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Abstract Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

Abstract Working memory deficits are linked to irregularities in the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC) in schizophrenia, effective intervention strategies are lacking. We evaluated the differential efficacy and underlying neuromechanisms of targeting transcranial direct current stimulation (tDCS) at the DLPFC and the PPC with concurrent cognitive performance for working memory in schizophrenia. In a randomized and double-blind clinical trial, sixty clinically stable schizophrenic patients with below-average working memory were randomly assigned to active DLPFC, active PPC, and sham tDCS groups. Two sessions of tDCS during N-back task were delivered daily for five days. The primary outcome was changes in spatial span test scores from baseline to week 1. The secondary outcomes included changes in scores of color delay-estimation task, other cognitive tasks, and mismatch negativity (biomarker of N-methyl-d-aspartate receptor functioning). Compared with the active DLPFC group, the active PPC group demonstrated significantly greater improvement in spatial span test scores (p = 0.008, d = 0.94) and an augmentation in color delay-estimation task capacity at week 1; the latter sustained to week 2. Compared with the sham tDCS group, the active PPC group did not show a significant improvement in spatial span test scores at week 1 and 2; however, significant enhancement was observed in their color delay-estimation task capacity at week 2. Additionally, mismatch negativity amplitude was enhanced, and changes in theta band measures were positively correlated with working memory improvement in the active PPC group, while no such correlations were observed in the active DLPFC group or the sham tDCS group. Our results suggest that tDCS targeting the PPC relative to the DLPFC during concurrent cognitive performance may improve working memory in schizophrenia, meriting further investigation. The improvement in working memory appears to be linked to enhanced N-methyl-d-aspartate receptor functioning.

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and contributes to high morbidity and mortality. However, our current understanding of the development and progression of aGVHD after allo-HSCT remains limited. To identify the potential biomarkers for the prevention and treatment of aGVHD during the early hematopoietic reconstruction after transplantation, we meticulously performed a comparative analysis of single-cell RNA sequencing data from post-transplant patients with or without aGVHD. Prior to the onset of aGVHD, monocytes in the peripheral blood of patients with aGVHD experienced a dramatic rise and activation on day 21 post-transplantation. This phenomenon is closely aligned with clinical cohort results obtained from blood routine examinations. Furthermore, in vitro co-culture experiments showed that peripheral blood monocytes extracted from patients with aGVHD approximately 21 days post-transplantation induced a significantly higher proliferation rate of allogeneic T cells compared to those from patients without aGVHD. Our study indicates that monocytes could be a crucial early clinical risk factor for the development of aGVHD, and this insight could potentially guide the timing of monitoring efforts, recommending assessments at the pivotal juncture of approximately day 21 post-transplantation, shedding fresh light on the significance of early hematopoietic regeneration in relation to the onset of aGVHD.

The regulation of the immune system and the occurrence of inflammation are vital factors in the pathophysiology of ischemic stroke. This study aims to screen target molecules which play key roles in alleviating the brain injury following ischemic stroke via regulating neuroinflammation. Several bioinformatics methods were used to identify immune-related genes in ischemic stroke. A total of 218 genes were identified as differentially expressed genes within the GSE97537 dataset. By performing GO, KEGG, and GSEA analyses, DEGs were mainly enriched in pathways related to immunity and inflammation. By utilizing the MCODE plugin in conjunction with Cytoscape software, a total of six crucial genes were identified, including C1qb, C1qc, Fcer1g, Fcgr3a, Tyrobp, and CD14. Based on the above crucial genes, 13 miRNAs were predicted. Furthermore, 71 potential drugs with therapeutic properties that target the crucial genes were screened, including lovastatin, ASPIRIN, and PREDNISOLONE. Moreover, the results of RT-qPCR showed that compared with Sham group, the expressions of C1qb, C1qc, Fcer1g, Fcgr3a, Tyrobp, and CD14 in MCAO group were significantly increased, which was consistent with the expression trend of validation dataset and training dataset. In conclusion, immune-related genes may play a key role in ischemic stroke. In addition, six crucial genes were identified as potential biomarkers and 71 promising drugs were screened to treat ischemic stroke patients.

Summary: Bone marrow (BM) is the dominant site of hematopoiesis after 20 post-conception weeks (PCWs), but the intricacies of hematopoietic development in fetal BM up to birth and its involvement in malignancies remain unknown. Here, we compared the single-cell transcriptomic profile of BM hematopoietic stem and progenitor cells (HSPCs) at the early (12–14 PCW), middle (19–22 PCW) second trimester, and the neonatal stage. The stemness of hematopoietic stem cell and multipotent progenitor (HSC/MPP) is established at the middle second trimester, then maintained until birth. Furthermore, differentiation potentials toward three lineages are enhanced after the middle second trimester for birth, accompanied by the upregulation of aerobic metabolism. Notably, decreased stemness in HSCs/MPPs and higher interferon signals in progenitors at the early second trimester rendered the HSPCs more proximal to leukemogenesis. Collectively, our work elucidated the dynamics of fetal hematopoiesis in preparation for birth, offering valuable insights into the pathological processes underlying leukemia.

ObjectiveThis study aimed to identify plasma biomarkers that are significantly altered in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and are closely associated with AAV disease activity, as well as to explore their role in the pathogenesis of AAV.MethodsCytokines were measured using Human Immune Response Panel 80-Plex in plasma from 59 patients with AAV and 20 healthy controls (HCs). The differentially expressed cytokines between the two groups and the possible signaling pathway involved in the pathogenesis of AAV were analyzed by bioinformatics. Relationship analysis was performed between these cytokines and clinical parameters to identify the biomarkers that can effectively indicate disease activity.ResultsWe identified 65 differentially expressed cytokines between the two groups. Among them, 43 cytokines significantly affected the risk of AAV. Bioinformatic analysis showed that the 43 cytokines were primarily enriched in signaling pathways such as cytokine-cytokine receptor interaction, viral protein interaction with cytokine and cytokine receptor, chemokine signaling pathway, and IL-17 signaling pathway. The levels of 25 cytokines were significantly positively correlated with Birmingham Vasculitis Activity Score (BVAS), and the levels of 2 cytokines were significantly negatively correlated with BVAS. Receiver operating characteristic analysis showed that 9 cytokines can distinguish between disease relapse and remission (PTX3: area under curve (AUC)=0.932, IL34: AUC=0.856, IL2RA: AUC=0.833, CCL23: AUC=0.826, VEGFA: AUC=0.811, TNFSF13: AUC=0.795, Granzyme A: AUC=0.788, CSF3: AUC=0.773 and IL1A: AUC=0.765). The elevated levels of these 9 cytokines suggested a risk of disease relapse. The AUC of CCL11 in disease relapse and remission was 0.811 (p=0.0116). Unlike the other 9 cytokines, a negatively association existed between CCL11 level and the risk of disease relapse.ConclusionA group of cytokines that may be involved in AAV pathogenesis was identified. Increased PTX3, IL34, IL2RA, CCL23, and VEGFA levels correlate with active disease in AAV and may be used as biomarkers to identify the disease relapse of AAV.

Abstract Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.

To address the issues of low coordination in low-carbon operation between Carbon Capture and Storage (CCS) devices and Power to Gas (P2G) devices in integrated energy systems (IES), as well as the inaccurate characterization of carbon emissions from energy storage devices, this paper proposes an extended carbon emission flow model that integrates the collaborative operation mode of CCS-P2G and the low-carbon characteristics of energy storage. The model establishes a coupling relationship between CCS and P2G on the energy supply side to achieve low-carbon economic operation of P2G. On the energy storage side, the concept of “electricity-carbon ratio (ECR)” is introduced to characterize the carbon emission characteristics of energy storage devices, exploring the potential for coordinated low-carbon dispatch on both the energy supply and energy storage sides. Based on this, a low-carbon economic dispatch model for integrated energy systems is constructed, considering multiple uncertainties such as wind power, electricity prices, and electric-heat-gas loads. To achieve fast and efficient solving of the model, a parallel multi-dimensional approximate dynamic programming algorithm is adopted, which significantly improves solving efficiency by constructing a multi-layer parallel loop nested framework without losing solving accuracy. The effectiveness of the proposed model and algorithm is validated using an improved E14-H6-G6 system, consisting of a 14-node power grid, a 6-node heating network, and a 6-node gas network. The CCS-P2G (Carbon Capture, Storage, and Power-to-Gas) collaborative operation mode discussed in this article significantly enhances the economic and low-carbon performance of the Integrated Energy System (IES) by fully reutilizing CO2. Compared to unmodified coal-fired power units, the total cost is reduced by 137,900 yuan, thereby validating the effectiveness of the CCS-P2G collaborative operation mode in low-carbon scheduling.

