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Abstract Objectives Surrogate decision-making by family caregivers for patients with severe brain injury is influenced by the availability and understanding of relevant information and expectations for future rehabilitation. We aimed to compare the consistency of family caregivers’ perceptions with clinical diagnoses and to inform their expectation of prognosis in the future. Methods The Coma Recovery Scale-Revised was used to assess the diagnosis of inpatients with severe brain injury between February 2019 and February 2020. A main family caregiver was included per patient. The family caregiver’s perception of the patient’s consciousness and expectations of future recovery were collected through questionnaires and compared consistently with the clinical diagnosis. Results The final sample included 101 main family caregivers of patients (57 UWS, unresponsive wakefulness syndrome, 37 MCS, minimally conscious state, 7 EMCS, emergence from MCS) with severe brain injury. Only 57 family caregivers correctly assessed the level of consciousness as indicated by the CRS-R, showing weak consistency (Kappa = 0.217, P = 0.002). Family caregivers’ demographic characteristics and CRS-R diagnosis influenced the consistency between perception and clinical diagnosis. Family caregivers who provided hands-on care to patients showed higher levels of consistent perception (AOR = 12.24, 95% CI = 2.06-73.00, P = 0.006). Compared to UWS, the family caregivers of MCS patients were more likely to have a correct perception (OR = 7.68, 95% CI = 1.34–44.06). Family caregivers had positive expectations for patients’ recovery in terms of both communication and returning to normal life. Conclusion Nearly half of family caregivers have inadequate understanding of their relative’s level of consciousness, and most of them report overly optimistic expectations that do not align with clinical diagnosis. Providing more medical information to family caregivers to support their surrogate decision-making process is essential.

Abstract Background Cervical cancer is a human papillomavirus (HPV)-related disease. HPV type 16 (HPV16), which is the predominant cause of cervical cancer, can encode miRNAs (HPV16-miRNAs). However, the role of HPV16-miRNAs in the pathogenesis of cervical cancer remains unclear. Methods Human cervical cancer cell lines SiHa (HPV16-positive) and C33A (HPV-negative), and cervical cancer tissues were collected to investigate the expression levels of two HPV16-miRNAs (HPV16-miR-H1 and HPV16-miR-H6). The overexpression and knockdown of HPV16-miR-H1 and HPV16-miR-H6 were performed using the lentiviral vector system and miRNA inhibitors, respectively. RNA-sequencing (RNA-seq) analysis and H3K27ac chromatin immunoprecipitation and sequencing (CHIP-seq) experiments were utilized to explore the roles of HPV16-miR-H1 and HPV16-miR-H6 facilitated by enhancers. CCK8, EdU, transwell, and wound healing assays were performed to verify the effects of HPV16-miR-H1 and HPV16-miR-H6 on cell proliferation and migration. Results HPV16-miR-H1 and HPV16-miR-H6 were highly expressed in both SiHa cells and tissue samples from HPV16-positive cervical cancer patients. RNA-seq analysis showed that HPV16-miR-H1 and HPV16-miR-H6 induced the upregulation of numerous tumor progression-associated genes. H3K27ac CHIP-seq experiments further revealed that HPV16-miR-H1 and HPV16-miR-H6 modulated the expression of critical genes by regulating their enhancer activity. The functional study demonstrated that HPV16-miR-H1 and HPV16-miR-H6 increased the migratory capacity of SiHa cells. Conclusions Our data shed light on the role of HPV16-encoded miRNAs in cervical cancer, particularly emphasizing their involvement in the miRNA-enhancer-target gene system. This novel regulatory mechanism of HPV16-miRNAs provides new insights and approaches for the development of therapeutic strategies by targeting HPV16-positive cervical cancer.

Abstract Objective This study was based on a retrospective clinical observational cohort study of a two‐center application of nusinersen in China to evaluate the clinical efficacy and adverse effects of nusinersen in the treatment of SMA (spinal muscular atrophy) Types 1–3. Methods Clinical data from children with clinically and genetically confirmed 5qSMA from a double center in western China (the Second Affiliated Hospital of Xi'an Jiaotong University and the Second Hospital of West China of Sichuan University). All children were younger than 18 years of age. Patients were assessed for motor function and underwent blood and fluid tests before each nusinersen injection. Results At 14‐month follow‐up, 100% of children had improved their HFMSE (Hammersmith Functional Motor Scale Expanded) score, 83.6% had improved their CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) score, and 66.6% had improved their RULM (Revised Upper Limb Module) score by ≥3 points from baseline, and their 6MWT (6‐min walk test) was 216.00 ± 52.08 m longer than at baseline. The age of the child at the start of treatment was negatively correlated with the clinical efficacy of nusinersen; the younger the child, the better the response to treatment. No significant adverse effects affecting the treatment and quality of life of the child were observed during the treatment of SMA with nusinersen. Conclusion This study concluded that nusinersen is clinically beneficial for children with SMA in western China, with mild adverse effects.

ABSTRACT: The combination of inflammatory factors resulting from an influenza A virus infection is one of the main causes of death in host animals. Studies have shown that guinea pig guanosine monophosphate binding protein 1 (guanylate-binding protein 1, gGBP1) can downregulate cytokine production induced by the influenza virus. Therefore, exploring the innate immune defense mechanism of GBP1 in the process of H5N1 influenza virus infection has important implications for understanding the pathogenic mechanism, disease prevention, and the control of influenza A virus infections. We found that, in addition to inhibiting the early replication of influenza virus, gGBP1 also inhibited the production of CCL2 and CXCL10 cytokines induced by the influenza virus as well as the proliferation of mononuclear macrophages induced by these cytokines. These findings further confirmed that gGBP1 inhibited the production of cytokines through its GTPase activity and cell proliferation through its C-terminal α-helix structure. This study revealed the effect of gGBP1 on the production of cellular inflammatory factors during influenza virus infection and determined the key amino acid residues that assist in the inhibitory processes mediated by gGBP1.

The evaluation of fruit quality greatly relies on the presence of soluble sugars. In this study, we investigated the dynamics of soluble sugars and basic fruit quality of 'Zaozhong 6' loquat after the application of methyl jasmonate (MeJA). As loquats approached full ripeness, the study unveiled a notable increase in their soluble sugar content, predominantly attributed to the rise in fructose levels. MeJA application accelerated sugar accumulation, suggesting its potential for expediting fruit maturation and enhancing sugar content. Importantly, MeJA-treated fully ripe loquats exhibited a significantly higher sugar-acid ratio. In addition to compositional analyses, the study delves into the molecular aspects of sugar metabolism. Despite the absence of detectable sucrose and glucose, the expressions of FK, HK, SPP, SPS, and SS genes were notably influenced, emphasizing the complex regulatory mechanisms governing sugar metabolism in loquat fruit. This research provides valuable insights into the temporal changes in sugar composition during loquat fruit development, underscores the role of MeJA in shaping these dynamics, and highlights the significance of the sugar-acid ratio in fruit quality determination.

