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Abstract Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA biosynthesis in adult mouse mDA neurons. Mice carrying Jmjd3 conditional knockout or undergoing pharmaceutical inhibition of JMJD3 showed consistent reduction of DA content in midbrain and striatum. Histological examination of both mice confirmed that TH and NURR1, two key molecules in DA biosynthesis pathway, were decreased in mDA neurons. Mechanistic experiments in vivo and in vitro further demonstrated that the transcriptions of Th and Nurr1 in mDA neurons were suppressed by JMJD3 deficiency, because of increased repressive H3K27me3 and attenuated bindings of JMJD3 and NURR1 on the promoters of both genes. On behavioral level, a significant prolonged inflammation-induced mechanical hyperalgesia was found in conditional knockout mice regardless of sex and age, whereas motor function appeared to be intact. Our findings establish a novel link between DA level in mDA neurons with intrinsic JMJD3 activity, and suggest prolonged chronic inflammatory pain as a major loss-of-function consequence.

Purpose The objective of this study was to evaluate the diagnostic value of transvaginal contrast-enhanced ultrasound (CEUS) in differentiating benign from malignant endometrial lesions and assessing the extent of myometrial invasion. Methods A total of 70 patients who underwent surgery for endometrial lesions at the authors’ hospital were selected. Transvaginal ultrasound examination and CEUS were performed for quantitative and qualitative analysis. Based on the CEUS results, an International Federation of Gynecology and Obstetrics (FIGO) disease grade was assigned and compared with pathological findings. Results Postmenopausal vaginal bleeding is a key clinical manifestation of endometrial carcinoma. Among the patients with endometrial carcinoma, compared with normal myometrium, the lesion areas exhibited a greater rate of rise (defined as enhanced intensity divided by enhancement time) and a shorter half-clearance time (P

Abstract Breast cancer is the most common malignant tumor in women, and triple-negative breast cancer (TNBC) is a specific subtype of breast cancer characterized by high invasiveness, high metastatic potential, ease of recurrence, and poor prognosis. Src-like adaptor protein 2 (SLAP2), which can be involved in the regulation of multiple signaling pathways, may be a key target for TNBC. The aim of this study was to investigate the effect of overexpression of SLAP2 on TNBC and to explore the underlying mechanisms. First, we constructed and transfected SLAP2 overexpressing lentivirus based on MDA-MB-231 human TNBC cell line, screened for differential downstream target genes in combination with mRNA high-throughput sequencing (RNA-Seq), and predicted their functions and enriched pathways in conjunction with bioinformatics analysis. The effects of SLAP2 overexpression on macrophage polarization, as well as on tumor proliferation and apoptosis, were assessed by tail vein injection of a stable transfection line of 4T1 cells transfected with SLAP2 overexpressing lentivirus. The effect of SLAP2 on macrophage polarization was assessed by inducing M1/M2 polarization and transfecting SLAP2 overexpressing lentivirus. Meanwhile, a transwell co-culture system was constructed between differently treated macrophages and 4T1 cells to assess the effect of SLAP2 overexpression on the malignant behavior of the cells via macrophage polarization. Overexpression of SLAP2 revealed 179 genes up-regulated and 74 genes down-regulated by mRNA high-throughput sequencing, and the enriched functions and pathways of differential genes were mainly related to immunity response. In vivo experiments revealed that overexpression of SLAP2 inhibited the growth of tumor in nude mice, decreased the expression of ki67 in tumor tissues, and increased the rate of apoptosis in tumor tissues. Meanwhile, we found that overexpression of SLAP2 promoted macrophage polarization toward M1 type and inhibited M2 type polarization in tumors. In vitro experiments further verified its effect on M1/M2 polarization by transfecting SLAP2 overexpressing lentivirus. By transwell co-culture system, we further demonstrated that overexpression of SLAP2 inhibits cell proliferation and invasion, promotes apoptosis, up-regulates the expression of Bax in cells, and down-regulates the expression of Bcl-2 in cells by promoting macrophage M1-type polarization. Overexpression of SLAP2 inhibits TNBC progression by promoting macrophage M1-type polarization.

ABSTRACT Background Angiopoietin‐like protein 4 (ANGPTL4) is critical for vascular integrity and reducing inflammation in ischemic and hypoxic brain injuries. However, limited studies have evaluated ANGPTL4's role in acute ischemic stroke (AIS) assessment, and its expression patterns across AIS phases remain unclear. Methods The severity of AIS at admission was assessed using the National Institutes of Health Stroke Scale (NIHSS). The association between serum ANGPTL4 level and the occurrence of AIS was examined using logistic regression analysis. The diagnostic accuracy of serum ANGPTL4 level for AIS severity was assessed using receiver operating characteristic curves. Results This study included 389 AIS patients and 133 healthy individuals. There was a notable increase in the occurrence of AIS associated with rising serum ANGPTL4 levels (odds ratio [OR] 1.03, 95% confidence interval [CI]: 1.02–1.06; p

IntroductionTraditional Miao and Dai Chinese medicines have used nicotine-rich leaf tobacco to treat traumatic injuries by promoting hemostasis. While nicotine is known to enhance platelet aggregation, its effects on other platelet functions and underlying mechanisms remain unclear.Methods and ResultsThis study aimed to thoroughly investigate nicotine’s effects on human platelets and its pharmacological mechanisms, using thromboelastography to assess nicotine’s impact on platelet function during coagulation. This study aimed to investigate the functional effects of nicotine on human platelets and elucidate its pharmacological mechanisms. The impact of nicotine on platelet function during the coagulation process was assessed using thromboelastography. Further studies showed that nicotine fully activates washed platelets, promoting aggregation, granule release, adhesion, spreading, and plaque retraction. Concurrently, nicotine was found to enhance the intracellular concentration of calcium ions in platelets ([Ca2+]i). To explore the underlying mechanisms, molecular docking software was employed to identify the platelet membrane receptors PAR1 and PAR4, which exhibited the highest docking scores with nicotine. Intervention with two receptor inhibitors demonstrated that only the PAR4 inhibitor could reverse the stimulatory effects of nicotine on platelet granule release. Through the examination of alterations in the downstream signaling pathways of PAR4 receptors, it was determined that nicotine promo-facilitates the phosphorylation of PI3K, AKT, and ERK1/2 proteins, subsequently contributing to the activation of αIIbβ3 receptors in platelets. Conversely, the application of PAR4 inhibitors was found to reverse these effects.DiscussionIn conclusion, nicotine activates αIIbβ3 receptors and significantly enhances platelet function by promoting the phosphorylation of the platelet PAR4 receptor signaling pathway. These findings suggest the potential utility of nicotine as a hemostatic agent.