ABSTRACTThis study aimed to provide data for the clinical features of invasive pneumococcal disease (IPD) and the molecular characteristics of Streptococcus pneumoniae isolates from paediatric patients in China. We conducted a multi-centre prospective study for IPD in 19 hospitals across China from January 2019 to December 2021. Data of demographic characteristics, risk factors for IPD, death, and disability was collected and analysed. Serotypes, antibiotic susceptibility, and multi-locus sequence typing (MLST) of pneumococcal isolates were also detected. A total of 478 IPD cases and 355 pneumococcal isolates were enrolled. Among the patients, 260 were male, and the median age was 35 months (interquartile range, 12–46 months). Septicaemia (37.7%), meningitis (32.4%), and pneumonia (27.8%) were common disease types, and 46 (9.6%) patients died from IPD. Thirty-four serotypes were detected, 19F (24.2%), 14 (17.7%), 23F (14.9%), 6B (10.4%) and 19A (9.6%) were common serotypes. Pneumococcal isolates were highly resistant to macrolides (98.3%), tetracycline (94.1%), and trimethoprim/sulfamethoxazole (70.7%). Non-sensitive rates of penicillin were 6.2% and 83.3% in non-meningitis and meningitis isolates. 19F-ST271, 19A-ST320 and 14-ST876 showed high resistance to antibiotics. This multi-centre study reports the clinical features of IPD and demonstrates serotype distribution and antibiotic resistance of pneumococcal isolates in Chinese children. There exists the potential to reduce IPD by improved uptake of pneumococcal vaccination, and continued surveillance is warranted.

The blunt snout bream, Megalobrama amblycephala, is a commercially significant freshwater fish species indigenous to China. In recent decades, fishery resources of blunt snout bream in the Yangtze River have been severely depleted owing to human activities, and limited information is available regarding their genetic characteristics. This study aimed to assess the genetic diversity and population structure of different native populations of blunt snout bream in the Yangtze River. We analyzed 222 samples from six natural populations in the middle reaches of the Yangtze River and its affiliated lakes were analyzed using ten microsatellite DNA markers and concatenated sequences of two mitochondrial DNA markers (Cytb and ND2). Microsatellite analysis showed that the average observed heterozygosity (Ho), expected heterozygosity (He), and polymorphic information content (PIC) for all populations were determined as 0.687, 0.739, and 0.748 respectively. Mitochondrial sequence analysis showed that the number of haplotypes (h), haplotype diversity (Hd) and nucleotide diversity (π) of the six populations were 29, 0.768, and 0.00641, respectively. The above findings reveal high genetic diversity within blunt snout bream populations, suggesting a robust potential for selective breeding. The phylogenetic relationship results showed that the six blunt snout bream populations clustered into two branches, indicating a measurable degree of differentiation among the populations in the middle reaches of the Yangtze River Basin and its affiliated lakes. The populations may represent distinct spawning grounds, and corresponding conservation units should be implemented to protect them. In summary, these findings provide vital genetic information for the conservation and commercialization of blunt snout bream in the Yangtze River Basin of China.

Hematopoietic stem cells (HSCs) have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage. However, recent studies have suggested that megakaryocyte progenitors (MkPs) are generated at the level of HSCs. In this study, we newly identified early megakaryocyte lineage-committed progenitors (MgPs) mainly in CD201−CD48− cells and CD48+ cells separated from the CD150+CD34−Kit+Sca-1+Lin− HSC population of the bone marrow in adult mice. Single-cell colony assay and single-cell transplantation showed that MgPs, unlike platelet-biased HSCs, had little repopulating potential in vivo, but formed larger megakaryocyte colonies in vitro (on average 8 megakaryocytes per colony) than did previously reported MkPs. Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway. Single-cell reverse transcription polymerase chain reaction (RT-PCR) analysis showed that MgPs expressed Mk-related genes, but were transcriptionally heterogenous. Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs. We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs, supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.

We report a case of well-differentiated papillary mesothelial tumor (WDPMT) diagnosed using internal thoracoscopic biopsy in a patient who has suffered from recurrent pleural effusions for over 35 years together with a history of elevated CA125. We hope to provide a case for the diagnosis of this rare benign and preinvasive pleural tumor and recommend that internal thoracoscopy may be a good choice in these recurrent pleural effusion patients especially for those minimal lesions not easily detected using CT scan.

ABSTRACT: Objectives: This study firstly identified an IncHI5 plasmid pK254-KPC_NDM co-carrying two different class carbapenemase genes blaKPC-2 and blaNDM-1 in Klebsiella michiganensis K254. Methods: The strain K254 was sequenced by high-throughput genome sequencing. A detailed genomic and phenotypic characterization of pK254-KPC_NDM was performed. Results: pK254-KPC_NDM displayed the conserve IncHI5 backbone and carried a resistant accessory region: Tn1696-related transposon Tn7414 containing blaKPC-2 and blaNDM-1. A sequence comparison was applied to a collection of four Tn1696-related transposons (Tn7414–Tn7417) harbouring carbapenemase genes. For all these four transposons, the blaNDM-1 was carried by Tn125 derivatives within three different mobile genetic elements. Tn7414 further acquired another carbapenemase gene, blaKPC-2, because of the integration of the local blaKPC-2 genetic environment from Tn6296, resulting in the high-level carbapenem resistance of K. michiganensis K254. The conjugal transfer and plasmid stability experiments confirmed that pK254-KPC_NDM could be transferred intercellularly and keep the stable vertical inheritance in different bacteria, which would contribute to the further dissemination of multiple carbapenemase genes and enhance the adaption and survival of K. michiganensis under complex and diverse antimicrobial selection pressures. Conclusion: This study was the first to report the K. michiganensis isolate coharbouring blaKPC-2 and blaNDM-1 in the Tn1696-related transposon in IncHI5 plasmid. The emergence of novel transposons simultaneously carrying multiple carbapenemase genes might contribute to the further dissemination of high-level carbapenem resistance in the isolates of the hospital settings and pose new challenges for the treatment of nosocomial infection.

Abstract Background This is a cross-sectional study comparing the degree of subjective quality of life (QOL) impairment and its predictive factors in first-episode schizophrenia (FES) and individuals at clinical high-risk (CHR) for psychosis. Methods Seventy-seven FES, 59 CHR, and 64 healthy controls (HC) were included. The QOL of all participants was assessed using the World Health Organization Quality of Life (WHOQOL)-Brief Form (BREF). Psychiatric symptoms of individuals with FES were assessed with the Positive and Negative Syndrome Scale (PANSS), five factors were further identified through factor analysis; for individuals with CHR and HC, the Scale of Prodromal Symptoms (SOPS) was used. Results The total and four sub-domain scores of the WHOQOL-BREF in the FES and CHR groups were lower than those of the HC group. The overall and psychological health scores in the CHR group were lowest. In the FES group, after applying Bonferroni’s correction, there is a negative correlation between the total QOL scores and anxiety/depressive symptom scores (r = –0.34, P = 0.003). The stepwise multiple regression analysis showed that the QOL of both FES and CHR group were negatively affected by anxiety/depressive symptoms and unemployment (P

