic differentiation enhancement of BM-MSCs.ConclusionThese findings suggested that IL-12 may exert BM-MSCs-based hematopoietic recovery by repairing osteogenic differentiation abilities damages through IL-12Rβ1/TYK2/STAT3 signaling pathway post-irradiation.

Interface icons are often scaled to adapt to different displays in cross-device collaborations. However, adaptive scaling of icons may cause perceptual bias in how icon arrays are visually perceived, which reduces usability and coherent user experience. This article presents an empirical study that evaluates the perceptual bias in the consistency of icon spacing and size caused by adaptive scaling. Then the impact of various visual features of icons (i.e., the border shape, polarity, and composition) on the perceptual bias are investigated. In this study, we found that cross-device scaling of icons causes a perceptual bias in the consistency of icon spacing and size. The shape of the icon border has a significant difference in the perceived spacing of icons, and the bias of the round shape is smaller than that of the square shape. Moreover, changing the icon polarity can affect the perceptual bias of consistency in icon size. These findings are expected to propose scaling recommendations for improving the visual consistency of icon arrays across. [ABSTRACT FROM AUTHOR]

Abstract Background Bone marrow stromal cells (BMSCs) are extensively used in regeneration therapy and cytology experiments simulate how BMSCs respond to radiation. Due to the small number and the heterogeneity of primary isolated BMSCs, extensive in vitro expansion is usually required before application, which affects the cellular characteristics and gene expression of BMSCs. However, whether the radiation response of BMSCs changes during in vitro expansion is unclear. Methods In this study, BMSCs were passaged in vitro and irradiated at passage 6 (P6) and passage 10 (P10). Then, apoptosis, the cell cycle, senescence, the cytokine secretion and the gene expression profile were analysed for the P6, P10, and non-irradiated (control) BMSCs at different post-irradiation time points. Results The P6 BMSCs had a lower percentage of apoptotic cells than the P10 BMSCs at 24 and 48 h post-irradiation but not compared to that of the controls at 2 and 8 h post-irradiation. The P6 BMSCs had a lower percentage of cells in S phase and a higher percentage in G1 phase than the P10 BMSCs at 2 and 8 h post-irradiation. The radiation had similar effects on the senescent cell level and impaired immunomodulation capacity of the P6 and P10 BMSCs. Regardless of whether they were irradiated, the P6 and P10 BMSCs always expressed a distinctive set of genes. The upregulated genes were enriched in pathways including the cell cycle, DNA replication and oocyte meiosis. Then, a subset of conserved irradiation response genes across the BMSCs was identified, comprising 12 differentially upregulated genes and 5 differentially downregulated genes. These genes were especially associated with the p53 signaling pathway, DNA damage and DNA repair. Furthermore, validation experiments revealed that the mRNA and protein levels of these conserved genes were different between the P6 and P10 BMSCs after irradiation. Weighted gene co-expression network analysis supported these findings and further revealed the effects of cell passage on the irradiation response in BMSCs. Conclusion The results indicated that cell passage in vitro affected the irradiation response of BMSCs via molecular mechanisms that mediated differences in apoptosis, the cell cycle, senescence and the cytokine secretion. Thus, accurate cell passage information is not only important for transplantation therapy but also for future studies on the radiation response in BMSCs.

Imprecision is commonly encountered with respect to powers and predictive powers in clinical trials. In this article, we investigate the imprecision issues of four powers (Classical Power, Classical Conditional Power, Bayesian Power, and Bayesian Conditional Power) and eight predictive powers. To begin with, we derive the probabilities of Control Superior (CS), Treatment Superior (TS), and Equivocal (E) of the four powers and the eight predictive powers, and evaluate the limits of the probabilities at point 0. Moreover, we conduct extensive numerical experiments to exemplify the imprecision issues of the four powers and the eight predictive powers. In the numerical experiments, first, we compute the probabilities of CS, TS, and E for the four powers as functions of the sample size of the future data when the true treatment effect favors control, treatment, and equivocal, respectively. Second, we compute the probabilities of CS, TS, and E for the eight predictive powers as functions of the sample size of the future data under the sceptical prior and the optimistic prior, respectively. Finally, we carry out a real data example to show the prominence of the methods.

Background: Depression is associated with the increased risk of mortality and morbidity and is an independent risk factor for many cardiovascular diseases. Depression may promote cardiac arrhythmias, but little is known about the mechanisms. Pinocembrin mitigated depressive-like behaviors and exhibited cardioprotective effects in several models; however, whether pinocembrin benefits ventricular arrhythmias in depression models has not been elucidated. Thus, this study was to evaluate the effects of pinocembrin on ventricular fibrillation susceptibility in rat models of depression.Methods: Male Sprague-Dawley rats were randomly assigned into control, control + pinocembrin, MDD (major depressive disorder), and MDP (MDD + pinocembrin) groups, respectively. Depressive-like behaviors, ventricular electrophysiological parameters, electrocardiogram parameters, heart rate variability, ventricular histology, serum norepinephrine, tumor necrosis factor-α, and interleukin-1β were detected. Protein levels in left ventricle were measured by Western blot assays.Results: Compared with the MDD group, pinocembrin significantly mitigated depressive-like behaviors, prolonged ventricular effective refractory period, action potential duration, QT, and corrected QT (QTc) interval, improved heart rate variability, decreased Tpeak–Tend interval, ventricular fibrillation inducibility rate, ventricular fibrosis, ventricular positive nerve densities, and protein expression of tyrosine hydroxylase and growth associated protein-43, reduced serum norepinephrine, tumor necrosis factor-α, interleukin-1β concentrations, and the expression levels of p-IκBα and p-p65, and increased the protein expression of Cx43, Cav1.2, and Kv.4.2 in the MDP group.Conclusion: Pinocembrin attenuates ventricular electrical remodeling, autonomic remodeling, and ion-channel remodeling, lowers ventricular fibrosis, and suppresses depression-induced inflammatory responses, providing new insights in pinocembrin and ventricular arrhythmias in depressed patients.