In this study, we investigated the effects of supplemental Glycyrrhiza polysaccharide (GCP) on growth performance and intestinal health of weaned piglets. Ninety piglets weaned at 28 days of age were randomly allocated to three groups with five replicates per treatment. Piglets were fed the following diets for 28 days: (1) CON (control group), basal diet; (2) G500, CON + 500 mg/kg GCP; (3) G1000, CON + 1000 mg/kg GCP. The results showed that supplementation with 1000 mg/kg GCP increased the average daily gain (ADG) and decreased the feed-to-gain ratio (F/G) (P

Salt stress is a major abiotic stress that affects the growth of Reaumuria soongorica and many psammophytes in the desert areas of Northwest China. However, various Plant Growth-Promoting Rhizobacteria (PGPR) have been known to play an important role in promoting plant growth and alleviating the damaging effects of salt stress. In this study, three PGPR strains belonging to Bacillaceae were isolated from the rhizosphere of Reaumuria soongorica by morphological and molecular identification. All isolated strains exhibited capabilities of producing IAA, solubilizing phosphate, and fixing nitrogen, and were able to tolerate high levels of NaCl stress, up to 8–12%. The results of the pot-based experiment showed that salt (400 mM NaCl) stress inhibited Reaumuria soongorica seedlings’ growth performance as well as biomass production, but after inoculation with strains P2, S37, and S40, the plant’s height significantly increased by 26.87, 17.59, and 13.36%, respectively (p

This study seeks to advance the scholarship on the phenomenon of social media platform-swinging in the context of the polymedia environment in China. Specifically, drawing on the theoretical frameworks of uses and gratifications and channel complementarity theory, we propose that the platform-swinging behavior is driven by users’ various complementary and supplementary needs. Drawing on 32 semi-structured interviews, we identify four distinct types of platform-swinging behavior: social connecting, impression managing, information seeking, and aimless swinging. We further reveal that, depending on various complementary and supplementary needs, each type of platform-swinging behavior has distinct media affordance preferences. By profiling the distinct platform-swinging behaviors and examining their preferred affordances, the study advances our theoretical understanding of the dynamics between the polymedia ecology and users’ gratifications.

BackgroundThe systemic immuno-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are widely used and have been shown to be predictive indicators of various diseases. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) are the most prominent and common microvascular complications, which have seriously negative impacts on patients, families, and society. Exploring the associations with these three indicators and diabetic microvascular complications are the main purpose.MethodsThere were 1058 individuals with type 2 diabetes mellitus (T2DM) in this retrospective cross-sectional study. SII, NLR, and PLR were calculated. The diseases were diagnosed by endocrinologists. Logistic regression and subgroup analysis were applied to evaluate the association between SII, NLP, and PLR and diabetic microvascular complications.ResultsSII, NLR, and PLR were significantly associated with the risk of DN [odds ratios (ORs): 1.52, 1.71, and 1.60, respectively] and DR [ORs: 1.57, 1.79, and 1.55, respectively] by multivariate logistic regression. When NLR ≥2.66, the OR was significantly higher for the risk of DPN (OR: 1.985, 95% confidence interval: 1.29–3.05). Subgroup analysis showed no significant positive associations across different demographics and comorbidities, including sex, age, hypertension, HbA1c (glycated hemoglobin), and dyslipidemia.ConclusionThis study found a positive relationship between NLR and DN, DR, and DPN. In contrast, SII and PLR were found to be only associated with DN and DR. Therefore, for the diagnosis of diabetic microvascular complications, SII, NLR and PLR are highly valuable.

Self-sensing cementitious coatings are a promising alternative in structural health monitoring due to their high sensing performance and simple production and deployment. The sensing behavior of coatings though differs compared to conventional self-sensing materials due to the interface between the coating and substrate. In this study, the bonding and sensing performance of geopolymer coatings under cyclic compression was investigated by employing four surface treatments – untreated, chipping, brooming, and chemical treatment. The coatings' splitting tensile bond strength ranged between 3.52 MPa and 6.54 MPa. The strain ratio between the coatings and substrates was between 0.62 and 0.67 and the gauge factor was found between 29 and 34. A numerical analysis involving finite element models on the strain behavior of coatings and parametric studies on the coatings' elastic modulus and thickness was carried out. A bonding coefficient, that accounts for the coatings’ mechanical and geometric properties, was proposed to accurately determine the gauge factor.

Abstract In recent years, lung adenocarcinoma (LUAD) has become a focus of attention due to its low response to treatment, poor prognosis, and lack of reliable indicators to predict the progression or therapeutic effect of LUAD. Different cell death patterns play a crucial role in tumor development and are promising for predicting LUAD prognosis. From the TCGA and GEO databases, we obtained bulk transcriptomes, single-cell transcriptomes, and clinical information. Genes in 15 types of cell death were analyzed for cell death index (CDI) signature establishment. The CDI signature using necroptosis + immunologic cell death-related genes was established in the TCGA cohort with the 1-, 2-, 3-, 4- and 5-year AUC values were 0.772, 0.736, 0.723, 0.795, and 0.743, respectively. The prognosis was significantly better in the low CDI group than in the high CDI group. We also investigated the relationship between the CDI signature and clinical variables, published prognosis biomarkers, immune cell infiltration, functional enrichment pathways, and immunity biomarkers. In vitro assay showed that HNRNPF and FGF2 promoted lung cancer cell proliferation and migration and were also involved in cell death. Therefore, as a robust prognosis biomarker, CDI signatures can screen for patients who might benefit from immunotherapy and improve diagnostic accuracy and LUAD patient outcomes.

This study aimed to explore the application status of natural products in gastric ulcer research and explore the research hotspots and future research directions. CiteSpace was used to conduct metrological and visual analysis on the number of articles published in the core set of Web of Science database about natural medicines therapy for gastric ulcer, including co-cited journals, co-cited authors, co-cited literatures and keywords. From 1953 to 2021, the number of articles published on natural medicines therapy for gastric ulcer was 1 373, the total number of articles had increased rapidly in recent years. China and the United States were the driving force in this field, and the main research institution was Chinese Univ. Hong Kong. Most of the publications are in the journal Gastroenterology. ''peptic ulcer'', ''Helicobacter pylori'', ''infection'', ''duodenal ulcer'', ''disease'', ''gastric ulcer'', ''peptic ulcer disease'', ''gastric cancer'', and ''prevalence'' were the research frontiers in recent years. This study was the first to conduct literature metrology visualization analysis on the research status and hot spots and development trend of natural medicines against gastric ulcer, in order to provide reference for follow-up researchers to quickly understand the research focus of natural medicines against gastric ulcer and literature retrieval. In addition, this paper also put forward suggestions and prospected for the future development of this field, which will help researchers to open up new directions for future research in this field.