Abstract Background Breast cancer (BC) is the most common malignant disease in female patients worldwide. In HER-2+ BC patients, trastuzumab therapy is associated with a better prognosis. However, many HER-2+ BC patients experience recurrence or metastasis because of trastuzumab resistance. The mechanisms underlying trastuzumab resistance remain unclear. Recently, substantial evidence has suggested that exosomes are associated with drug resistance, and lncRNAs have attracted increasing attention due to their potential role in the regulation of trastuzumab resistance. Methods We collected the exosomes from the plasma of BC patients with and without trastuzumab resistance, sequenced the whole transcriptomes, identified differentially expressed lncRNAs, and identified lncRNA Linc00969, which was overexpressed in trastuzumab-resistant patients. Then, we established trastuzumab-resistant BC cell lines and explored the role of exosomal Linc00969 in trastuzumab resistance in vitro and in vivo by silencing or overexpressing Linc00969 and performing a series of functional analyses. Furthermore, to explore the mechanism by which exosomal Linc00969 contributes to trastuzumab resistance, we measured changes in HER-2, HUR and autophagy-related protein expression levels after regulating Linc00969 expression. In addition, we investigated the interaction between Linc00969 and HUR via pull-down and RIP assays and the effect of HUR on HER-2 expression and trastuzumab resistance after blocking HUR. Results We first found that exosomal lncRNA Linc00969 was overexpressed in trastuzumab-resistant BC patients and that exosome-mediated Linc00969 transfer could disseminate trastuzumab resistance in BC. Then, we found that silencing Linc00969 could reduce trastuzumab resistance and that overexpressing Linc00969 could enhance trastuzumab resistance. Furthermore, our results showed that Linc00969 could upregulate HER-2 expression at the protein level and maintain the stability of HER-2 mRNA by binding to HUR. Additionally, we found that exosomal Linc00969 could regulate trastuzumab resistance by inducing autophagy. Conclusions In this study, we first identified that exosomal lncRNA Linc00969 could induce trastuzumab resistance by increasing HER-2 protein expression and mRNA stability by binding to HUR, and Linc00969 might also be involved in trastuzumab resistance by inducing autophagy. Our results elucidate a novel mechanism underlying trastuzumab resistance, and Linc00969 might be a new target for improving the treatment of HER-2+ BC patients.

The CoCrFeMnNi high-entropy alloy is commonly used for vascular stents due to its excellent mechanical support and ductility. However, as high-entropy alloy stents can cause inflammation in the blood vessels, leading to their re-narrowing, drug-eluting stents have been developed. These stents have nanopores on their surfaces that can carry drug particles to inhibit inflammation and effectively prevent re-narrowing of the blood vessels. To optimize the mechanical properties and drug-carrying capacity of high-entropy alloy stents, a high-entropy alloy system with different wide and deep square-shaped nanopore distributions is created using molecular dynamics. The mechanical characteristics and dislocation evolution mechanism of different nanopore high-entropy alloy systems under tensile stress were studied. The results showed that the CoCrFeMnNi high-entropy alloy with a rational nanopore distribution can effectively maintain the mechanical support required for a vascular stent. This research provides a new direction for the manufacturing process of nanopores on the surfaces of high-entropy alloy stents.

The vibrations in functionally graded porous Cu-Si microcantilever beams are investigated based on physical neutral plane theory, modified coupled stress theory, and scale distribution theory (MCST&SDT). Porous microcantilever beams define four pore distributions. Considering the physical neutral plane theory, the material properties of the beams are computed through four different power-law distributions. The material properties of microcantilever beams are corrected by scale effects based on modified coupled stress theory. Considering the fluid driving force, the amplitude-frequency response spectra and resonant frequencies of the porous microcantilever beam in three different fluids are obtained based on the Euler–Bernoulli beam theory. The quality factors of porous microcantilever beams in three different fluids are derived by estimating the equation. The computational analysis shows that the presence of pores in microcantilever beams leads to a decrease in Young’s modulus. Different pore distributions affect the material properties to different degrees. The gain effect of the scale effect is weakened, but the one-dimensional temperature field and amplitude-frequency response spectra show an increasing trend. The quality factor is decreased by porosity, and the degree of influence of porosity increases as the beam thickness increases. The gradient factor n has a greater effect on the resonant frequency. The effect of porosity on the resonant frequency is negatively correlated when the gradient factor is small (n<1) but positively correlated when the gradient factor is large (n>1).

Background: Understanding the epidemiology of Streptococcus pneumoniae (S. pneumoniae) isolates is important for pneumonia treatment and prevention. This research aimed to explore the epidemiological characteristics of S. pneumoniae isolated from pediatric inpatients and outpatients during the same period. Methods: S. pneumoniae were isolated from unsterile samples of inpatients and outpatients younger than five years old between March 2013 and February 2014. The serotypes were determined using diagnostic pneumococcal antisera. The resistance of each strain to 13 antibiotics was tested using either the E-test or the disc diffusion method. The Sequence Types (STs) were analyzed via Multilocus Sequence Typing (MLST). Results: The dominant serotypes obtained from inpatients were 19F (32.9 %), 19A (20.7 %), 23F (10.7 %), 6A (10.0 %), and 14 (8.6 %), while those from outpatients were 19F (13.6 %), 23F (12.9 %), 6A (10.0 %), 6B (10.0 %), and 19A (7.9 %). The coverage rates of 13-valent Pneumococcal Conjugate Vaccine (PCV) formulations were high in both groups. The nonsusceptibility to penicillin, cefuroxime, imipenem, erythromycin, and trimethoprim-sulfamethoxazole among the inpatient isolates was 7.1 %, 92.8 %, 65.7 %, 100 %, and 85.0 %, respectively, while that among the outpatient isolates was 0.7 %, 50.0 %, 38.6 %, 96.4 %, and 65.7 %, respectively. There were 45 and 81 STs detected from the pneumococci isolated from inpatients and outpatients, respectively. CC271 was common among both inpatients and outpatients (43.6 % and 14.3 %). Conclusions: Pneumococcal vaccine-related serotypes are prevalent among both inpatients and outpatients, especially among inpatients, who exhibit more severe antibiotic resistance. Therefore, universal immunization with PCV13 would decrease the hospitalization rate due to S. pneumoniae and the antibiotic resistance rate of S. pneumoniae.

Fermentation is a vital process occurred under the premise of rolling affecting black tea quality. Theoretically, re-rolling during fermentation will remodel the biochemical conditions of tea leaves, and thus influence black tea quality. Herein, we studied the effect of re-rolling on black tea taste and liquor color. Sensory evaluation showed that re-rolling significantly weakened the astringency taste and improved the redness and luminance of liquor. With re-rolling, the color attributes of a* and L* and the contents of theaflavins and thearubigins were significantly improved. Metabolomics analysis showed that the contents of 110 non-volatile compounds were significantly different among black teas with different rolling treatments. In summary, re-rolling accelerated the oxidation of polyphenols into pigments, the hydrolysis of proteins into amino acids, and the metabolism of alkaloids, organic acids, glycosidically-bound volatiles, and lipids during the fermentation period. Our study provided a novel and simple way to improve black tea quality.

Stroke is a prevalent cerebrovascular condition with a global impact, causing significant rates of illness and death. Despite extensive research, the available treatment options for stroke remain restricted. Hence, it is crucial to gain a deeper understanding of the molecular mechanisms associated with the onset and advancement of stroke in order to establish a theoretical foundation for novel preventive and therapeutic approaches. NF-κB, also known as nuclear factor κB, is a transcription factor responsible for controlling the expression of numerous genes and plays a crucial role in diverse physiological processes. NF-κB is triggered and regulates neuroinflammation and other processes after stroke, promoting the generation of cytokine storms and contributing to the advancement of ischemic stroke (IS). Therefore, NF-κB could potentially play a vital role in stroke by regulating diverse pathophysiological processes. This review provides an overview of the functions of NF-κB in stroke and its governing mechanisms. In addition, our attention is directed towards various potential therapies that aim to inhibit the NF-κB signaling pathway in order to offer valuable insights for the advancement of innovative treatment approaches for stroke.