Thrombocytopenia 2 (THC2) is a major type of inherited thrombocytopenia caused by the persistent ANKRD26 expression during the late stage of megakaryocytopoiesis. For the first time, we generated a human induced pluripotent stem cell (hiPSC) line SHAMUi001-A from the bone marrow hematopoietic progenitor cells of a THC2 patient, who has a heterozygous mutation (c.-128G>T) in the 5′-UTR of ANKRD26 gene. SHAMUi001-A cells retain the mutation, display pluripotent stem cell characteristics, and have a normal female karyotype. This disease-specific hiPSC line will be a useful model for THC2 research.

Thrombocytopenia 2 (THC2) is one of the most prevalent forms of inherited thrombocytopenia. It is caused by a heterogeneous group of ANKRD26 gene mutation and shows a heterogeneous clinical and laboratory characteristics. We present a big Chinese family with 10 THC2 patients carrying c.-128G > T heterozygous substitution in the 5-untranslated region of the ANKRD26 gene. Although the platelets are fewer than 50 × 109/L in 8 THC2 family members, only the proband and her son show a higher WHO bleeding score. The proband and her son are also beta-thalassemia carriers with heterozygous c.52A > T mutation of HBB, which might not be associated with the increased bleeding tendency since 3 other family members with low bleeding tendency also carried both ANKRD26 c.-128G > T and HBB c.52A > T mutations. However, the proband and her son also show hypofibrinogenaemia, which is likely the cause of their more severe clinical manifestation. HID1 c.442G > T mutation was detected not only in these two hypofibrinogenaemia family members but also in the other 8 family members with normal blood fibrinogen levels. Our study suggests that the co-occurrence of other inherited genetic conditions associated with blood coagulation might contribute to the heterogeneity of clinical and laboratory characteristics in THC2 patients. Considering the hematologic and myeloid malignancy predisposition of THC2 patients and a large population of immune thrombocytopenia in China, we urge more attention to be paid to the diagnosis of THC2 patients to avoid misdiagnosis and mistreatment.

Background: Many drugs for anti-tumour have been developed, nevertheless, seeking new anticancer drug is the focus of ongoing investigation. Withanolides have been reported to possess potent antiproliferative activity. Literature findings revealed that a diversity of withanolides were obtained from Physalis peruviana, however, the antitumor activity of these bioactive compounds is still unclear. Methods: The EtOAc fraction of P. peruviana were decolorized on Middle Chromatogram Isolated (MCI) Gel column, repeatedly subjected to column chromatography (CC) over sephadex LH-20, preparative High Performance Liquid Chromatography (HPLC) and silica gel to afford compounds. Their chemical structures of the new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All these obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7 by MTT assay, and in vitro antibacterial activity of the isolated compounds (1–7) were evaluated against E. coli, B. cereus and S. aureus. Results: Four new withanolides, including one withaphysalin-type withanolide (peruranolide A, 1), two 13,14-seco-withaphysalins (peruranolides B–C, 2–3), as well as one normal withanolide (peruranolide D, 4), were purified and separated from P. peruviana L.. Compound 5 was discovered to exhibit potent cytotoxic effect with an IC50 value of 3.51 μM. In vitro antibacterial activities, compounds 1–7 had no obvious inhibitory activity against E. coli, but had moderate inhibitory activities against B. cereus and S. aureus. Conclusions: Our findings might offer valuable clues for the utilization of withanolides as lead compounds for antineoplastic or antibacterial drug development.

Abstract Rhizoma coptidis has been used in China for thousands of years with the functions of heating dampness and purging fire detoxification. But the underlying molecular mechanisms of Rhizoma coptidis are still far from being fully elucidated. Alkaloids, especially berberine, coptisine and palmatine, are responsible for multiple pharmacological effects of Rhizoma coptidis. In this review, we studied on the effects and molecular mechanisms of Rhizoma coptidis on NF-κB/MAPK/PI3K–Akt/AMPK/ERS and oxidative stress pathways. Then we summarized the mechanisms of these alkaloid components of Rhizoma coptidis on cardiovascular and cerebrovascular diseases, diabetes and diabetic complications. Evidence presented in this review implicated that Rhizoma coptidis exerted beneficial effects on various diseases by regulation of NF-κB/MAPK/PI3K–Akt/AMPK/ERS and oxidative stress pathways, which support the clinical application of Rhizoma coptidis and offer references for future researches.