Abstract Hydrocephalus can affect brain function and motor ability. Current treatments mostly involve invasive surgeries, with a high risk of postoperative infections and failure. A successful animal model plays a significant role in developing new treatments for hydrocephalus. Hydrocephalus was induced in Sprague–Dawley rats by injecting 25% kaolin into the subarachnoid space at the cerebral convexities with different volumes of 30, 60 and 90 μL. Magnetic resonance imaging (MRI) was performed 1 month and 4 months after kaolin injection. The behavioral performance was assessed weekly, lasting for 7 weeks. The histopathological analyses were conducted to the lateral ventricles by hematoxylin–eosin (HE) staining. Transcriptomic analysis was used between Normal Pressure Hydrocephalus (NPH) patients and hydrocephalus rats. MRI showed a progressive enlargement of ventricles in hydrocephalus group. Kaolin‐60 μL and kaolin‐90 μL groups showed larger ventricular size, higher anxiety level, bigger decline in body weight, motor ability and cognitive competence. These symptoms may be due to higher‐grade inflammatory infiltrate and the damage of the structure of ependymal layer of the ventricles, indicated by HE staining. The overlap upregulated genes and pathways mainly involve immunity and inflammation. Transcriptomic revealed shared pathogenic genes CD40, CD44, CXCL10, and ICAM1 playing a dominance role. 60 μL injection might be recommended for the establishment of hydrocephalus animal model, with a high successful rate and high stability. The hydrocephalus model was able to resemble the inflammatory mechanism and behavioral performance observed in human NPH patients, providing insights for identifying therapeutic targets for hydrocephalus.

Abstract The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual’s genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner’s fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.

Abstract Ketamine has recently become an anesthetic drug used in human and veterinary clinical medicine for illicit abuse worldwide, but the detection of illicit abuse and inference of time intervals following ketamine abuse are challenging issues in forensic toxicological investigations. Here, we developed methods to estimate time intervals since ketamine use is based on significant metabolite changes in rat serum over time after a single intraperitoneal injection of ketamine, and global metabolomics was quantified by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF–MS). Thirty-five rats were treated with saline (control) or ketamine at 3 doses (30, 60, and 90 mg/kg), and the serum was collected at 21 time points (0 h to 29 d). Time-dependent rather than dose-dependent features were observed. Thirty-nine potential biomarkers were identified, including ketamine and its metabolites, lipids, serotonin and other molecules, which were used for building a random forest model to estimate time intervals up to 29 days after ketamine treatment. The accuracy of the model was 85.37% in the cross-validation set and 58.33% in the validation set. This study provides further understanding of the time-dependent changes in metabolites induced by ketamine abuse.

In this study, we delve into the intrinsic mechanisms of cell communication in hepatocellular carcinoma (HCC). Initially, employing single-cell sequencing, we analyze multiple malignant cell subpopulations and cancer-associated fibroblast (CAF) subpopulations, revealing their interplay through receptor-ligand interactions, with a particular focus on SPP1. Subsequently, employing unsupervised clustering analysis, we delineate two clusters, C1 and C2, and compare their infiltration characteristics using various tools and metrics, uncovering heightened cytotoxicity and overall invasion abundance in C1. Furthermore, our gene risk scoring model indicates heightened activity of the immune therapeutic pathway in C1. Lastly, employing a formulated scoring system, we stratify patients into high and low-risk groups, revealing notably poorer outcomes in the high-risk cohort on Kaplan-Meier curves. Risk scores exhibit a negative correlation with model genes and immune cell infiltration scores, indicating poor prognosis in the high-risk group. Further characterization elucidates the regulatory landscape of the high and low-risk groups across various signaling pathways. In addition, we used wet lab experiments to prove that ABCA1 plays a pro-oncogenic role in hepatocellular carcinoma cells by promoting proliferation, invasion, migration, and reducing apoptosis. In summary, these findings provide crucial insights, offering valuable clues and references for understanding HCC pathogenesis and patient prognosis.

Organisms detect temperature signals through peripheral neurons, which relay them to central circadian networks to drive adaptive behaviors. Despite recent advances in Drosophila research, how circadian circuits integrate temperature cues with circadian signals to regulate sleep/wake patterns remains unclear. In this study, we used the FlyWire brain electron microscopy connectome to map neuronal connections, identifying lateral posterior neurons LPNs as key nodes for integrating temperature information into the circadian network. LPNs receive input from both circadian and temperature-sensing neurons, promoting sleep behavior. Through connectome analysis, genetic manipulation, and behavioral assays, we demonstrated that LPNs, downstream of thermo-sensitive anterior cells (ACs), suppress activity-promoting lateral dorsal neurons LNds via the AstC pathway, inducing sleep Disrupting LPN-LNd communication through either AstCR1 RNAi in LNds or in an AstCR1 mutant significantly impairs the heat-induced reduction in the evening activity peak. Conversely, optogenetic calcium imaging and behavioral assays revealed that cold-activated LNds subsequently stimulate LPNs through NPF-NPFR signaling, establishing a negative feedback loop. This feedback mechanism limits LNd activation to appropriate levels, thereby fine-tuning the evening peak increase at lower temperatures. In conclusion, our study constructed a comprehensive connectome centered on LPNs and identified a novel peptidergic circadian feedback circuit that coordinates temperature and circadian signals, offering new insights into the regulation of sleep patterns in Drosophila.

BackgroundKabuki syndrome is a genetic syndrome that affects multiple organs and systems. Gene mutations are the main cause of KS. Mutations in the KMT2D and KDM6A genes have been reported as two relatively clear pathogenic pathways. This article reports a case of KS with congenital heart disease, hearing abnormalities, and hypoglycemia caused by a KMT2D gene mutation confirmed by clinical exome sequencing, enriching the clinical phenotype and gene mutation spectrum of KS and helping to improve understanding of the disease.Case presentationThrough clinical exome sequencing, we performed genetic diagnosis on a newborn with congenital heart malformation and identified a heterozygous mutation in the KMT2D gene, NM_003482.3:c.4195C>T (p.Gln1399*), which has not been reported as a pathogenic mutation before. This variant was not detected in the peripheral blood of the patient's parents, suggesting it is a de novo mutation.DiscussionKS has strong clinical characteristics and biological heterogeneity. Genetic diagnosis can help identify the types of mutated genes. Our results provide some clues for KS caused by KMT2D gene mutations associated with congenital heart disease, hearing abnormalities, and hypoglycemia. However, the relationship between genotype and phenotype is not yet fully understood. The molecular pathogenesis of KS still needs further exploration and clarification.