BackgroundBoswellic acids (BAs) showed promising effects in cancer treatment, immune response regulation, and anti-inflammatory therapy. We aimed to assess the roles of alpha-BA (α-BA) in treating acute wound healing.MethodsIn vivo wound-healing models were established to evaluate the therapeutic effects of α-BA. Cell assays were conducted to assess the impact of α-BA on cellular biological functions. Western blot analysis was employed to validate the potential mechanisms of action of α-BA.ResultsAnimal models indicated that wound healing was notably accelerated in the α-BA group compared to the control group (P < 0.01). Hematoxylin and eosin (HE) staining and enzyme-linked immunosorbent assay (ELISA) assay preliminarily suggested that α-BA may accelerate wound healing by inhibiting excessive inflammatory reactions and increasing the protein levels of growth factors. Cell function experiments demonstrated that α-BA suppressed the proliferation and migration ability of human hypertrophic scar fibroblasts (HSFBs), thereby favoring wound healing. Additionally, α-BA exerted a significant impact on cell cycle progression. Mechanistically, the protein levels of key genes in nuclear factor kappa beta (NF-κB) signaling pathway, including cyclin D1, p65, IκBα, and p-IκBα, were downregulated by α-BA.Conclusionsα-BA demonstrated the ability to counteract the abnormal proliferation of skin scar tissues, consequently expediting wound healing. These findings suggest its potential for development as a new agent for treating acute wound healing.

This study was to explore whether transcutaneous electrical acupoint stimulation (TEAS) treatment could mediate inflammation, apoptosis, and pyroptosis of neuronal cells and microglia activation through the TLR4/MyD88/NF-κB pathway in the early stage of ischemic stroke. TEAS treatment at Baihui (GV20) and Hegu (LI4) acupoints of the affected limb was administered at 24, 48, and 72 h following middle cerebral artery occlusion/reperfusion (MCAO/R), with lasting for 30 min each time. Neurological impairment scores were assessed 2 h and 72 h after ischemia/reperfusion (I/R). TTC staining was used to evaluate the volume of brain infarction. The histopathologic changes of hippocampus were detected by H&E staining. WB analysis was performed to assess the levels of TLR4, MyD88, p-NF-κB p65/NF-κB p65, and inflammation, apoptosis, pyroptosis-related proteins. TLR4 expression was measured using immunohistochemistry. The expression of inflammation-related proteins was also measured using ELISA. Immunofluorescence was used to detect the expression level of Iba1. Our findings demonstrated that TEAS intervention after I/R improved neurological function, reduced the volume of brain infarction, and mitigated pathological damage. Moreover, TEAS reduced the levels of TLR4, MyD88, p-NF-κB p65/NF-κB p65, TNF-α, IL-6, Bax, NLRP3, cleaved caspase-1/pro caspase-1, IL-1β, IL-18, GSDMD, and Iba1 while enhancing Bcl-2 expression. Moreover, the protective effects of TEAS could be counteracted by lipopolysaccharide (LPS, a TLR4 agonist). In conclusion, TEAS can reduce cerebral damage and suppress inflammation, cell death, and microglia activation after ischemic stroke via inhibiting the TLR4/MyD88/NF-κB pathway.

Abstract Thrombocytopenia is a major and fatal complication in patients with acute myeloid leukemia (AML), which results from disrupted megakaryopoiesis by leukemic niche and blasts. Our previous research revealed that elevated interleukin-4 (IL-4) in AML bone marrow had adverse impact on multiple stages throughout megakaryopoiesis including hematopoietic stem cells (HSCs), but the specific mechanism remains unknown. In the present study, we performed single-cell transcriptome analysis and discovered activated oxidative stress pathway and apoptosis pathway in IL-4Rαhigh versus IL-4Rαlow HSCs. IL-4 stimulation in vitro led to apoptosis of HSCs and down-regulation of megakaryocyte-associated transcription factors. Functional assays displayed higher susceptibility of IL-4Rαhigh HSCs to tunicamycin and irradiation-induced apoptosis, demonstrating their vulnerability to endoplasmic reticulum (ER) stress injury. To clarify the downstream signaling of IL-4, we analyzed the transcriptomes of HSCs from AML bone marrow and found a remarkable down-regulation of the proteasome component Psmd13, whose expression was required for megakaryocytic-erythroid development but could be inhibited by IL-4 in vitro. We knocked down Psmd13 by shRNA in HSCs, and found their repopulating capacity and megakaryocytic differentiation were severely compromised, with increased apoptosis in vivo. In summary, our study uncovered a previous unrecognized regulatory role of IL-4-Psmd13 signaling in anti-stress and megakaryocytic differentiation capability of HSCs.

As the source of intense electron beam, the cathodes have an important effect on the performance of high power microwave source. Graphite is a common material for explosive emission cathodes of high power microwave source, which have the advantages of stable operation and long life under high pressure and repetition frequency. The carbon fiber with high aspect ratio and low emission threshold was chosen to be composited with the graphite cathode, and the field emission and high power microwave test platforms were adopted to analyse field emission properties, intense electron emission performances and output microwave characteristics of pure graphite cathodes and carbon fiber composited graphite cathodes. Meanwhile the effect of carbon fiber on the electron emission properties of graphite cathodes was studied combined with the microstructure characterization of the cathodes. The results show that compared with the flake graphite cathodes, the field emission threshold of 40%(mass fraction) carbon fiber composited graphite cathodes decreases from 143 kV/cm to 119 kV/cm, a reduction of about 16.8%, and the output pulse width and peak of 480 kV increase by 13.5% and 5.7%, respectively. Considering the structural stability of carbon-fiber in the process of explosive electron emission, the carbon-fiber is also beneficial for improving the service life of the cathodes.

In this work, the ethanol extracts of the branches and leaves of Peristrophe baphica (Spreng.) Bremk (PB) as well as the different solvent extracted part of the ethanol extracts were prepared and their antioxidant and antibacterial activities were studied. The contents of total polyphenols and flavonoids of the extracts were determined by Folin-Ciocalteu and NaNO2-Al(NO3)3 method, respectively. The antioxidant activities were evaluated by DPPH radical scavenging ability, ABTS+ radical scavenging ability and total reducing power. The relation between the antioxidant activities and the ethanol extracts as well as the different solvent extracted parts was correlated. The antimicrobial activities of the extracts against several common pathogenic bacteria were determined by Oxford cup method. The results showed that the content of total polyphenols in ethyl acetate part were the highest for both branches and leaves, which was 79.76 mg/g and 80.21 mg/g, respectively. The highest content of flavonoids located in chloroform part of branches and the ethanol extract of leaves, which was 95.88 mg/g and 96.75 mg/g, respectively. The correlation analysis showed that the antioxidant activities of each part were strongly correlated with the contents of total polyphenols. In the test concentration range, different parts of tissue and different solvents had important influence on the antioxidant and antimicrobial activities. The antioxidant activities of branches were better than those of leaves, but the antibacterial activities of leaves were better than those of branches. The ethyl acetate part of branches, the ethyl acetate part and the n-butanol part of leaves showed better antioxidant and antimicrobial activities and could be used for further application.

The emergence of biodegradable stents addresses the limitations of the long-term presence of permanent bare metal stents in the human body. Following implantation, these stents can significantly reduce the occurrence of chronic complications such as inflammation and thrombosis, thus becoming a mainstream approach in the treatment of interventional cardiovascular diseases. Currently, the materials used for biodegradable stents are typically polymers. However, the inherent properties of the materials dictate that polymer stents exhibit lower mechanical performance and biocompatibility. Magnesium alloy materials, on the basis of their biodegradability, exhibit superior mechanical performance when compared to polymers, possessing the potential to address this issue. However, the presence of stress concentration in the stent structure necessitates further designs and mechanical performance analyses of magnesium alloy stents. In this work, a biodegradable stent based on WE43 alloy is designed. The stent incorporates the micro-protrusion structure to enhance the mechanical performance. Furthermore, to evaluate the clinical applicability of the stent, the mechanical performance of the biodegradable magnesium alloy stent is conducted through finite element analysis (FEA). The results show that the maximum equivalent stress in all four aspects is below the ultimate tensile strength of 370 MPa for the WE43 magnesium alloy, demonstrating excellent mechanical performance. Additionally, after crimping and expansion, the radial support strength and radial support force reached 780 mN/mm and 1.56 N, respectively. Compared to the advanced reported stent structures, the radial support strength and radial support force are enhanced by 13% and 47%, respectively. Additionally, flexibility analysis indicated that the flexibility of the stent design in this study is improved by a factor of 9.76, ensuring the stent’s capability to navigate through complex vasculature during implantation.