Endometriosis is a disease characterized by the ectopic growth of endometrial tissue (glands and stroma) outside the confines of the uterus and often involves vital organs such as the intestines and urinary system. Endometriosis is considered a refractory disease owing to its enigmatic etiology, propensity for recurrence following conservative or surgical interventions, and the absence of radical treatment and long-term management. In recent years, the incidence of endometriosis has gradually increased, rendering it a pressing concern among women of childbearing age. A more profound understanding of its pathogenesis can significantly improve prognosis. Recent research endeavors have spotlighted the molecular mechanisms by which microRNAs (miRNAs) regulate the occurrence and progression of endometriosis. Many miRNAs have been reported to be aberrantly expressed in the affected tissues of both patients and animal models. These miRNAs actively participate in the regulation of inflammatory reactions, cellular proliferation, angiogenesis, and tissue remodeling. Their capacity to modulate crucial signaling pathways, such as the Wnt/β-catenin signaling pathway, reinforces their potential utility as diagnostic markers or therapeutic agents for endometriosis. In this review, we provide the latest insights into the role of miRNAs that interact with the Wnt/β-catenin pathway to regulate the biological behaviors of endometriosis cells and disease-related symptoms, such as pain and infertility. We hope that this review will provide novel insights and promising targets for innovative therapies addressing endometriosis.

BackgroundIn China, children commonly display body cognitive biases, which constitute a significant yet hidden public health issue. These biases potentially jeopardize children’s well-being, hinder the cultivation of human capital, and impede societal progress. However, limited research employs theoretical analysis and econometric testing to investigate the formation of different body cognitive biases among Chinese children and their health impacts.MethodsBased on a local average network model for theoretical analysis, this study utilizes a sample of 4,289 children from four phases of the China Health and Nutrition Survey (CHNS) conducted from 2004 to 2011. Utilizing Logit and IV Probit models, systematically evaluate the peer effect, heterogeneity of effects, and health impacts of children’s different body cognitive biases.Results(1) The peer effect contributes to the development of light- and heavy-body cognitive biases in Chinese children. (2) The heterogeneity analysis shows that the peer effect of body cognitive biases is more significant in rural and female children. (3) The influence of heavy-body cognitive bias is more pronounced in adolescent children. (4) The “eating-activity balance” is disrupted by the two body cognitive biases in children, leading to deviations from normal body type. (5) Specifically, the light-body cognitive bias leads children to intake more and burn fewer calories, increasing their risk of obesity. (6) Conversely, the heavy-body cognitive bias prompts children to intake less and expend more calories, resulting in a higher prevalence of thinness.DiscussionThis study innovates by exploring peer effects on body cognitive biases in Chinese children, elucidating their direction and health implications. While overweight and obesity are recognized as overt health issues, the spread and impact of implicit issues like body cognitive biases should not be overlooked. Nevertheless, the issue is largely neglected in developing countries, such as China, where existing children’s health policies are inadequate in addressing it. Promoting accurate body image perception and understanding of health prevention strategies among children requires adequate attention to peer effects.

As neural network inference demands are ever-increasing in intelligent applications, the performance optimization of model serving becomes a challenging problem. Dynamic batching is an important feature of contemporary deep learning serving systems, which combines multiple requests of model inference and executes them together to improve the system’s throughput. However, the behavior characteristics of each part in deep neural network batching systems as well as their performance impact on different model structures are still unknown. In this paper, we characterize the batching system by leveraging three representative deep neural networks on GPUs, performing a systematic analysis of the performance effects from the request batching module, model slicing module, and stage reorchestrating module. Based on experimental results, several insights and recommendations are offered to facilitate the system design and optimization for deep learning serving.

It has been recognized that depth of invasion (DOI) is closely associated with patient survival for most types of cancer. The purpose of this study was to determine the DOI optimal cutoff value and its prognostic value in laryngeal squamous carcinoma (LSCC). Most importantly, we evaluated the prognostic performance of five candidate modified T-classification models in patients with LSCC. LSCC patients from Harbin Medical University Cancer Hospital and Chinese Academy of Medical Sciences Cancer Hospital were divided into training group (n = 412) and validation group (n = 147). The primary outcomes were overall survival (OS) and relapse-free survival (RFS), and the effect of DOI on prognosis was analyzed using a multivariable regression model. We identified the optimal model based on its simplicity, goodness of fit and Harrell’s consistency index. Further independent testing was performed on the external validation queue. The nomograms was constructed to predict an individual’s OS rate at one, three, and five years. In multivariate analysis, we found significant associations between DOI and OS (Depth of Medium-risk invasion HR, 2.631; P

Background The 2009 Institute of Medicine (IOM) gestational weight gain (GWG) guidelines were initially developed for pregnant women in the United States. Objective This study aimed to investigate whether the IOM guidelines were suitable for pregnant Chinese women. Methods A retrospective cohort study comprising 20,593 singleton pregnant women was conducted at the Beijing Obstetrics and Gynaecology Hospital (1 January 2018 to 31 December 2019). Applicability was evaluated by comparing the GWG corresponding to the lowest point of the predicted composite risk curve with the 2009 IOM GWG Guidelines. The IOM Guidelines serve as the standard for the GWG categories and the pre-pregnancy body mass index. An exponential function model was used to fit the weight gain during pregnancy and the probability of caesarean section, preterm birth, small for gestational age, and large for gestational age. A quadratic function model was used to fit the combined probability of the above-mentioned adverse pregnancy outcomes. The applicability of the IOM guidelines was evaluated by comparing the weights corresponding to the lowest predicted probability with the GWG range recommended by the IOM guidelines. Results According to the 2009 IOM GWG Guidelines, 43% of the women achieved adequate weight, almost 32% gained excessive weight, and 25% gained inadequate weight. The GWG range proposed by the IOM included the lowest predicted probability value for underweight women and exceeded the lowest predicted probability for normal weight, overweight, and obese women. Conclusions The 2009 IOM guidelines were suitable for Chinese women whose pre-pregnancy body mass index was classified as underweight. The guidelines were not suitable for normal, overweight, or obese pre-pregnancy body mass index classifications. Therefore, based on the above evidence, the 2009 IOM guidelines are not suitable for all Chinese women.

Abstract Background Intrinsic capacity (IC) is a comprehensive indicator of an individual’s positive attributes. The World Health Organization (WHO) recommends a two-step approach to assess IC decline among older people. The first step involves the used of the integrated care for older people (ICOPE) screening tool to identify potential issues, and the second step involves using detailed assessments for confirmation. This study aimed to assess the diagnostic performance of the ICOPE screening tool as a simple preliminary screening to identify IC decline among community-dwelling older people, which has been rarely reported in China. Methods This cross-sectional study included 228 community-dwelling older individuals aged ≥ 75 (mean age, 84.0 ± 4.4 years; 131 [57.5%] females) who completed the IC evaluation according to the WHO IC assessment pathway. The diagnostic performance of the ICOPE screening tool was calculated using a 2 × 2 table and a receiver operating characteristic curve. Results The proportion of possible IC decline identified by the ICOPE screening tool was 79.4%, whereas the actual IC decline assessed by the detailed assessment was 73.2%, mainly in locomotion. The ICOPE screening tool showed sensitivity and specificity of 94.6% and 62.3%, respectively, with an overall diagnostic accuracy of 86.0%. The diagnostic effectiveness of the ICOPE screening tool was 0.91 (95% confidence interval: 0.87–0.95, p = 0.020). Except for the sensory dimension, the sensitivity of the ICOPE screening tool for diagnosing impairments in each dimension of the IC was the highest in the cognition domain (100%) and the lowest in the vitality domain (51.3%), whereas the specificity was the highest in vitality (94.7%) and the lowest in cognition (55.6%). Conclusions The ICOPE screening tool exhibits high sensitivity and can be used as an IC screening tool in community-dwelling older people. However, further improvements are needed in the vitality dimension of the ICOPE screening tool to enhance its sensitivity in identifying individuals at risk of malnutrition.