Abstract Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress‐related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome‐related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte‐specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive‐like behaviors by inhibiting lysosomal exocytosis‐mediated adenosine 5′‐triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive‐like behaviors induced by astrocyte‐specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress‐sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

Abstract Anaplasma and Ehrlichia are tick-borne bacterial pathogens that cause anaplasmoses and ehrlichioses in humans and animals. In this study, we examined the prevalence of Anaplasma and Ehrlichia species in ticks and domesticated animals in Suizhou County, Hubei Province in the central China. We used PCR amplification and DNA sequencing of the 16S rRNA, groEL, and gltA genes to analyze. We collected 1900 ticks, including 1981 Haemaphysalis longicornis and 9 Rhipicephalus microplus, 159 blood samples of goats (n = 152), cattle (n = 4), and dogs (n = 3) from May to August of 2023. PCR products demonstrated that Anaplasma bovis, Anaplasma capra, and an Ehrlichia species were detected in the H. longicornis with the minimum infection rates (MIR) of 1.11%, 1.32%, and 0.05%, respectively; A. bovis, A. capra, and unnamed Anaplasma sp. were detected in goats with an infection rate of 26.31%, 1.31% and 1.97%, respectively. Anaplasma and Ehrlichia species were not detected from cattle, dogs and R. microplus ticks. The genetic differences in the groEL gene sequences of the Anaplasma in the current study were large, whereas the 16S rRNA and gltA gene sequences were less disparate. This study shows that ticks and goats in Suizhou County, Hubei Province carry multiple Anaplasma species and an Ehrlichia species, with relatively higher infection rate of A. bovis in goats. Our study indicates that multiple Anaplasma and Ehrlichia species exist in ticks and goats in the central China with potential to cause human infection.

Abstract Background Family-centered empowerment programs have been widely used in the pediatric field. Therefore, the current study investigated the effectiveness of family empowerment programs on caregiving ability and adverse mood among caregivers of children with acute leukemia. Objective To evaluate the effect of a family empowerment program on the caregiving ability and adverse mood of caregivers of children with acute leukemia. Methods Sixty-eight children with acute leukemia and their family caregivers admitted to our hospital were selected for the study. The control group received routine care during hospitalization, and the family empowerment program was implemented in the intervention group to compare the changes in caregiving capacity (FCTI), illness uncertainty (PPUS) and anxiety(SAS)of the caregivers of the two groups. Results After 8 weeks of intervention, the FCTI score of the intervention group was significantly lower than that of the control group (P

Abstract Under long-standing threat of seasonal influenza outbreaks, it remains imperative to understand the drivers of influenza dynamics which can guide mitigation measures. While the role of absolute humidity and temperature is extensively studied, the possibility of ambient ozone (O3) as an environmental driver of influenza has received scant attention. Here, using state-level data in the USA during 2010–2015, we examined such research hypothesis. For rigorous causal inference by evidence triangulation, we applied 3 distinct methods for data analysis: Convergent Cross Mapping from state-space reconstruction theory, Peter-Clark-momentary-conditional-independence plus as graphical modeling algorithms, and regression-based Generalised Linear Model. The negative impact of ambient O3 on influenza activity at 1-week lag is consistently demonstrated by those 3 methods. With O3 commonly known as air pollutant, the novel findings here on the inhibition effect of O3 on influenza activity warrant further investigations to inform environmental management and public health protection.

Abstract Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients’ blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Abstract Oncolytic viruses (OVs) offer a novel approach to treat solid tumors; however, their efficacy is frequently suboptimal due to various limiting factors. To address this challenge, we engineered an OV containing targets for neuron-specific microRNA-124 and Granulocyte-macrophage colony-stimulating factor (GM-CSF), significantly enhancing its neuronal safety while minimally compromising its replication capacity. Moreover, we identified PARP1 as an HSV-1 replication restriction factor using genome-wide CRISPR screening. In models of glioblastoma (GBM) and triple-negative breast cancer (TNBC), we showed that the combination of OV and a PARP inhibitor (PARPi) exhibited superior efficacy compared to either monotherapy. Additionally, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy sensitized TNBC to immune checkpoint blockade, and the incorporation of an immune checkpoint inhibitor (ICI) further increased the survival rate of tumor-bearing mice. The combination of PARPi and ICI synergistically enhanced the ability of OV to establish durable tumor-specific immune responses. Our study effectively overcomes the inherent limitations of OV therapy, providing valuable insights for the clinical treatment of TNBC, GBM, and other malignancies.

The quality detection of alfalfa hay is crucial for the development of animal husbandry. In this study, a method for quality detection of alfalfa hay based on the fusion of multisource information including near-infrared spectroscopy, image processing techniques, and electronic nose is proposed. After SG convolution smoothing, feature wavelengths were extracted using Competitive Adaptive Re-weighting Scheme and Successive Projections Algorithm from the spectral data. The image data were denoised using adaptive wavelet thresholding, and color and texture features were extracted using color histograms and random forest algorithms, respectively. Electronic nose data using principal component analysis was used for data dimensionality reduction. Support Vector Machine, Extreme Learning Machine, and Multi-Layer Perceptron were employed to establish quality detection models of alfalfa hay based on spectroscopy, image, gas information, and their combination, respectively. Experimental results demonstrate that the fusion of near-infrared spectroscopy, image data, and gas information effectively enhances the classification accuracy of the model. The accuracy of the test set reaches 100%, with root mean square error and determination coefficient values of 0.1728 and 0.9239, respectively, surpassing prediction models established solely on individual information. This study provides new insights into alfalfa hay quality detection.

Biosynthesis of atypical angucyclines involves unique oxidative B-ring cleavage and rearrangement reactions, which are catalyzed by AlpJ-family oxygenases, including AlpJ, JadG, and GilOII. Prior investigations established the essential requirement for FADH2/FMNH2 as cofactors when utilizing the quinone intermediate dehydrorabelomycin as a substrate. In this study, we unveil a previously unrecognized facet of these enzymes as cofactor-independent oxygenases when employing the hydroquinone intermediate CR1 as a substrate. The enzymes autonomously drive oxidative ring cleavage and rearrangement reactions of CR1, yielding products identical to those observed in cofactor-dependent reactions of AlpJ-family oxygenases. Furthermore, the AlpJ- and JadG-catalyzed reactions of CR1 could be quenched by superoxide dismutase, supporting a catalytic mechanism wherein the substrate CR1 reductively activates molecular oxygen, generating a substrate radical and the superoxide anion O2•−. Our findings illuminate a substrate-controlled catalytic mechanism of AlpJ-family oxygenases, expanding the realm of cofactor-independent oxygenases. Notably, AlpJ-family oxygenases stand as a pioneering example of enzymes capable of catalyzing oxidative reactions in either an FADH2/FMNH2-dependent or cofactor-independent manner.