In this paper, A high-order response surface method is proposed for finite element model updating of continuous beam bridges. Firstly, based on visual inspection and environmental vibration testing, the peak picking (PP) method and random subspace identification (SSI) method are used to identify the dynamic characteristic parameters of the structure. Then, the finite element model of the continuous beam bridge is updated based on the third-order response surface method. It can be concluded that the results of the updated finite element model are in good agreement with the test results, and the maximum error between the calculated and measured frequency is less than 3%, with MAC values greater than 85%. Moreover, the updated finite element model can reflect the current situation of real bridges and serve as the basis for bridge health monitoring, damage detection, and safety assessment.

Abstract The SARS-CoV-2 Omicron variant evades most currently approved neutralizing antibodies (nAbs) and caused drastic decrease of plasma neutralizing activity elicited by vaccination or prior infection, urging the need for the development of pan-variant antivirals. Breakthrough infection induces a hybrid immunological response with potentially broad, potent and durable protection against variants, therefore, convalescent plasma from breakthrough infection may provide a broadened repertoire for identifying elite nAbs. We performed single-cell RNA sequencing (scRNA-seq) and BCR sequencing (scBCR-seq) of B cells from BA.1 breakthrough-infected patients who received 2 or 3 previous doses of inactivated vaccine. Elite nAbs, mainly derived from the IGHV2–5 and IGHV3-66/53 germlines, showed potent neutralizing activity across Wuhan-Hu-1, Delta, Omicron sublineages BA.1 and BA.2 at picomolar NT50 values. Cryo-EM analysis revealed diverse modes of spike recognition and guides the design of cocktail therapy. A single injection of paired antibodies cocktail provided potent protection in the K18-hACE2 transgenic female mouse model of SARS-CoV-2 infection.

The Internet of Vehicles (IoV) has witnessed a substantial surge in its expansion during recent years, with the integration of edge servers emerging as an increasingly prevalent practice to cater to content requests that demand a superior quality of service. Nonetheless, conventional cache policies often prove inadequate for IoV applications, primarily due to their incapacity to effectively handle a diverse array of content requests, the high-speed mobility of vehicles, and the inherent instability of network connections. Within the scope of this study, we commence by bifurcating various content requests into two distinct categories: latency-sensitive content request and bandwidth-sensitive content request. Subsequently, we establish a model to evaluate the service quality under the joint consideration of different types of content requests, the mobility of vehicles and storage capacity of edge nodes. Furthermore, we transform the quality-of-service (QoS) penalty function into a system reward function. This adaption enables us to propose an innovative edge cache scheme founded upon the Deep Deterministic Policy Gradient (DDPG) algorithm of Reinforcement Learning (RL) method, which empowers dynamic adjustments in response to the evolving IoV environment. To validate the effectiveness of our proposed approach, we harness the Simulation of Urban Mobility (SUMO) traffic simulation software and construct a traffic road scenario based on a specific part segment of Nanjing Beltway. A wide-ranging set of contrast experiments was performed to ensure the improved performance of the DDPG based deep reinforcement learning method. Simulation experimental results show that the proposed algorithm converges quickly and outperforms existing algorithms in terms of service quality-hit ratio for latency-sensitive content and transmission speed for bandwidth-sensitive content.

Background: Since depression, sex hormones, and fatty acid status are interrelated, it is important to understand their relationships. In this study, we aimed to investigate sex differences in erythrocyte membrane fatty acid composition among first-diagnosed, drug-naïve patients with major depressive disorders.Methods: The study included 139 individuals with first-diagnosed, drug-naïve depression (male/female = 48/91) and 55 healthy controls (male/female = 24/31). The levels of erythrocyte membrane fatty acids were analyzed to compare the difference between males and females in both patients with depression and healthy controls, as well as to study their correlation with depressive symptoms.Results: In first-diagnosed, drug-naïve patients with major depressive disorders, sex disparities were observed in the levels of erythrocyte saturated fatty acids (SFAs) and n-6 PUFAs (such as C18:0, C20:4n6 and C22:4n6), where higher levels evident in females compared to in males. We found a noteworthy correlation between fatty acid levels and depressive symptoms, in which there is a significant association between female patients and depression but a weaker association between male patients and depression.Conclusion: Our findings demonstrate higher levels of n-6 PUFAs and SFAs in female patients with depression. The relationship between fatty acid composition and depressive symptoms was more prominent in females than males. These findings highlight the significance of considering sex as a crucial and interconnected factor in future investigations and potential adjunctive treatment for mood disorders by targeting fatty acid metabolism.

BackgroundCognitive deficits are core characteristics of schizophrenia, presenting before the emergence of psychotic symptoms. Individuals with a clinical high-risk for psychosis (CHR) and those with genetically high-risk of psychosis (GHR) also exhibit cognitive impairments. Nonetheless, it remains uncertain in which domains of cognitive impairments in these two groups were more similar to those of schizophrenia patients. Moreover, it is unclear which domains of impairment are caused by quality factors and which are more related to the state of disease. This research initiative aimed to extensively examine the distinct cognitive impairment profiles among the CHR, GHR, and first-episode schizophrenia (FES) cohorts.MethodsWe compared the cognitive functions of the three groups and a healthy control group (HCs) using the MATRICS Consensus Cognitive Battery (MCCB). The participants for this study were recruited from the Beijing Anding Hospital of Capital Medical University. Our sample consisted of 56 patients with FES, 42 with CHR, 26 with GHR, and 62 HCs. The participants across all groups were matched in terms of gender, age, and level of education.ResultsIndividuals with FES, GHR, and CHR showed significant impairment across the majority of MCCB domains, with the exception of visual learning, in comparison to HCs. None of the MCCB domains demonstrated a discerning ability to accurately differentiate between individuals with CHR and those with GHR. In the speed of processing and attention/vigilance domains, individuals with GHR and CHR exhibited scores between those of FES and HCs, with all group differences reaching statistical significance. This pattern of results indicates an intermediate level of cognitive function in individuals with GHR and CHR. Conversely, the levels of impairment observed in working memory and verbal learning were relatively consistent across all three groups: FES, CHR, and GHR. Notably, individuals in the CHR group exhibited performance akin to that of the HCs in the reasoning/problem-solving domain, while showing significant differences from the FES group, with the CHR individuals demonstrating better performance. Additionally, individuals with GHR displayed performance in social cognition similar to that of the HCs, while also demonstrating significant distinctions from the FES group, with the GHR individuals demonstrating better performance.ConclusionSignificant cognitive deficits exist in individuals with CHR, GHR, and FES, and these deficits vary across domains. Processing speed and attention/vigilance could potentially serve as robust biomarkers for identifying individuals at a risk of psychosis. The impairment observed in reasoning/problem-solving abilities might signify a qualitative trait, whereas deficits in social recognition could indicate a state characteristic specific to schizophrenia.

Summary: Hematopoietic stem cell (HSC) surface markers improve the understanding of cell identity and function. Here, we report that human HSCs can be distinguished by their expression of the CEA Cell Adhesion Molecule 5 (CEACAM5, CD66e), which serves as a marker and a regulator of HSC function. CD66e+ cells exhibited a 5.5-fold enrichment for functional long term HSCs compared to CD66e− cells. CD66e+CD34+CD90+CD45RA− cells displayed robust multi-lineage repopulation and serial reconstitution ability in immunodeficient mice compared to CD66e−CD34+CD90+CD45RA−cells. CD66e expression also identified almost all repopulating HSCs within the CD34+CD90+CD45RA− population. Together, these results indicated that CEACAM5 is a marker that enriches functional human hematopoietic stem cells capable of long-term multi-lineage engraftment.