Abstract Advancements in microscale electrode technology have revolutionized the field of neuroscience and clinical applications by offering high temporal and spatial resolution of recording and stimulation. Flexible neural probes, with their mechanical compliance to brain tissue, have been shown to be superior to rigid devices in terms of stability and longevity in chronic recordings. Shuttle devices are commonly used to assist flexible probe implantation; however, the protective membrane of the brain still makes penetration difficult. Hidden damage to brain vessels during implantation is a significant risk. Inspired by the anatomy of the mosquito mouthparts, we present a biomimetic neuroprobe system that integrates high-sensitivity sensors with a high-fidelity multichannel flexible electrode array. This customizable system achieves distributed and minimally invasive implantation across brain regions. Most importantly, the system’s nonvisual monitoring capability provides an early warning detection for intracranial soft tissues, such as vessels, reducing the potential for injury during implantation. The neural probe system demonstrates exceptional sensitivity and adaptability to environmental stimuli, as well as outstanding performance in postoperative and chronic recordings. These findings suggest that our biomimetic neural-probe device offers promising potential for future applications in neuroscience and brain-machine interfaces. A mosquito mouthpart-like bionic neural probe consisting of a highly sensitive tactile sensor module, a flexible microelectrode array, and implanted modules that mimic the structure of mosquito mouthparts. The system enables distributed implantation of electrode arrays across multiple brain regions while making the implantation minimally invasive and avoiding additional dural removal. The tactile sensor array can monitor the implantation process to achieve early warning of vascular damage. The excellent postoperative short-term recording performance and long-term neural activity tracking ability demonstrate that the system is a promising tool in the field of brain-computer interfaces.

Abstract Background Exosomes are critical mediators of tumor cell‐microenvironment cross talk. However, the mechanisms by which hypoxic Lung adenocarcinoma (LUAD)‐derived exosomes modulate macrophage polarization remain largely unknown. The aim of this study was to investigate the effects of hypoxic LUAD‐derived exosome on macrophage polarization and explore the underlying molecular mechanism. Materials and methods LUAD‐derived exosomes were isolated, and then confirmed by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Internalization of exosomes in macrophages was detected by confocal microscope. Gain‐ and loss‐of‐function experiments, rescue experiments, and xenograft models were performed to uncover the underlying mechanisms of exosomal miR‐1290 induced macrophage polarization in vitro and in vivo. Results miR‐1290 was enriched in hypoxic LUAD cancer cell‐derived exosomes and could be transferred to macrophages. Overexpression of miR‐1290 in macrophages‐induced polarization of M2 phenotype. Luciferase assay verified SOCS3 was the target of miR‐1290. Hypoxic LUAD cell‐derived exosomal miR‐1290 activated the STAT3 signaling pathway by targeting SOCS3 to promote M2 macrophage polarization. Conclusion Hypoxic LUAD cells generate miR‐1290‐rich exosomes that promote M2 polarization of macrophages. Targeting exosomal miR‐1290 may provide a potential immunotherapeutic strategy for LUAD.

The type II Na/Pi co-transporter (NaPi2b), encoded by the solute carrier (SLC) transporter 34A2 (SLC34A2), is responsible for calcium (Ca) and phosphorus (P) homeostasis. Unbalanced Ca/P metabolism induces mastitis in dairy cows. However, the specific role of SLC34A2 in regulating this imbalance in Holstein cows with clinical mastitis (CM) remains unclear. The aim of this study was to investigate the role of SLC34A2 and identify differentially expressed proteins (DEPs) that interact with SLC34A2 and are associated with Ca/P metabolism in dairy cows with CM. Immunohistochemical and immunofluorescence staining results showed that SLC34A2 was located primarily in the mammary epithelial cells of the mammary alveoli in both the control (healthy cows, Con/C) and CM groups. Compared to the Con/C group, the relative expression of the SLC34A2 gene and protein were significantly downregulated in the CM group. We identified 12 important DEPs included in 11 GO terms and two pathways interacting with SLC34A2 using data-independent acquisition proteomics. The PPI (protein-and-protein interaction) network results suggested that these DEPs were associated with ion metabolism and homeostasis, especially SLC34A2. These results demonstrate that SLC34A2 downregulation is negatively correlated with the occurrence and development of CM in Holstein cows, providing a basis for exploring the function and regulatory mechanism of SLC34A2 in Ca/P metabolism and homeostasis in Holstein cows with CM.

Recent advancements in neural probe technology have become pivotal in both neuroscience research and the clinical management of neurological disorders. State-of-the-art developments have led to the advent of multichannel, high-density bidirectional neural interfaces that are adept at both recording and modulating neuronal activity within the central nervous system. Despite this progress, extant bidirectional probes designed for simultaneous recording and stimulation are beset with limitations, including elicitation of inflammatory responses and insufficient charge injection capacity. In this paper, we delineate the design and application of an innovative ultraflexible bidirectional neural probe engineered from polyimide. This probe is distinguished by its ability to facilitate high-resolution recordings and precise stimulation control in deep brain regions. Electrodes enhanced with a PEDOT:PSS/IrOx composite exhibit a substantial increase in charge storage capacity, escalating from 0.14 ± 0.01 mC/cm2 to an impressive 24.75 ± 0.18 mC/cm2. This augmentation significantly bolsters the electrodes’ charge transfer efficacy. In tandem, we observed a notable reduction in electrode impedance, from 3.47 ± 1.77 MΩ to a mere 41.88 ± 4.04 kΩ, while the phase angle exhibited a positive shift from −72.61 ± 1.84° to −34.17 ± 0.42°. To substantiate the electrodes’ functional prowess, we conducted in vivo experiments, where the probes were surgically implanted into the bilateral motor cortex of mice. These experiments involved the synchronous recording and meticulous analysis of neural signal fluctuations during stimulation and an assessment of the probes’ proficiency in modulating directional turning behaviors in the subjects. The empirical evidence corroborates that targeted stimulation within the bilateral motor cortex of mice can modulate the intensity of neural signals in the stimulated locale, enabling the directional control of the mice’s turning behavior to the contralateral side of the stimulation site.