Abstract The circadian clock regulates animal physiological activities. How temperature reorganizes circadian-dependent physiological activities remains elusive. Here, using in-vivo two-photon imaging with the temperature control device, we investigated the response of the Drosophila central circadian circuit to temperature variation and identified that DN1as serves as the most sensitive temperature-sensing neurons. The circadian clock gate DN1a’s diurnal temperature response. Trans-synaptic tracing, connectome analysis, and functional imaging data reveal that DN1as bidirectionally targets two circadian neuronal subsets: activity-related E cells and sleep-promoting DN3s. Specifically, behavioral data demonstrate that the DN1a-E cell circuit modulates the evening locomotion peak in response to cold temperature, while the DN1a-DN3 circuit controls the warm temperature-induced nocturnal sleep reduction. Our findings systematically and comprehensively illustrate how the central circadian circuit dynamically integrates temperature and light signals to effectively coordinate wakefulness and sleep at different times of the day, shedding light on the conserved neural mechanisms underlying temperature-regulated circadian physiology in animals.

Abstract Background Traditional biochemical screening for neonatal inherited metabolic diseases has high false-positive rates and low positive predictive values, which are not conducive to early diagnosis and increase parents’ anxiety. This study analysed the relationship between gene variant carriers and their biochemical indicators in traditional biochemical screening, aiming to find explanations for false positives in newborns. Results This retrospective study included 962 newborns. Newborns underwent traditional biochemical screening at birth using blood staining and genomic sequencing of their stored blood staining using the NeoSeq Pro panel, which was able to detect 154 pathogenic genes and 86 diseases. A total of 632 newborns were carriers of gene variants. 56% of congenital hypothyroidism carriers had higher thyroid-stimulating hormone levels than normal newborns. Abnormal biochemical indices were detected in 71% of carriers of organic acid metabolic diseases, 69% of carriers of amino acid metabolic diseases, and 85% of carriers of fatty acid β oxidation disorders. In carriers associated with organic acid metabolic diseases, the propionylcarnitine (C3), C3/acetylcarnitine (C2), and methylmalonylcarnitine (C4DC) + 3-hydroxyisovalerylcarnitine (C5OH) levels were higher than those in non-carriers (C3: 4.12 vs. 1.66 µmol/L; C3/C2: 0.15 vs. 0.09; C4DC + C5OH: 0.22 vs. 0.19 µmol/L). In carriers associated with amino acid metabolic diseases, phenylalanine levels were higher than those in non-carriers (68.00 vs. 52.05 µmol/L). For carriers of fatty acid β oxidation disorders, butyrylcarnitine levels were higher than those in non-carriers (0.31 vs. 0.21 µmol/L), while the free carnitine levels were lower than those in non-carriers (14.65 vs. 21.87 µmol/L). There was a higher occurrence of carriers among newborns who received false-positive results for amino acid metabolic diseases compared to those who received negative results (15.52% vs. 6.71%). Similarly, there was a higher occurrence of carriers among newborns who received false-positive results for fatty acid β oxidation disorders compared to those who received negative results (28.30% vs. 7.29%). Conclusions This study showed that the carriers comprised a large number of newborns. Carriers had abnormal biochemical indicators compared with non-carriers, which could explain the false-positive rate for newborns using traditional newborn biochemical screening, especially in amino acid metabolic and fatty acid β oxidation disorders.

In this study, a quantitative model was developed using near-infrared spectroscopy to analyze protein content in dried purple alfalfa, employing preprocessing methods (SG, SNV, MSC, FD) and variable selection algorithms (CARS, IRIV) to optimize spectra. Models using ELM, PLSR, SVM, and LSTM were tested; the MSC-CARS-PLSR-SVM model achieved the highest accuracy, with a calibration determination coefficient (R²) of 0.9982 and root mean square error (RMSE) of 0.1088, and a prediction R² of 0.9645 with RMSE of 0.5230, offering a precise and reliable method for protein content prediction.

The phenomenon of patient mobility is becoming increasingly frequent, altering the actual service ranges of hospitals across various cities. However, its impact on the spatial equity of healthcare services at the national scale has yet to be fully explored. This paper aims to reveal the impact of intercity patient mobility on healthcare equity in China. Using one million patient mobility records from online healthcare platforms, we construct the 2023 Cross-City Patient Mobility Network in China and identify the patterns of cross-city patient mobility. Furthermore, we employ the Dagum Gini coefficient to measure the spatial disparities in per capita healthcare services before and after patient mobility. The results show that: (1) cross-city patient mobility exhibits administrative boundary effects and reflects the administrative hierarchy system, yet megacities extend their healthcare service ranges beyond provincial and urban agglomeration boundaries; (2) patient mobility enhances the equity of per capita healthcare services at both intra-provincial and inter-provincial levels, with inter-provincial disparities contributing significantly more than intra-provincial disparities—a trend further reinforced by patient mobility. This study not only provides a methodological framework for understanding the impact of patient mobility on the healthcare system but also offers empirical support for public health policymaking.

Regarding the issue of low granulation qualification rates during the granulation coating of red clover seeds, this study theoretically analyzed the force conditions of seeds and powder particles under the action of liquid to obtain the main factors affecting seed coating quality. During the seed granulation coating process, an intermittent powder supply method combined with continuous liquid supply was utilized to control the ratio of powder to liquid. Using the granulation qualification rate as the evaluation index, single-factor experiments were conducted to investigate the effects of coating pan fill ratio, single powder supply amount, powder supply interval, and liquid supply amount on the quality of red clover seed granulation coating. Based on the results of the single-factor experiments, orthogonal experiments were conducted, revealing that the interaction of factors would influence the experimental results. To further optimize the quality of seed granulation coating, the mechanisms of powder and liquid in the adhesion process on granulation coating were explored. Orthogonal experiments were conducted on the process parameters of the granulation coating machine, and the GA-BP model was employed for optimization and solution. The optimal process parameter combination obtained was a coating pan fill ratio of 33.78 %, a single powder supply amount of 5.17 g, a powder supply interval of 7.7 s, and a liquid supply amount of 0.42 mL/s. Under this optimal parameter combination, granulation coating experiments with red clover seeds were performed, and the seed granulation coating quality was relatively high, with a granulation qualification rate of 97.7 %. The research results can provide a reference for optimization experiments on coating irregular seeds.