ABSTRACT Public health threats posed by emerging respiratory infections are a significant concern, particularly in children and infants. Traditional culture-based detection methods are time-consuming and typically require 1–3 days. Herein, we developed and evaluated a 23-plex common respiratory pathogen mass spectrometry assay that enables the simultaneous detection of 18 common respiratory pathogens in children. This assay combines matrix-assisted laser desorption/ionization time of flight mass spectrometry with multiplex reverse transcription-PCR and targets 11 bacterial and 7 viral pathogens (including 10 subtypes), and two internal controls. The detection limit of the common respiratory pathogen mass spectrometry assay was as low as 1 copy/µL, with no cross-reactivity with other organisms. We assessed the clinical performance of the common respiratory pathogen mass spectrometry assay using respiratory samples from 450 children. The total 450 clinical specimens underwent analysis via matrix-assisted laser desorption/ionization time of flight mass spectrometry, and the outcomes were juxtaposed with those derived from real-time reverse-transcriptase PCR conducted concurrently. The concordance between these methods was 96.0%, and the multiple infection identification rate was 7.1%. This innovative approach enables the simultaneous analysis of numerous outcomes from a solitary examination across 192 specimens within a timeframe of approximately 7 hours, with a dramatically reduced sample use and cost. In summary, the common respiratory pathogen mass spectrometry assay is a sensitive, accurate, and cost-effective method for detecting common respiratory pathogens in children and has the potential to revolutionize the diagnosis of respiratory tract infections. IMPORTANCE This study aimed to present and evaluate a novel co-detection method that enables the simultaneous identification of 11 bacterial and 7 viral pathogens in about 7 hours using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Our approach utilizes a combination of multiplex reverse transcription-PCR and matrix-assisted laser desorption/ionization time of flight mass spectrometry, which overcomes the limitations of conventional assays, which include a long assessment time, technical difficulty, and high costs. As a screening method for common respiratory pathogens in children, common respiratory pathogen mass spectrometry assay has the potential to revolutionize the diagnosis of respiratory tract infections by providing an accurate etiological diagnosis. The common respiratory pathogen mass spectrometry assay is expected to be a critical tool for the diagnosis of respiratory infections in children, offering a more efficient, cost-effective, and accurate approach for the detection of common respiratory pathogens.

Introduction: Amisulpride is primarily eliminated via the kidneys. Given the clear influence of renal clearance on plasma concentration, we aimed to explicitly examine the impact of renal function on amisulpride pharmacokinetics (PK) via population PK modelling and Monte Carlo simulations.Method: Plasma concentrations from 921 patients (776 in development and 145 in validation) were utilized.Results: Amisulpride PK could be described by a one-compartment model with linear elimination where estimated glomerular filtration rate, eGFR, had a significant influence on clearance. All PK parameters (estimate, RSE%) were precisely estimated: apparent volume of distribution (645 L, 18%), apparent clearance (60.5 L/h, 2%), absorption rate constant (0.106 h−1, 12%) and coefficient of renal function on clearance (0.817, 10%). No other significant covariate was found. The predictive performance of the model was externally validated. Covariate analysis showed an inverse relationship between eGFR and exposure, where subjects with eGFR= 30 mL/min/1.73 m2 had more than 2-fold increase in AUC, trough and peak concentration. Simulation results further illustrated that, given a dose of 800 mg, plasma concentrations of all patients with renal impairment would exceed 640 ng/mL.Discussion: Our work demonstrated the importance of renal function in amisulpride dose adjustment and provided a quantitative framework to guide individualized dosing for Chinese patients with schizophrenia.

Abstract Long noncoding RNAs (lncRNAs) play crucial regulatory roles in the progression of various cancers. However, the functional roles of lncRNAs in breast cancer remain unclear. In this study, we investigated the functional role of a novel long noncoding RNA SEMA3B-AS1 (lncRNA SEAS1) in breast cancer progression and the underlying mechanisms. SEAS1 was downregulated in the triple-negative breast cancer (TNBC) tissues compared with the para-carcinoma tissues, which was associated with poor prognosis of TNBC patients. We demonstrated that SEAS1 knockdown significantly increased the proliferation, migration, and invasion of TNBC cell lines, whereas SEAS1 overexpression reversed these effects. Bioinformatics analysis demonstrated that microRNA (miR)-3940-3p was a potential target of SEAS1. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter assays confirmed that lncRNA SEMA3B-AS1 acted as sponge for miR-3940-3p, preventing the degradation of its target gene KLLN, which acts as a tumor-inhibiter in TNBC. Moreover, RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays confirmed that SMAD3 directly interacted with the promoter of SEAS1 and suppressed its transcription, thereby promoting TNBC progression. The clinical samples of TNBC confirmed SEAS1 was correlated inversely with lymphatic and distant metastasis. In conclusion, our findings reveal a novel pathway for TNBC progression via SMAD3/lncRNA SEAS1/miR-3940-3p/KLLN axis, and suggest that SEAS1 may serve as a potential biomarker and therapeutic target for TNBC.

ABSTRACT Importance Bacteremia tuberculosis (TB) is a severe form of extrapulmonary TB. Studies assessing bacteremia TB in children are limited, especially for HIV‐negative children. Objective To explore the detailed clinical features of the bacteremia TB in children under 18 years of age. Methods We reviewed the clinical records of the patients retrospectively and collected the strains isolated from their blood cultures. We used mycobacterial interspersed repetitive‐unit‐variable‐number tandem‐repeat (MIRU‐VNTR) to characterize the bacterial genotypes and alamarBlue to determine their drug susceptibility profiles. Polymerase chain reactions and DNA sequencing were used to identify drug‐resistant mutations. Results There were 13 pediatric bacteremia TB patients, 10 of whom were diagnosed with Bacillus Calmette–Guérin (BCG) bacteremia TB. Thirteen patients aged from 0.30 to 11.58 years were enrolled, of whom 76.92% were boys. All had fevers before hospitalization, and 76.92% had respiratory symptoms. All had received BCG vaccinations, and 46.15% had adverse post‐vaccination reactions. Compared with Mycobacterium tuberculosis, BCG bacteremia was more likely to appear in younger children. Patients with BCG bacteremia had primary immunodeficiency diseases, and lower CD4, IgA, and IgE levels. Interpretation Bacteremia TB was rapidly fatal in a large proportion of the immunodeficient children. Because classic findings may not be diagnostically specific, a high level of clinical suspicion is required, especially for patients with certain types of immunosuppression. Studies are needed to develop rapid diagnostic tests and to determine the value of empirical therapy in childhood bacteremia TB.

IntroductionApricot fruits are edible and serve as a source of medicinal compounds. Flavonols are important plant secondary metabolites that have antioxidant and antitumor effects and may promote cardiovascular health. MethodsThe flavonoid content in three stages of the ‘Kuijin’ and the ‘Katy’ was observed, followed by the combination of metabolome and transcriptome analysis to explore the metabolic basis of flavonol synthesis.ResultsThe differences in the metabolite contents between stages (of the same cultivar) and between cultivars (at the same stage) revealed decreases in the flavonoid content as fruits developed (i.e., from 0.28 mg/g to 0.12 mg/g in ‘Kuijin’ and from 0.23 mg/g to 0.05 mg/g in ‘Katy’). To decipher the regulation of flavonol synthesis in apricot (Prunus armeniaca L.), the metabolomes and transcriptomes of fruit pulp at three developmental stages of ‘Kuijin’ and the ‘Katy’ were analyzed. A total of 572 metabolites were detected in ‘Kuijin’ and the ‘Katy’ pulp, including 111 flavonoids. The higher flavonol content young ‘Kuijin’ fruits at 42 days after full bloom is mainly due to 10 types of flavonols. Three pairs of significant differences in flavonol content were identified. From these three comparison groups, three structural genes were strongly correlated with the levels of 10 types of flavonols (Pearson correlation coefficients > 0.8, p value < 0.05), including PARG09190, PARG15135, and PARG17939. The weighted gene co-expression network analysis showed that the turquoise module genes were highly correlated with flavonol contents (P < 0.01). There were 4897 genes in this module. Out of 4897 genes, 28 transcription factors are associated with 3 structural genes based on weight value. Two of the transcription factors are not only associated with PARG09190 but also with PARG15135, indicating their critical importance in the flavonols biosynthesis. The two TFs are PARG27864 and PARG10875.DiscussionThese findings provide new insights into the biosynthesis of flavonols and may explain the significant differences in flavonoid content between the ‘Kuijin’ and the ‘Katy’ cultivars. Moreover, it will aid in genetic improvement to enhance the nutritional and health value of apricots.