Well path design is an important factor in horizontal drilling. A reasonable well profile scheme can significantly reduce drilling drag and torque, which also can enhance drilling rate. This study proposes an approach to faster drill a three-dimensional horizontal well by integrating well path and bottomhole assembly (BHA) design. The shortcomings of two classic well path design principles of shortest well length and minimum drag are investigated and a method integrating well path and BHA design is developed by altering inclination holding section to a slightly build up section and predicting build rate of BHA. For two conventional design principles, the design processes are developed by minimum curvature model and genetic optimizing algorithm. Case studies show that the optimized well depth or drag of two conventional methods have little difference compared to the unoptimized ones, which indicates that these two optimization methods cannot significantly improve drilling efficiency. For proposed design method, the well path design is developed by minimum curvature model, and the drilling tendency prediction method is established by three-dimensional beam-column theory and the rock-bit interaction model. Besides, a set of bent-housing mud motor with double stabilizers (BH-PDM-D) BHA is chosen to drill the well, according to the build rate prediction of both slide drilling and rotary drilling. The predicted result of drilling cycle shows that for the six-section well profile, the proposed method can reduce the drilling time by 24.2 days.

Abstract Background Although the pressure of pulmonary vein increases before pulmonary artery in pulmonary hypertension due to left heart disease (PH-LHD), only a few studies have assessed pulmonary vein smooth muscle cells (PVSMCs) because of the lack of a simple and feasible isolation method. Methods In this study, we introduced a simple method to obtain PVSMCs. Primary pulmonary veins were removed by puncture needle cannula guidance. Then, PVSMCs were cultured by the tissue explant method and purified by the differential adhesion method. The cells were characterized by hematoxylin-eosin (HE) staining, immunohistochemistry, western blotting, and immunofluorescence to observe the morphology and verify the expression of alpha-smooth muscle actin (α-SMA). Results The HE staining results showed that the pulmonary vein media was thinner than the pulmonary artery, the intima and adventitia of the pulmonary vein were removed by this method, and the obtained cells with good activity exhibited morphological characteristics of smooth muscle cells. In addition, higher α-SMA expression was observed in the cells obtained by our isolation method than in the traditional method. Conclusion This study established a simple and feasible method to isolate and culture PVSMCs that might facilitate the cytological experiments for PH-LHD.

ABSTRACT: Fatty liver (i.e., hepatic lipidosis) is a prevalent metabolic disorder in dairy cows during the transition period, characterized by excess hepatic accumulation of triglyceride (TG), tissue dysfunction, and cell death. Detailed pathological changes, particularly hepatic fibrosis, during fatty liver remain to be determined. Liver fibrosis occurs as a consequence of liver damage, resulting from the excessive accumulation of extracellular matrix, which distorts the architecture of the normal liver, compromising its normal synthetic and metabolic functions. Thus, we aimed to investigate liver fibrosis status and its potential causal factors including oxidative stress, hepatocyte apoptosis, and production of inflammatory cytokines in the liver of cows with fatty liver. Forty-five dairy cows (parity, 3–5) were selected, and liver biopsy and blood were collected on the second week postpartum (days in milk, 10–14 d). On the basis of the degree of lipid accumulation in liver, selected cows were categorized into normal (n = 25; TG

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation “sensitizes” the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35–STARD4 axis is a promising therapeutic target for NAFLD.

Abstract The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation and distant metastasis. Anticancer treatments including adjuvant therapies and targeted therapies are effective in eliminating cancer cells but in a limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role in tumor development through changes in macromolecule components, degradation enzymes and stiffness. These variations are under the control of cellular components in tumor tissue via the aberrant activation of signaling pathways, the interaction of the ECM components to multiple surface receptors, and mechanical impact. Additionally, the ECM shaped by cancer regulates immune cells which results in an immune suppressive microenvironment and hinders the efficacy of immunotherapies. Thus, the ECM acts as a barrier to protect cancer from treatments and supports tumor progression. Nevertheless, the profound regulatory network of the ECM remodeling hampers the design of individualized antitumor treatment. Here, we elaborate on the composition of the malignant ECM, and discuss the specific mechanisms of the ECM remodeling. Precisely, we highlight the impact of the ECM remodeling on tumor development, including proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, and immune escape. Finally, we emphasize ECM "normalization" as a potential strategy for anti-malignant treatment.

Abstract Background and aims Diagnosis of leptomeningeal metastasis (LM) is challenging. In our previous study, CEACAM6 mRNA was found to be highly expressed in the circulating tumor cells of cerebrospinal fluid (CSF) from patients with lung adenocarcinoma with LM (LUAD‐LM). The aim of this study was to identify whether CEACAM6 could be used as a biomarker for LUAD‐LM. Materials and methods The level of CEACAM6 was determined by enzyme‐linked immunosorbent assay (ELISA) in CSF from 40 LUAD‐LM and 44 normal controls, and additional serum samples from 138 LUAD patients, including 12 LUAD‐LM patients, and 30 healthy controls. Carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21‐1) and neuron‐specific enolase (NSE) levels in the CSF and sera were detected by chemiluminescent immunoassay. Receiver operating characteristic curve was plotted to evaluate the diagnostic performance for LUAD‐LM. Results CSF CEACAM6 level was higher in LUAD‐LM than that in normal controls. In serum, LUAD patients had a higher level of CAECAM6 than healthy controls, and LM patients had the highest level among them. Serum CEACAM6 had a higher AUC than CEA in differentiating LM from non‐LM in LUAD patients (0.95 vs. 0.64, p

Abstract Surface analysis by X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry was applied to investigate the origin of the enhanced surface passivity and resistance to a chloride-induced breakdown provided by the protective ultrathin oxide films formed on Cr–Fe–Co–Ni–Mo single-phase fcc multi-principal element alloys. A bilayer structure of the oxide films is observed with the inner barrier layer mostly constituted of Cr(III) oxide and the outer layer enriched in Cr(III) hydroxides and Mo(IV,VI) oxides. The Mo(VI) and Mo(IV) species are mainly located in the outer and inner parts of the outer layer, respectively. Anodic passivation promotes mainly the growth of the inner layer on the alloy of higher Cr bulk content and the outer layer on the alloy of higher Mo bulk content. Passivation also promotes the enrichment of Cr(III) hydroxide and Mo(IV) and Mo(VI) oxides in the outer layer. Depth distribution analysis suggests that the ultra-thin protective inner barrier contains Cr(III)-depleted heterogeneities acting as weak sites for chloride attack, which are reinforced by the Mo(IV) oxide species concentrated close to the inner barrier layer. This elemental distribution provides an explanation for the reinforcement of the resistance to localized corrosion observed on these Cr–Fe–Co–Ni–Mo alloys.

This paper is devoted to investigating the impact of vaccination on mitigating COVID-19 outbreaks. In this work, we propose a compartmental epidemic ordinary differential equation model, which extends the previous so-called SEIRD model [1,2,3,4] by incorporating the birth and death of the population, disease-induced mortality and waning immunity, and adding a vaccinated compartment to account for vaccination. Firstly, we perform a mathematical analysis for this model in a special case where the disease transmission is homogeneous and vaccination program is periodic in time. In particular, we define the basic reproduction number $ \mathcal{R}_0 $ for this system and establish a threshold type of result on the global dynamics in terms of $ \mathcal{R}_0 $. Secondly, we fit our model into multiple COVID-19 waves in four locations including Hong Kong, Singapore, Japan, and South Korea and then forecast the trend of COVID-19 by the end of 2022. Finally, we study the effects of vaccination again the ongoing pandemic by numerically computing the basic reproduction number $ \mathcal{R}_0 $ under different vaccination programs. Our findings indicate that the fourth dose among the high-risk group is likely needed by the end of the year.