Accurate estimation of the State of Health (SOH) of batteries is important for intelligent battery management in energy storage systems. To solve the problems of poor quality of data features as well as the difficulty of model parameter adjustment, this study proposes a method for estimating the SOH of lithium batteries based on denoising battery health features and an improved Long Short-Term Memory (LSTM) neural network. First, in this study, three health features related to SOH decrease were selected from the battery charge/discharge data, and the singular value decomposition technique was applied to the noise reduction of the features to improve their correlation with the SOH. Then, the whale optimization algorithm is improved using cubic chaotic mapping to enhance its global optimization-seeking capability. Then, the Improved Whale Optimization Algorithm (IWOA) is used to optimize the model parameters of LSTM, and the IWOA-LSTM model is applied to the battery SOH estimation. Finally, the model proposed in this research is validated against the Center for Advanced Life Cycle Engineering (CALCE) battery dataset. The experimental results show that the prediction error of battery SOH by the method proposed in this study is less than 0.96%, and the prediction error is reduced by 49.42% compared to its baseline model. The method presented in the article achieves accurate estimation of the SOH, providing a reference for practical engineering applications.

Energy storage batteries still have usable capacity after retirement, with excellent secondary utilization value. Estimating the state of health (SOH) of retired batteries is critical to ensure their reuse. As the battery first reaches the end of its useful life, its performance degradation pattern significantly differs from that in service, increasing the difficulty of accurate SOH estimation. This study developed a SOH estimation method for retired batteries based on battery positive, negative, and center temperature data from 80% to 50% of retired battery health. The variational mode decomposition technique divides the temperature signal into multiple trends representing different battery aging mechanisms. The decomposed modes are given a physical meaningfulness, providing a new perspective to monitor battery health. In addition, this study proposes a multi-task learning framework that realizes the parallel processing of two tasks under this framework. On the one hand, the gated recurrent unit is used to estimate the relationship between the battery baseline temperature and SOH, which captures macro-degradation trends of the battery. On the other hand, the transformer network is responsible for analyzing short-term battery health fluctuations caused by subtle temperature changes. This multi-task approach can simultaneously process and analyze both macro-degradation trends and micro-fluctuations in battery degradation, estimating that the root mean square error of battery health is 5.22 × 10−5. Compared to the existing techniques, this study shows potential applications in the retired battery state of health assessment.

Modular Multilevel Converter Based High Voltage Direct Current (MMC-HVDC) system is an important technical means to realize grid connection and transmission of new energy. When the external disturbance occurs in the MMC-HVDC system, the submodule capacitance voltages suffer instant impact due to the mutual coupling in the MMC, which causes transient fluctuation and unstable operation of the system. In order to suppress the impact of external disturbance on the internal submodule capacitance voltage transient fluctuations of MMC-HVDC system, the transient fluctuation suppression strategy based on gain-varying extended disturbance observer is proposed in this paper. Firstly, the transient response characteristic equation of the submodule capacitor voltage fluctuation component for MMC-HVDC system is constructed, which reveals the relation between the external output and internal dynamic response of the system. Next, a gain-varying extended disturbance observer is proposed to effectively observe the time-varying disturbance current components in the system, and the corresponding submodule capacitor voltage transient fluctuation suppression strategy is then proposed to improve the dynamic response performance and anti-interference ability of the MMC-HVDC system under different disturbances. The simulation model of MMC-HVDC system is built on PSCAD/EMTDC platform, and the validity and correctness of the proposed method are verified by several simulation tests.

In this paper, a deep reinforcement learning (DRL) approach based on generative adversarial imitation learning (GAIL) and long short-term memory (LSTM) is proposed to resolve tracking control problems for robotic manipulators with saturation constraints and random disturbances, without learning the dynamic and kinematic model of the manipulator. Specifically, it limits the torque and joint angle to a certain range. Firstly, in order to cope with the instability problem during training and obtain a stability policy, soft actor–critic (SAC) and LSTM are combined. The changing trends of joint position over time are more comprehensively captured and understood by employing an LSTM architecture designed for robotic manipulator systems, thereby reducing instability during the training of robotic manipulators for tracking control tasks. Secondly, the obtained policy by SAC-LSTM is used as expert data for GAIL to learn a better control policy. This SAC-LSTM-GAIL (SL-GAIL) algorithm does not need to spend time exploring unknown environments and directly learns the control strategy from stable expert data. Finally, it is demonstrated by the simulation results that the end effector of the robot tracking task is effectively accomplished by the proposed SL-GAIL algorithm, and more superior stability is exhibited in a test environment with interference compared with other algorithms.

Although modern meteorological service and prediction systems have achieved good applications in numerical models, these models are often influenced by multiple random factors and cannot adapt well to the meteorological service and prediction needs of complex climate regions. Therefore, this article aims to designing an AI intelligent meteorological service platform to simulate what happens when people use it. Based on commonly used AI technologies in meteorological research, the temporal data algorithm mentioned in this article is used for prediction. This article selected the actual daily average water vapor pressure and daily average relative humidity data of three meteorological stations over the past 10 days for analysis. The maximum and minimum values of the actual daily average water vapor pressure in the 10 days of San Jose are 30.2 and 28.1 Pa, respectively, the maximum and minimum values of the actual daily average vapor pressure over 10 days of Cupertino are 30.4 and 28.4 Pa, respectively, and the maximum and minimum values of the actual daily average vapor pressure over 10 days of Santa Clara are 30.5 and 28.4 Pa, respectively, which can prove the effectiveness of AI-based intelligent virtual imaging meteorological services. HIGHLIGHTS Modern meteorological services and forecasting systems are susceptible to the influence of a variety of random factors and cannot well cope with the meteorological service and forecasting needs in complex climate areas.; With the continuous development and maturity of artificial intelligence (AI) algorithms represented by neural networks, meteorological departments are trying to use statistical methods to replace or compensate for traditional numerical models. This article also designs an AI weather service platform based on this to simulate what will happen when people use it.; This article selected the actual daily average water vapor pressure and daily average relative humidity data of three weather stations in the past 10 days for research and analysis, and found that the virtual imaging weather service system based on AI was more effective.;

[Introduction] Accurate estimation of the Li-ion batteries' State of Health (SoH) is essential for future intelligent battery management systems. To solve the problems of poor quality of data features and difficulties in adjusting model parameters, this study proposes a method for estimating the SoH of lithium batteries based on singular value fixed-order noise reduction and the sparrow search algorithm which can optimize the gated recurrent unit (GRU) neural network.[Method] Firstly, three indicators highly correlated with SoH decay were extracted from the battery charge and discharge data. Noise reduction was applied to the features using singular value decomposition techniques to improve their correlation with SoH. Next, using the sparrow search algorithm to optimize the model structure and parameters of the GRU neural network improve the accuracy of estimation of SoH. Finally, the battery data sets from Centre for Advanced Life Cycle Engineering (CALCE) were used to verify the validity of the proposed model. [Result] The experimental results show that the model proposed in this study applies to the battery SoH estimation, with a maximum root mean square error (RMSE) of only 0.018 4. After data noise reduction and algorithm optimization, the RMSE of the GRU model is reduced by 55.41% compared to the initial model. [Conclusion] The method proposed in this paper accurately estimates SoH and can be used as a reference for practical engineering applications.