IntroductionInternet addiction (IA) is becoming a significant public health issue that requires urgent attention, especially for adolescents. Previous studies mainly focused on the risk factors of Internet addiction and drawn some conclusions. The purpose of this study is to investigate the Internet addiction status and concurrent psychological problems in adolescent groups, and explore the differences in the relationship between IA and psychological problems in adolescents from gender and grade.MethodsA cross-sectional study was conducted among students of junior and senior high school in 21 prefecture-level cities of Guangdong Province. The Young Diagnostic Questionnaire (YDQ) and the validated Chinese version of the Depression Anxiety Stress Scale-21 (DASS-21) were used to assess participants’ Internet addiction and psychological status. Two-way ANOVA was used to verify the interaction between gender and Internet addiction, grade and Internet addiction on psychological problems. When the interaction was statistically significant, simple effect analysis was further carried out.ResultsThe prevalence of problematic Internet use (PIU), depression, anxiety, and stress symptoms among adolescents were 16.32%, 30.16%, 35.97% and 18.80% respectively. Although the prevalence of PIU among boys (17.89%) was higher than that of girls (14.86%), girls in PIU group had the highest scores of depression, anxiety and stress. Similarly, the interaction between grade and Internet addiction was also significant (p

BackgroundSensory gating deficits are a common feature of schizophrenia and may be indicative of higher-order psychopathological impairments. It has been proposed that incorporating subjective attention components into prepulse inhibition (PPI) measures may improve the accuracy of assessing these deficits. This study aimed to investigate the relationship between modified PPI and cognitive function, with a specific focus on subjective attention, to gain a better understanding of the underlying mechanisms of sensory processing deficits in schizophrenia.MethodsFifty-four unmedicated first-episode schizophrenia (UMFE) patients and 53 healthy controls participated in this study. The modified Prepulse Inhibition paradigm, including Perceived Spatial Separation PPI (PSSPPI) and Perceived Spatial Colocation PPI (PSCPPI), was used to evaluate sensorimotor gating deficits. Cognitive function was assessed in all participants using the Chinese version of the MATRICS Consensus Cognitive Suite Test (MCCB).ResultsUMFE patients had lower MCCB scores and deficient PSSPPI scores than healthy controls. PSSPPI was negatively correlated with total PANSS scores and positively correlated with the speed of processing, attention/ vigilance, and social cognition. Multiple linear regression analysis showed that the PSSPPI at 60 ms had a significant effect on attentional/ vigilance and social cognition, even after controlling for gender, age, years of education, and smoking.ConclusionThe study revealed notable impairments in sensory gating and cognitive function in UMFE patients, best reflected by the PSSPPI measure. Specifically, PSSPPI at 60 ms was significantly associated with both clinical symptoms and cognitive performance, suggesting that PSSPPI at 60 ms may capture psychopathological symptoms related to psychosis.

Abstrac Objectives This study aimed to preliminarily and exploratorily examine the associations between childhood trauma (CT), its subtypes, and personality traits among unaffected first-degree relatives (FDR, children, or siblings) of patients with major depressive disorder (MDD). Methods The study sample included three subgroups: MDD patients (N = 85), Patients’ FDRs (N = 35), and healthy control individuals (HC, N = 89). The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma and the Eysenck Personality Questionnaire was used to assess personality traits. Results Significant differences were found in a few personality traits (p

Abstract Myelodysplastic syndromes (MDS) are generally considered as a group of clonal diseases derived from hematopoietic stem cells, but a number of studies have suggested that they are derived from myeloid progenitor cells. We aimed to identify the cell of origin in MDS by single-cell analyses. Targeted single-cell RNA sequencing, covering six frequently mutated genes (U2AF1, SF3B1, TET2, ASXL1, TP53, and DNMT3A) in MDS, was developed and performed on individual cells isolated from the CD34+ and six lineage populations in the bone marrow of healthy donors (HDs) and patients with MDS. The detected mutations were used as clonal markers to define clones. By dissecting the distribution of clones in six lineages, the clonal origin was determined. We identified three mutations both in HDs and patients with MDS, termed clonal hematopoiesis (CH) mutations. We also identified fifteen mutations only detected in patients with MDS, termed MDS mutations. Clonal analysis showed that CH clones marked by CH mutations and MDS clones marked by MDS mutations were derived from hematopoietic stem cells as well as various hematopoietic progenitor cells. Most patients with MDS showed the chimeric state with CH clones and MDS clones. Clone size analysis suggested that CH mutations may not contribute to clonal expansion of MDS. In conclusion, MDS comprise multiple clones derived from hematopoietic stem and progenitor cells.

Abstract Androgen receptor (AR) signaling drives prostate cancer (PC) progression. Androgen deprivation therapy (ADT) is temporally effective, whereas drug resistance inevitably develops. Abnormal expression of AR/ARV7 (the most common AR splicing variant) is critical for endocrine resistance, while the detailed mechanism is still elusive. In this study, bioinformatics and immunohistochemical analyses demonstrate that RNF8 is high expressed in PC and castration-resistant PC (CRPC) samples and the expression of RNF8 is positively correlated with the Gleason score. The high expression of RNF8 in PCs predicts a poor prognosis. These results provide a potential function of RNF8 in PC progression. Furthermore, the mRNA expression of RNF8 is positively correlated with that of AR in PC. Mechanistically, we find that RNF8 upregulates c-Myc-induced AR transcription via altering histone modifications at the c-Myc binding site within the AR gene. RNF8 also acts as a co-activator of AR, promoting the recruitment of AR/ARV7 to the KLK3 (PSA) promoter, where RNF8 modulates histone modifications. These functions of RNF8 are dependent on its E3 ligase activity. RNF8 knockdown further reduces AR transactivation and PSA expression in CRPC cells with enzalutamide treatment. RNF8 depletion restrains cell proliferation and alleviates enzalutamide resistance in CRPC cells. Our findings indicate that RNF8 may be a potential therapeutic target for endocrine resistance in PC.

Abstract Ethylene-mediated leaf senescence and the compromise of photosynthesis are closely associated but the underlying molecular mechanism is a mystery. Here we reported that apple DEHYDRATASE-ENOLASE-PHOSPHATASE-COMPLEX1 (MdDEP1), initially characterized to its enzymatic function in the recycling of the ethylene precursor SAM, plays a role in the regulation of photosystem I (PSI) activity, activating reactive oxygen species (ROS) homeostasis, and negatively regulating the leaf senescence. A series of Y2H, Pull-down, CO-IP and Cell-free degradation biochemical assays showed that MdDEP1 directly interacts with and dephosphorylates the nucleus-encoded thylakoid protein MdY3IP1, leading to the destabilization of MdY3IP1, reduction of the PSI activity, and the overproduction of ROS in plant cells. These findings elucidate a novel mechanism that the two pathways intersect at MdDEP1 due to its moonlighting role in destabilizing MdY3IP1, and synchronize ethylene-mediated leaf senescence and the compromise of photosynthesis.