Salmonella enterica serovar Typhimurium (S. typhimurium) is an important foodborne pathogen that infects both humans and animals and develops acute gastroenteritis. As porcine intestines are relatively similar to the human ones due to their relatively similar sizes and structural similarity, S. typhimurium causes analogous symptoms in both. Novel strategies for controlling S. typhimurium infection are also desired, such as mucosal-targeted delivery of probiotics and antimicrobial peptides. The bovine lactoferricin-lactoferrampin-encoding Limosilactobacillus reuteri (LR-LFCA) strain improves intestinal barrier function by strengthening the intestinal barrier. Weaned piglets were selected for oral administration of microencapsulated LR-LFCA (microcapsules entrap LR-LFCA into gastro-resistant polymers) and then infected with S. typhimurium for 3 days. We found that orally administering microencapsulated LR-LFCA to weaned piglets attenuated S. typhimurium-induced production of inflammatory factors in the intestinal mucosa by inhibiting the nuclear factor-kappa B (NF-κB) and P38 mitogen-activated protein kinases (MAPK) signaling pathway. Moreover, microencapsulated LR-LFCA administration significantly suppressed the oxidative stress that may correlate with gut microbiota (reduced Salmonella population and increased α-diversity and Lactobacillus abundance) and intestinal function (membrane transport and metabolism). Our work demonstrated that microencapsulated LR-LFCA effectively targeted intestine delivery of Lactobacillus and antimicrobial peptides and modulated gut microbiota and mucosal immunity. This study reveals a novel targeting mucosal strategy against S. typhimurium infection.

Florfenicol (FLO) has been shown to elicit diverse toxic effects in plants, insects, and mammals. Previously, our investigations revealed that FLO induced abnormal cardiac development and early embryonic mortality in chicken embryos. However, the effect of FLO on mitochondrial responses in stem cells remains unclear. In this study, we show that FLO significantly diminishes proliferation viability and obstructs the directed differentiation of P19 stem cells (P19SCs) into cardiomyocytes. Proteomic analysis revealed 148 differentially expressed proteins in response to FLO. Functional analysis has pinpointed FLO interference with biological processes associated with oxidative phosphorylation within the mitochondria. In alignment with the results of proteomic analysis, we confirmed that FLO inhibits the expression of both nuclear DNA-encoded and mitochondrial DNA-encoded subunits of the electron transport chain. Subsequent experiments demonstrated that FLO disrupts mitochondrial dynamics and induces the mitochondrial unfolded protein response to maintain mitochondrial homeostasis. These findings collectively highlight the significance of mitochondrial dynamics and the mitochondrial unfolded protein response to mediate the decreased proliferation viability and directed differentiation potential in P19SCs treated with FLO. In conclusion, this study provides a comprehensive overview of mitochondrial responses to FLO-induced cytotoxicity and enhances our understandings of the molecular mechanisms underlying FLO-induced embryonic toxicity.

Background: Dilated cardiomyopathy (DCM) has a poor prognosis and high mortality. The relationship between the deformation capacity of the biatrial and biventricular regions in patients with DCM remains unclear. Methods: This retrospective study used cardiovascular magnetic resonance (CMR) to assess patient enrollment between September 2020 to May 2022. Feature tracking (FT) was used to evaluate biventricular global radial strain (GRS), global circumferential strain (GCS) and global longitudinal strain (GLS). Fast long-axis method was used to evaluate biatrial GLS by analyzing balanced steady-state free precession cine images. The median follow-up period was 362 days (interquartile range: 234 to 500 days). DCM patients were divided into two groups based on the occurrence or non-occurrence of major adverse cardiac event (MACE). The primary endpoint was defined as all-cause death, heart transplantation, and adverse ventricular arrhythmia. The secondary end point included hospitalizations due to heart failure. Cox regression analysis was utilized for variables and Kaplan-Meier survival was utilized for clinical outcomes. Results: There were 124 DCM patients (52.82 ± 12.59 years, 67.74% male) and 53 healthy volunteers (53.17 ± 14.67 years, 52.83% male) recruited in this study. Biventricular GRS, GCS, GLS, and biatrial GLS were significantly impaired in the DCM group compared with the healthy group. In receiver-operating characteristic curve, biatrial GLS and biventricular GRS, GCS, and GLS showed significant prognostic value in predicting MACEs (all p < 0.05). In multivariate Cox regression analysis, left ventricular (LV) GLS offered a significant and independent prognostic value surpassing other CMR parameters in predicting MACE. In Kaplan-Meier analysis, patients with a LV GLS >–4.81% had a significantly higher rate of MACE (Log-rank p < 0.001). Conclusions: LV GLS was independently associated with MACEs in DCM patients by using FT and fast long-axis method derived from CMR. Comprehensive CMR examination including biatrial and biventricular functions should be systematically performed, to understand disease characteristics, as well as improve the risk stratification and therapeutic management for patients with DCM.

ObjectiveTo study the changes in epileptic seizures and sleep quality in children with epilepsy (CWE) and the changes in anxiety of their caregivers after infection with COVID-19.MethodsOutpatients and inpatients of CWEs were selected as subjects and a questionnaire survey was used to carry out this case-series study. The demographic information of the CWEs and their caregivers, information about epilepsy, and information about the vaccination, infection, and treatment of COVID-19 were collected. The changes in sleep quality of CWEs and the changes in anxiety of their caregivers were assessed by the Child Sleep Habits Questionnaire (CSHQ) and Caregiver Anxiety Scale (CAS). Risk factors affecting sleep habits in CWEs and caregiver anxiety were further analyzed by one-way analysis of variance.ResultsA total of 312 children were included in the study. Among them, 134 patients (42.9%) were female. The average age of the children was 9.30 ± 3.88 years, and the duration of epilepsy was 4.59 ± 3.36 years. A total of 221 of the 312 children were infected with COVID-19, and all the infected children developed fever, which lasted for 1.71 ± 1.13 days. 10 children were satisfied with controlled seizures for more than 1 year and relapsed after COVID-19 infection (4.2%), 4 cases (3.6%) with increased seizures, and 8 children with reduced seizures (7.7%), 17 children (7.7%) had no change in seizures, and 182 children (82.3%) remained seizure-free after the COVID-19 infection. The average sleep time of the CWEs was 9.25 ± 1.04 h and the average total score of the CSHQ was 37.25 ± 5.19, among which 44 cases (14.1%) had more than 41 points. As the result of the CAS, 16 of them (5.13%) scored above 50 and the average total score was 31.49 ± 8.09. The control of seizures, age of onset, types of anti-seizure medicines (ASMs), and seizure duration were risk factors affecting sleep quality. Accordingly, the score of CAS was significantly lower when there was more than one caregiver who cared for the CWE.ConclusionsCOVID-19 infection did not cause an increase in seizures in CWEs, nor did it worsen their sleep quality of them or aggravate the anxiety of their caregivers.