Investigating the role of surface-modified 3D printed titanium implants in modulating oral soft tissue closure and antimicrobial properties. Eighteen 6-month-old healthy adult New Zealand White rabbits were selected as experimental animals, the left and right mandibular teeth of each experimental animal were randomly divided into two groups, and the bilateral first premolar teeth were extracted after general anesthesia, and one implant was implanted into each of the magnesium/zinc ionized surface-treated group (experimental group) and the surface-untreated group (control group), with a total of 36 implants, i.e., 18 implants for the experimental group and 18 implants for the control group. Bilateral mandibular samples from both groups were removed after 2 and 4 weeks of implantation to investigate the attachment and spreading of human gingival fibroblasts (HGFs) on the surface of the samples, their proliferative and migratory behaviors as well as the expression levels of related gene proteins (CoL-1 and TGF-β), and HE staining of the soft tissues of the samples and inflammatory cell counts. After 2 and 4 weeks of implantation, the experimental group’s HGFs adhesion and spreading were significantly better than that of the control group, the migration and proliferation of HGFs were significantly greater than that of the control group ( p < .05), and the expression of CoL-1 and TGF-β genes was significantly higher than that of the control group ( p < .05), and the inflammatory cell count was significantly smaller than that of the control group ( p < .05). Surface modification by magnesium and zinc ions enhances the sealing performance and antimicrobial performance of 3D printed titanium implants in oral soft tissues, with significant effects.

[Introduction] With the development of new loads, such as distributed power sources and electric vehicles, DC(Direct Current) microgrids have the advantages of fewer commutation links and lower system losses than AC(Alternating Current) microgrids, and have become the current research hotspot. Due to the small coverage of the DC microgrid and access to a large amount of distributed power sources, the fault current rises quickly with a large amplitude when inter-pole short-circuit fault occurs, making it difficult to achieve differential coordination with traditional overcurrent protection used in AC distribution networks and posing a great challenge to fault localization. [Method] Therefore, in response to the characteristics of fault current in DC microgrids, the method for designing overcurrent protection setting value based on the precise control value of fault current through the integration of current limiting and protection was proposed. Combined with the reasonable capacity design of each branch, it can easily achieve differential coordination and accurately locate faults. [Result] A corresponding DC microgrid model is built on the PSCAD/EMTDC simulation platform. The proposed protection scheme is simulated and verified, and the result shows that the scheme can correctly locate the fault point and quickly remove the fault. [Conclusion] The proposed protection scheme can ensure the selectivity of overcurrent, which verifies the rationality of the scheme.

[Introduction] With the rapid development of AC/DC distribution networks and distributed generation technology, the role of DC microgrids in distribution networks is becoming increasingly important and will become an important component of future distribution networks. Due to the small coverage area and low line impedance of the DC microgrid, when an inter pole short circuit fault occurs, the fault current increases rapidly and has a large amplitude, which can reach more than 10 times the rated working current. This makes it difficult to set the protection of DC microgrids and requires high equipment selection, which restricts the rapid development of DC microgrids. [Method] In response to the above issues, taking the DC microgrid as the research object, starting from the working principle of inter pole faults in the DC microgrid, the fault characteristics on the DC side of the DC microgrid were analyzed. In response to the shortcomings of existing main current limiting methods, a voltage controllable fault current controller was proposed to achieve precise control of fault current. The simulation model of DC microgrid and fault current controller was built for simulation verification. [Result] The simulation results show that the fault current controller can significantly reduce the fault current and achieve precise control of the fault current, making the system controllable before and after the fault without locking the protection. During steady-state operation, the fault current controller can also assist the VSC (Voltage Source Converter) in further stabilizing the DC bus voltage. [Conclusion] To cooperate with the normal operation of the relay protection device and avoid VSC triggering overcurrent protection blocking, it is recommended to set the fault current control range between 1~2 pu.

Developing environmentally friendly bulk materials capable of easily and thoroughly removing trace amounts of dye pollutants from water to rapidly obtain clean water has always been a goal pursued by researchers. Herein, a green material with a 3D architecture and with strong underwater rebounding and fatigue resistance ability was prepared by means of the assembly of biopolymer chitosan (CS) and natural caraganate fibers (CKFs) under freezing conditions. The CKFs can randomly and uniformly distribute in the lamellar structure formed during the freezing process of CS and CKFs, playing a role similar to that of “steel bars” in concrete, thus providing longitudinal support for the 3D-architecture material. The 2D layers formed by CS and CKFs as the main basic units can provide the material with a higher strength. The 3D-architecture material can bear the compressive force of a weight underwater for multiple cycles, meeting the requirements for water purification. The underwater compression test shows that the 3D-architecture material can quickly rebound to its original shape after removing the stress. This 3D-architecture material can be used to purify dye-containing water. When its dosage is 3 g/L, the material can remove 99.65% of the Congo Red (CR) in a 50 mg/L dye solution. The adsorption performance of the 3D architecture adsorbent for CR removal in actual water samples (i.e., tap water, seawater) is superior than that of commercial activated carbon. Due to its porous block characteristics, this material can be used for the continuous and efficient treatment of wastewater containing trace amounts of CR dye to obtain pure clean water, meaning that it has great potential for the effective purification of dye wastewater.

ContextMa Xing Shi Gan Decoction (MXSGD) is a traditional remedy for treating lung injuries that was developed by the Typhoid and Fever School of Pharmaceutical Biology. It has antitussive and expectorant effects, anti-inflammatory, antiviral, regulates the body’s immunity, etc.AimThe aim of this study is to investigate whether MXSGD can ameliorate cyclosporine A (CsA)-induced hypoimmunity lung injury by regulating microflora metabolism. Methods: Establishment of a model for CsA-induced hypoimmunity lung injury. Using 16S rRNA high-throughput sequencing and LC-MS, the effects of MXSGD on gut flora and lung tissue microecology of mice with CsA-induced hypoimmunity were investigated.ResultsMXSGD was able to preserve lung tissue morphology and structure, reduce serum inflammatory marker expression and protect against CsA-induced lung tissue damage. Compared to the model, MXSGD increased beneficial gut bacteria: Eubacterium ventriosum group and Eubacterium nodatum group; decreased intestinal pathogens: Rikenellaceae RC9 intestinal group; reduced the abundance of Chryseobacterium and Acinetobacter, promoted the production of Lactobacillus and Streptococcus, and then promoted the lung flora to produce short-chain fatty acids. MXSGD was able to enhance the expression of serum metabolites such as Americine, 2-hydroxyhexadecanoylcarnitine, Emetine, All-trans-decaprenyl diphosphate, Biliverdin-IX-alpha, Hordatin A and N-demethyl mifepristone in the CsA-induced hypoimmunity lung injury model.ConclusionMXSGD can restore gut and lung microbiota diversity and serum metabolite changes to inhibit inflammation, ameliorate CsA-induced hypoimmunity lung injury.