Abstract Objectives Lifestyles, accounting for 53% in determining death, play a vital role in improving the health of older adults. Thus, this study aimed to explore the influencing factors of the health-promoting-lifestyles and interaction mechanisms among older adults. Methods A total of 8526 elders were selected by a three-stage stratified random cluster sampling method. Socioeconomic status, family relationships, social support, health-related quality of life (QOL), and health-promoting-lifestyles (HPLP) of older adults were assessed with the Social Support Rating Scale, the short form 36 health survey (SF-36) and Health-Promoting Lifestyle Profile. A structural equation model (SEM) was conducted to test the direct and indirect association between influencing factors with HPLP. Results In this study, there were 4901 older adults who were empty nesters, and 3625 were non-empty nesters. Of all respondents, the average QOL score of older adults was 62.28 ± 16.51, average social support score was 78.06 ± 7.50. The HPLP score of older adults was 105.9 ± 19.6, and the average score of subscales was 2.5 ± 0.5, which was at the medium level. Social support had a positive and direct effect on HPLP of older adults (total effect, 0.34). Meanwhile, social support mediated the relationship between socioeconomic (total effect, 0.17), QOL (total effect, 0.33) and HPLP. Family relationships had a small indirect effect on HPLP via social support (0.01). Conclusions Social support is the strongest influencing factor in the health-promoting-lifestyles among older adults, followed by socioeconomic, health-related quality of life and family support. Thus, maintaining higher social support was important to improve the HPLP of older adults.

Abstract Background To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing. Methods Paediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed. Results Overall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count

BackgroundChildren with benign childhood epilepsy with centro-temporal spikes (BECT) have spikes, sharps, and composite waves on their electroencephalogram (EEG). It is necessary to detect spikes to diagnose BECT clinically. The template matching method can identify spikes effectively. However, due to the individual specificity, finding representative templates to detect spikes in actual applications is often challenging.PurposeThis paper proposes a spike detection method using functional brain networks based on phase locking value (FBN-PLV) and deep learning.MethodsTo obtain high detection effect, this method uses a specific template matching method and the ‘peak-to-peak' phenomenon of montages to obtain a set of candidate spikes. With the set of candidate spikes, functional brain networks (FBN) are constructed based on phase locking value (PLV) to extract the features of the network structure during spike discharge with phase synchronization. Finally, the time domain features of the candidate spikes and the structural features of the FBN-PLV are input into the artificial neural network (ANN) to identify the spikes.ResultsBased on FBN-PLV and ANN, the EEG data sets of four BECT cases from the Children's Hospital, Zhejiang University School of Medicine are tested with the AC of 97.6%, SE of 98.3%, and SP 96.8%.

Background. As a noninvasive treatment, transcutaneous electrical nerve stimulation (TENS) has been utilized to treat various diseases in clinic. However, whether TENS can be an effective intervention in the acute stage of ischemic stroke still remains unclear. In the present study, we aimed to explore whether TENS could alleviate brain infarct volume, reduce oxidative stress and neuronal pyroptosis, and activate mitophagy following ischemic stroke. Methods. TENS was performed at 24 h after middle cerebral artery occlusion/reperfusion (MCAO/R) in rats for 3 consecutive days. Neurological scores, the volume of infarction, and the activity of SOD, MDA, GSH, and GSH-px were measured. Moreover, western blot was performed to detect the related protein expression, including Bcl-2, Bax, TXNIP, GSDMD, caspase-1, NLRP3, BRCC3, HIF-1α, BNIP3, LC3, and P62. Real-time PCR was performed to detect NLRP3 expression. Immunofluorescence was performed to detect the levels of LC3. Results. There was no significant difference of neurological deficit scores between the MCAO group and the TENS group at 2 h after MCAO/R operation (P>0.05), while the neurological deficit scores of TENS group significantly decreased in comparison with MCAO group at 72 h following MACO/R injury (P

The sublingual combination of buprenorphine (BUP) and naloxone (NLX) is a new treatment option for opioid use disorder (OUD) and is effective in preventing drug abuse. This study aimed to explore rational dosing regimen for OUD patients in China via a model-based dose optimization approach. BUP, norbuprenorphine (norBUP), and NLX plasma concentrations of 34 healthy volunteers and 12 OUD subjects after single or repeated dosing were included. A parent-metabolite population pharmacokinetics (popPK) model with transit compartments for absorption was implemented to describe the pharmacokinetic profile of BUP-norBUP. In addition, NLX concentrations were well captured by a one-compartment popPK model. Covariate analysis showed that every additional swallow after the administration within the observed range (0–12) resulted in a 3.5% reduction in BUP bioavailability. This provides a possible reason for the less-than-dose proportionality of BUP. There were no differences in the pharmacokinetic characteristics between BUP or NLX in healthy volunteers and OUD subjects. Ethnic sensitivity analysis demonstrated that the dose-normalized peak concentration and area-under-the-curve of BUP in Chinese were about half of Puerto Ricans, which was consistent with a higher clearance observed in Chinese (166 L/h vs. 270 L/h). Furthermore, Monte Carlo simulations showed that an 8 mg three-times daily dose was the optimized regimen for Chinese OUD subjects. This regimen ensured that opioid receptor occupancy remained at a maximum (70%) in more than 95% of subjects, at the same time, with NLX plasma concentrations below the withdrawal reaction threshold (4.6 ng/mL).

BackgroundIsthmic papillary thyroid carcinoma (IPTC) is an aggressive thyroid cancer associated with a poor prognosis. Guidelines elaborating on the extent of surgery for IPTC are yet to be developed. This study aims to construct and validate a model to predict central lymph node metastasis (CLNM) in patients with IPTC, which could be used as a risk stratification tool to determine the best surgical approach for patients.MethodsElectronic medical records for patients diagnosed with isolated papillary thyroid carcinoma who underwent surgery at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2010 to December 2021 were reviewed. All patients who underwent thyroidectomy with central neck dissection (CND) for isolated IPTC were included. We conducted univariate and multivariate logistic regression analyses to assess risk factors for ipsilateral and contralateral CLNM and the number of CLNM in IPTC patients. Based on the analysis, the nomogram construction and internal validations were performed.ResultsA total of 147 patients with isolated IPTC were included. The occurrence of CLNM was 53.7% in the patients. We identified three predictors of ipsilateral CLNM, including age, gender, and size. For contralateral CLNM, three identified predictors were age, gender, and capsular invasion. Predictors for the number of CLNM included age, gender, capsular invasion, tumor size, and chronic lymphocytic thyroiditis (CLT). The concordance index(C-index) of the models predicting ipsilateral CLNM, contralateral CLNM, 1-4 CLNM, and ≥5 CLNM was 0.779 (95%CI, 0.704, to 0.854), 0.779 (95%CI, 0.703 to 0.855), 0.724 (95%CI, 0.629 to 0.818), and 0.932 (95%CI, 0.884 to 0.980), respectively. The corresponding indices for the internal validation were 0.756 (95%CI, 0.753 to 0.758), 0.753 (95%CI, 0.750 to 0.756), 0.706 (95%CI, 0.702 to 0.708), and 0.920 (95%CI, 0.918 to 0.922). Receiver operating characteristic (ROC) curves, calibration, and decision curve analysis (DCA) results confirmed that the three nomograms could precisely predict CLNM in patients with isolated IPTC.ConclusionWe constructed predictive nomograms for CLNM in IPTC patients. A risk stratification scheme and corresponding surgical treatment recommendations were provided accordingly. Our predictive models can be used as a risk stratification tool to help clinicians make individualized surgical plans for their patients.

PurposeThis study aimed to assess the feasibility of synchronous bilateral laparoscopic or open cortical-sparing adrenalectomy (SB-LCSA or SB-OCSA) for bilateral pheochromocytomas (bPHEOs) in multiple endocrine neoplasia type 2 (MEN2).MethodsAltogether, 31 patients (54.8% were women) were diagnosed with MEN2-related bPHEOs, and 29 of them underwent varying specific adrenalectomies. We systematically analyzed and evaluated their clinical profiles, mutation types, tumor histopathological features, and follow-up records.ResultsAll 31 patients with bPHEOs presented with RET-C634 (90.3%) and RET-M918T (9.7%) mutations, and the median age at initial presentation was 38 years (range, 23–78). bPHEOs were synchronous in 27 patients and metachronous in 4 (12.9%) patients. In total, 29 patients underwent initial cortical-sparing adrenalectomy (CSA) including 23 (79.3%) undergoing synchronous bilateral CSA (18 SB-LCSA and 5 SB-OCSA) and 6 (20.7%) undergoing metachronous CSA. SB-LCSA and synchronous surgery were associated with less bleeding volume and shorter length of hospital stay than SB-OCSA and metachronous surgery (all P’s