Brain disorders are the leading cause of disability worldwide, affecting people’s quality of life and causing economic burdens. The current clinical diagnosis of brain disorders relies solely on individual phenotypes and lacks accurate molecular biomarkers. An emerging field of research centers around extracellular vesicles (EVs), nanoscale membrane vesicles which can easily cross the blood–brain barrier. EVs in the blood are derived from various tissues, including the brain. Therefore, purifying central nervous system (CNS)-derived EVs from the blood and analyzing their contents may be a relatively non-invasive way to analyze brain molecular alterations and identify biomarkers in brain disorders. Recently, methods for capturing neuron-derived EVs (NDEs), astrocyte-derived EVs (ADEs), and oligodendrocyte-derived EVs (ODEs) in peripheral blood were reported. In this article, we provide an overview of the research history of EVs in the blood, specifically focusing on biomarker findings in six major brain disorders (Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar disorder, depression, and autism spectrum disorder). Additionally, we discuss the methodology employed for testing CNS-derived EVs. Among brain disorders, Alzheimer’s disease has received the most extensive attention in EV research to date. Most studies focus on specific molecules, candidate proteins, or miRNAs. Notably, the most studied molecules implicated in the pathology of these diseases, such as Aβ, tau, and α-synuclein, exhibit good reproducibility. These findings suggest that CNS-derived EVs can serve as valuable tools for observing brain molecular changes minimally invasively. However, further analysis is necessary to understand the cargo composition of these EVs and improve isolation methods. Therefore, research efforts should prioritize the analysis of CNS-derived EVs’ origin and genome-wide biomarker discovery studies.

Groundwater plays a crucial role in regulating plant growth in arid regions and has significant effects on plant physiological mechanisms. However, research on the influence of groundwater change on plant ecological stoichiometry is still limited. Therefore, this study was carried out to obtain the variations in assimilated branches and soil ecological stoichiometry of two dominant species in the Gurbantunggut Desert (Haloxylon ammodendron and Haloxylon persicum) at different groundwater depths to reveal the responses of desert plants to groundwater depth changes. The results showed that (1) H. persicum branches’ stress tolerance indicators (C:N, C:P) are higher, while nutritional indicators (N:P) are lower. The soil nutrient of H. ammodendron is richer. (2) The ecological stoichiometry varied significantly along the groundwater gradient. With the deepening of groundwater, the branches C, N and P increased, and the variation in element ratio was inconsistent. Most of the soil properties was inversely proportional to the depth of groundwater. (3) Groundwater depth was a vital environmental factor affecting the assimilated branches ecological stoichiometry. Soil properties also had a significant influence on element accumulation in assimilated branches. (4) Regulating the allocation of branches ecological stoichiometry is an adaptation of two Haloxylon species to cope with local hydrological conditions changes. These findings provide novel insights into desert plant responses to different groundwater conditions within fragile desert ecosystems and may have implications for the implementation of effective measures related to the stability and sustainability of desert ecosystems.

Objective Preoperative evaluation of lateral lymph node metastasis (LLNM) in patients with papillary thyroid carcinoma (PTC) has been one of the major clinical challenges. This study aims to develop and validate iodine nutrition-related nomogram models to predict lateral cervical lymph node metastasis in patients with PTC. Methods This is a retrospective study. Urinary iodine concentration (UIC) and serum iodine concentration (SIC) were measured in 187 LLNM patients and 289 non-LLNM (NLLNM) patients. All patients were randomized 3:1 into the training cohort (n = 355) and the validation cohort (n = 121). Using logistic regression analysis, we analyzed the influence of iodine nutrition-related factors and clinicopathological characteristics on LLNM in PTC patients. Lasso regression method was used to screen risk factors and construct a nomogram for predicting LLNM. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) of the nomogram models were carried out for the training and validation cohorts. Results Gender, SIC, smoking history, drinking history, family history of PTC, multifocality, bilateral or unilateral tumors, TSH, Tg, and tumor size were included in the nomogram model predicting LLNM, with an area under the curve (AUC) of .795. The nomogram model showed good calibration and clinical benefit in both the training and validation cohorts. Conclusion The nomogram model based on iodine nutrition and other clinicopathological features is effective for predicting the lateral lymph node metastasis in PTC patients.

Black rockfish (Sebastes schlegelii) is one of the most important marine economic viviparous fishes. Recently, germplasm degradation and genetic diversity reduction have occurred due to overfishing and long-term artificial breeding. Germ cell transplantation combined with cryopreservation may be an alternative way to protect genetic resources. However, in viviparous fish that undertake fertilization and embryo development in vivo, transplantation is more difficult than in oviparous fish, including selection of transplantation stage, isolation of germ stem cells, and preparation of sterile recipients. This seriously restricts the development of viviparous transplantation. Therefore, in this study, we aimed to explore a transplantation method suitable for these species. Donor cells were isolated from cryopreserved whole testes of 300–400 ​g male Sebastes schlegelii in May, labeled by PKH26, and intra-peritoneally transplanted into allogeneic larvae at 5–10 days post-birth. Subsequently, the development of donor-derived cells in recipients were continuously detected by fluorescence labeling, histology, microsatellite markers, and fecundity tests. The results showed that donors were rich in spermatogonia (75%) and recipients maintained a high survival rate after transplantation, with a rate of >20% at sexual maturity. Further, donor-derived cells successfully migrated (100%), colonized, and incorporated into the developing recipient gonad (93.33%). Finally, transplanted recipients could normally develop and differentiate into male and female individuals, with donor-derived gametes found in 65.38% of mature recipients. In the present study, we first establish a simple and suitable transplantation method for Sebastes schlegelii using immature males and specific larvae, which will serve as a promising tool in the protection of germplasm resources for this transplantation-restricted marine viviparous species.

ABSTRACT Bacteria are known to cope with amino acid starvation by the stringent response signaling system, which is mediated by the accumulation of the (p)ppGpp alarmones when uncharged tRNAs stall at the ribosomal A site. While a number of metabolic processes have been shown to be regulatory targets of the stringent response in many bacteria, the global impact of amino acid starvation on bacterial metabolism remains obscure. This work reports the metabolomic profiling of the human pathogen Streptococcus pneumoniae under methionine starvation. Methionine limitation led to the massive overhaul of the pneumococcal metabolome. In particular, methionine-starved pneumococci showed a massive accumulation of many metabolites such as glutamine, glutamic acid, lactate, and cyclic AMP (cAMP). In the meantime, methionine-starved pneumococci showed a lower intracellular pH and prolonged survival. Isotope tracing revealed that pneumococci depend predominantly on amino acid uptake to replenish intracellular glutamine but cannot convert glutamine to methionine. Further genetic and biochemical analyses strongly suggested that glutamine is involved in the formation of a “prosurvival” metabolic state by maintaining an appropriate intracellular pH, which is accomplished by the enzymatic release of ammonia from glutamine. Methionine starvation-induced intracellular pH reduction and glutamine accumulation also occurred to various extents under the limitation of other amino acids. These findings have uncovered a new metabolic mechanism of bacterial adaptation to amino acid limitation and perhaps other stresses, which may be used as a potential therapeutic target for infection control. IMPORTANCE Bacteria are known to cope with amino acid starvation by halting growth and prolonging survival via the stringent response signaling system. Previous investigations have allowed us to understand how the stringent response regulates many aspects of macromolecule synthesis and catabolism, but how amino acid starvation promotes bacterial survival at the metabolic level remains largely unclear. This paper reports our systematic profiling of the methionine starvation-induced metabolome in S. pneumoniae. To the best of our knowledge, this represents the first reported bacterial metabolome under amino acid starvation. These data have revealed that the significant accumulation of glutamine and lactate enables S. pneumoniae to form a “prosurvival” metabolic state with a lower intracellular pH, which inhibits bacterial growth for prolonged survival. Our findings have provided insightful information on the metabolic mechanisms of pneumococcal adaptation to nutrient limitation during the colonization of the human upper airway.