Introduction: Idiopathic normal pressure hydrocephalus (iNPH) is a kind of hydrocephalus that is easily to be misdiagnosed with brain atrophy due to the similarity of ventricular dilation and cognitive impairment. In this case, we present an old male patient who was diagnosed with iNPH by multimodality approaches. Outcomes: A 68-year-old male patient, with deteriorated gait, declined cognitive function for at least 3 years and urinary incontinence for 3 months. The doctors suspected him a patient with hydrocephalus or Alzheimer's disease based on his symptoms. We used multimodality diagnostic approaches including brain imaging, cerebrospinal fluid tap test, continuous intracranial pressure monitoring, and infusion study to make the final diagnosis of iNPH. He underwent ventriculoperitoneal shunt surgery and was well recovered. Conclusion: This case demonstrates the efficacy of using multimodality approaches for iNPH diagnosis, which saves patient time and clinical cost, worthy of further promotion.

Objetivo: Investigar si los implantes de titanio impresos en 3D modificados con superficies de iones de magnesio y zinc pueden promover el cierre de tejidos blandos orales. Método: Se seleccionaron conejos grandes blancos de Nueva Zelanda como animales experimentales, y los dientes mandibulares izquierdo y derecho de cada animal se dividieron al azar en grupo experimental y grupo control, cada uno con 18 casos. Se extrajeron los primeros premolares bilaterales después de administrar anestesia general y se colocaron implantes en los grupos tratados con y sin modificación iónica de la superficie de magnesio/ zinc. Resultados: Bajo observación a simple vista, la combinación del material del implante y el tejido blando circundante en el grupo experimental fue significativamente mejor que en el grupo de control. La tinción de fluorescencia mostró que el valor de densidad de fluorescencia del grupo experimental fue significativamente mayor que el del grupo control (p < 0.05). Conclusiones: Los implantes de titanio impresos en 3D basados en la modificación iónica de la superficie de magnesio/zinc promueven el cierre de los tejidos blandos orales con resultados significativos.

In this study, tracking control and saturation nonlinearities problems of a flexible mobile vehicle-manipulator with disturbance uncertainty are investigated. Based on differential equations model, a novel iterative learning control (ILC) algorithm is designed, where two saturation functions and two hyperbolic tangent functions are developed to deal with actuator saturation constraint and an adaptive law is developed to reduce the impact of disturbance uncertainty. With the ILC algorithm, the target of tracking control and vibration attenuation of mobile manipulator can come true. Simulations are executed to verify the effectiveness of designed algorithm.

Background: Short-term exposure to fine particulate matter (PM2.5) and its specific constituents might exacerbate allergic rhinitis (AR) conditions. However, the evidence is still inconclusive. Method: We conducted a panel study of 49 patients diagnosed with AR > 1 year prior to the study in Taiyuan, China, to investigate associations of individual exposure to PM2.5 and its constituents with oxidative parameters, symptoms, and quality of life among AR patients. All participants underwent repeated assessments of health and PM exposure at 4 time points in both the heating and nonheating seasons from June 2017 to January 2018. AR patients’ oxidative parameters were assessed using nasal lavage, and their subjective symptoms and quality of life were determined through in-person interviews using a structured questionnaire. Short-term personal exposure to PM2.5 and its constituents was estimated using the time-microenvironment-activity pattern and data from the nearest air sampler, respectively. We applied mixed-effects regression models to estimate the short-term effects of PM2.5 and its constituents. Results: The results showed that exposure to PM2.5 and its constituents, including BaP, PAHs, SO42−, NH4+, V, Cr, Cu, As, Se, Cd, and Pb, was significantly associated with increased oxidative stress, as indicated by an increase in the malondialdehyde (MDA) index. Exposure to PM2.5 and its components (V, Mn, Fe, Zn, As, and Se) was associated with decreased antioxidant activity, as indicated by a decrease in the superoxide dismutase (SOD) index. Additionally, increased visual analog scale (VAS) and rhinoconjunctivitis quality of life questionnaire (RQLQ) scores indicated that exposure to PM2.5 and its constituents exacerbated inflammatory symptoms and affected quality of life in AR patients. Conclusion: Exposure to PM2.5 and specific constituents, could exacerbate AR patients' inflammatory symptoms and adversely affect their quality of life in the heavily industrialized city of Taiyuan, China. These findings may have potential biological and policy implications.

The challenge of mixing high-viscosity materials is a common issue encountered in the manufacturing process of food materials. The advantages of the internal meshing screw mixer have led to its adoption in various manufacturing processes, but it has yet to be implemented in the food industry. The paper presents a design method for an internal meshing screw mixer based on kinematic principles. The mixer features a helical chamber created by alternating volumes formed by the stator and rotor, establishing an extension-dominated environment for mixing high-viscosity fluids. A kinematic model based on the internal cycloid principle was established, providing trajectories and equations for key points on the rotor, simulating both its rotation and revolution processes, and revealing the velocity variations at different points on the rotor. Based on the kinematic analysis results, a stator and rotor design method was developed according to relevant functional divisions. To achieve the desired motion effects, transmission and support devices were designed, and the relationship between the transmission device and the internal cycloid surface of the fixed rotor was established. The mixer’s application and mixing effectiveness in the food industry were validated using corn syrup and flour. Experimental results showed that the extensional mixer described in the paper effectively mixed high-viscosity fluids while also efficiently blending fine powders. Slurry viscosity was tested with a rheometer at different speeds with an eccentric rotor mixer. Results showed that viscosity decreased with increasing shear rate, with a more pronounced decrease at higher shear rates. The apparent viscosity trend remained consistent at different speeds, although variations were observed at lower shear rates, especially concerning speed. The non-Newtonian fluid index exhibited minimal variations at different speeds, while the consistency coefficient showed significant fluctuations. The mixing uniformity index of the slurry was used to evaluate the mixing uniformity and dispersion uniformity of this extensional mixer. At different rotational speeds, the density of the slurry changes little. The uniformity index of mixing decreases gradually with the increase of rotational speed, reaching its maximum at 15 r/min. The overall trend of the uniformity index decreases with increasing rotational speed, indicating a decrease in density uniformity. A peak appears at 45 r/min, possibly due to the maximum values of elongation rate and shear rate at this speed. As the rotational speed increases, the residence time of the material in the mixer decreases, which may be the main reason for the decrease in mixing uniformity. These findings provide valuable insights into the design and utilization of extension-dominated screw mixers within the food industry, laying a solid foundation for future research and practical applications in this field.