ABSTRACTObjectives T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL.Methods We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).Results All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170–1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1).Conclusion Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated.

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.

To determine the composition and protective effect on Raw 264.7 cells of polysaccharide from Pseudostellaria heterophylla as a traditional Chinese medicinal, the main active ingredient-Pseudostellaria heterophylla polysaccharide (PHP) was extracted by water, precipitated by ethanol, and purified by anion exchange column chromatography. Gel permeation chromatography (GPC) and high performance liquid chromatography (HPLC) were used to determine molecular weight and monosaccharide composition of PHP. Ultraviolet spectroscopy (UV) and Fourier transform infrared spectroscopy (FT-IR) were used for primary structural characterization of PHP. Furthermore, the Raw 264.7 cell model was used to explore protective effect of PHP on Raw 264.7 cells induced by LPS. The results showed that the yield of crude polysaccharide of Pseudostellaria heterophylla was 8.23%, and the polysaccharide content was 51.47%. After purification by DEAE-52 column chromatography, the polysaccharide content increased to 80.52%, and the molecular weight distribution was between 500 to 92×103 Da. The monosaccharide components of PHP include glucose, galactose, arabinose, mannose and glucuronic acid. Cell experiments showed that the safe dose of PHP was 80~640 µg/mL and could increase the survival rate of cells induced by lipopolysaccharide (LPS). At a dose of 640 µg/mL, the survival rate increased by 7.21%, and it was found that PHP could improve the morphology of Raw 264.7 cells. In summary, in this study the polysaccharides from Pseudostellaria heterophylla were purified, the structure of PHP was characterized, and it was preliminarily confirmed that PHP had potential protective effect on LPS-induced damage to Raw 264.7 cells. This laid the foundation for the follow-up exploration of functional activity, structure-effect and dose-effect of PHP.

Abstract Enzymes with dedicated cofactor preference are essential for advanced biocatalysis and biomanufacturing, especially when employing nonnatural nicotinamide cofactors in redox reactions. However, directed evolution of an enzyme to switch its cofactor preference is often hindered by the lack of efficient and affordable method for screening as the cofactor per se or the substrate can be prohibitively expensive. Here, we developed a growth-based selection platform to identify nonnatural cofactor-dependent oxidoreductase mutants. The growth of bacteria depended on the nicotinamide cytosine dinucleotide (NCD) mediated conversion of non-metabolizable phosphite into phosphate. The strain BW14329 lacking the ability to oxidize phosphite was suitable as host, and NCD-dependent phosphite dehydrogenase (Pdh*) is essential to the selection platform. Previously confirmed NCD synthetase with NCD synthesis capacity and NCD-dependent malic enzyme were successfully identified by using the platform. The feasibility of this strategy was successfully demonstrated using derived NCD-active malic enzyme as well as for the directed evolution of NCD synthetase in Escherichia coli. A phosphite-based screening platform was built for identification of enzymes favoring nonnatural cofactor NCD. In the future, once Pdh variants favoring other biomimetic or nonnatural cofactors are available this selection platform may be readily redesigned to attain new enzyme variants with anticipated cofactor preference, providing opportunities to further expand the chemical space of redox cofactors in chemical biology and synthetic biology.

Abstract Prostate cancer (PC) is a common tumor in men, and the incidence rate is high worldwide. Exosomes are nanosized vesicles released by all types of cells into multiple biological fluid types. These vesicles contribute to intercellular communication by delivering both nucleic acids and proteins to recipient cells. In recent years, many studies have explored the mechanisms by which exosomes mediate the epithelial-mesenchymal transition, angiogenesis, tumor microenvironment establishment, and drug resistance acquisition in PC, and the mechanisms that have been identified and the molecules involved have provided new perspectives for the possible discovery of novel diagnostic markers in PC. Furthermore, the excellent biophysical properties of exosomes, such as their high stability, high biocompatibility and ability to cross biological barriers, have made exosomes promising candidates for use in novel targeted drug delivery system development. In this review, we summarize the roles of exosomes in the growth and signal transmission in PC and show the promising future of exosome contributions to PC diagnostics and treatment.

Abstract In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune “cold” tumors into “hot” tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.

The large-scale access of distributed energy resources has a certain impact on the power grid, so distributed energy resources cannot participate in the power market transactions alone. The concept of the virtual power plant (VPP) has thus emerged, which can aggregate distributed power sources and controllable loads in a region for coordinated regulation. The trading of VPPs should not only consider the economy but also its degree of low carbon. Therefore, this paper constructs a unified bidding strategy for multi-VPPs that considers carbon–electricity integration trading. We design a multi-game trading strategy among multi-VPPs to achieve unified trading, after each VPP determines its internal trading strategy. Finally, through simulation, we verify that the multiple game strategy between multi-VPPs that considers carbon trading here proposed can effectively improve the efficiency and trading income of VPPs and promote the consumption of new energy.

Abstract Primary liver cancer, with the predominant form as hepatocellular carcinoma (HCC), remains a worldwide health problem due to its aggressive and lethal nature. Transarterial chemoembolization, the first‐line treatment option of unresectable HCC that employs drug‐loaded embolic agents to occlude tumor‐feeding arteries and concomitantly delivers chemotherapeutic drugs into the tumor, is still under fierce debate in terms of the treatment parameters. The models that can produce in‐depth knowledge of the overall intratumoral drug release behavior are lacking. This study engineers a 3D tumor‐mimicking drug release model, which successfully overcomes the substantial limitations of conventional in vitro models through utilizing decellularized liver organ as a drug‐testing platform that uniquely incorporates three key features, i.e., complex vasculature systems, drug‐diffusible electronegative extracellular matrix, and controlled drug depletion. This drug release model combining with deep learning‐based computational analyses for the first time permits quantitative evaluation of all important parameters associated with locoregional drug release, including endovascular embolization distribution, intravascular drug retention, and extravascular drug diffusion, and establishes long‐term in vitro–in vivo correlations with in‐human results up to 80 d. This model offers a versatile platform incorporating both tumor‐specific drug diffusion and elimination settings for quantitative evaluation of spatiotemporal drug release kinetics within solid tumors.