Renewable, green, and safe natural biopolymer-derived materials are highly desired for the purification of pollutants, but significantly improving their performance without the introduction of additional harmful chemicals remains a huge challenge. Based on the concept of “structure optimization design”, environment-friendly composite beads (named SA/PASP/RE) with excellent adsorption performance and recyclability were rationally constructed through a green ionic crosslinking route, using the completely green biopolymer sodium alginate (SA), sodium salt of polyaspartic acid (PASP), and the natural nanoclay rectorite (RE) as starting materials. The nano-layered RE was embedded in the polymer matrix to prevent the polymer chain from becoming over-entangled so that more adsorption sites inside the polymer network were exposed, which effectively improved the mass transfer efficiency of the adsorbent and the removal rate of contaminants. The composite beads embedded with 0.6% RE showed high adsorption capacities of 211.78, 197.13, and 195.69 mg/g for Pb(II) and 643.00, 577.80, and 567.10 mg/g for methylene blue (MB) in Yellow River water, Yangtze River water, and tap water, respectively. And the beads embedded with 43% RE could efficiently adsorb Pb(II) and MB with high capacities of 187.78 mg/g and 586.46 mg/g, respectively. This study provides a new route to design and develop a green, cost-effective, and efficient adsorbent for the decontamination of wastewater.

Abstract Background Icariin (ICA), a main active ingredient of Herba Epimedium, could promote bone formation, inhibit bone resorption and alleviate inflammatory responses. The aim of this study was to investigate the effect of ICA on the inhibition of bacteria associated with peri-implantitis, and fabricate a calcium phosphate cement (CPC) with ICA-loaded gelatin microspheres (GMs) as a local drug delivery system efficiently promoting bone formation and alleviating inflammation. Results In this study, ICA exhibited antibacterial activity against P. gingivalis with a MIC value of 1 × 10–4 mol/L. When the concentration of ICA was 0.5 mM, the encapsulation efficiency of GMs reached the maximum value of 76.26 ± 3.97%. GMs with ICA revealed a controlled release profile, 0.5 mM ICA exhibited a higher ICA release profile than the other groups during a 21 d monitoring span. The results of SEM and XRD demonstrated successful fabrication of a calcium phosphate cement with ICA-loaded GMs. ICA released from CPC/GMs (ICA) was slower than ICA released from GMs within 10 days. CPC/GMs (ICA) exhibited antibacterial activity against P. gingivalis, but the antibacterial rate of CPC/GMs (ICA) was only 17.15 ± 6.06%. In addition, CPC/GMs (ICA) promoted the proliferation of BMSCs and significantly stimulated the differentiation and maturation of BMSCs. In vivo, H&E and Masson staining experiments demonstrated that CPC/GMs (ICA) exhibited better capacity for bone regeneration than CPC/GMs and CPC, and the expression of TNF-α and IL-1β in the tissue around CPC/GMs (ICA) was significantly lower than CPC/GMs and CPC in IHC staining (P

Abstract Background Drug-target interactions (DTIs) prediction becomes more and more important for accelerating drug research and drug repositioning. Drug-target interaction network is a typical model for DTIs prediction. As many different types of relationships exist between drug and target, drug-target interaction network can be used for modeling drug-target interaction relationship. Recent works on drug-target interaction network are mostly concentrate on drug node or target node and neglecting the relationships between drug-target. Results We propose a novel prediction method for modeling the relationship between drug and target independently. Firstly, we use different level relationships of drugs and targets to construct feature of drug-target interaction. Then, we use line graph to model drug-target interaction. After that, we introduce graph transformer network to predict drug-target interaction. Conclusions This method introduces a line graph to model the relationship between drug and target. After transforming drug-target interactions from links to nodes, a graph transformer network is used to accomplish the task of predicting drug-target interactions.

Abstract Background Given malignant ascites with a terrible prognosis and a unique immune microenvironment, our purpose is to evaluate whether oncolytic herpes simplex virus type 2(OH2) is able to safely eliminate ascites of colon cancer and through which specific mechanism it exerts antitumor immunity. Methods We established an ascites mice model through intraperitoneal injection of CT26 cells and obtained an appropriate dose range for in vivo tests. Efficacy and safety of OH2 were detected by weight of ascites, blood routine analysis, histopathological examination, and the survival time of mice. The specific mechanism underlying antitumor immunity was analyzed by cytometric bead array, flow cytometry, and single‐cell RNA sequencing. Furthermore, anti‐interleukin (IL)‐6R antibody tocilizumab was synchronously or sequentially delivered with OH2 to explore the role of the regional cytokine storm, mainly IL‐6 hypersecretion. Results OH2 was able to eliminate ascites and significantly prolong the survival of mice‐bearing CT26 tumor cells by intraperitoneal injection, without obvious systemic damage to the main organs even though a regional cytokine storm. Hypersecretion of pro‐inflammatory cytokines, mainly IL‐6, and increased infiltration of CD4+ and CD8+ T cells were observed in ascites mice treated by OH2, compared with those treated by 5‐fluorouracil or nonresponders. Furthermore, the initial‐stage blocking of the IL‐6 pathway was able to considerably suppress antitumor immune responses driven by OH2. Surprisingly, we discovered upregulations of the immune checkpoint genes such as Cd274 and Pdcd1 by single‐cell RNA sequencing. Conclusions OH2 could safely eliminate malignant ascites of colon cancer and convert the cold immune microenvironment by inducing a remarkably regional cytokine storm in ascites, mainly IL‐6, in the early stage of antitumor immune responses beyond directed oncolytic virotherapy.

Long-term drug treatment for Restless Legs Syndrome (RLS) patients can frequently result in augmentation, which is the deterioration of symptoms with an increased drug dose. The cause of augmentation, especially derived from dopamine therapy, remains elusive. Here, we review recent research and clinical progress on the possible mechanism underlying RLS augmentation. Dysfunction of the dopamine system highly possibly plays a role in the development of RLS augmentation, as dopamine agonists improve desensitization of dopamine receptors, disturb receptor interactions within or outside the dopamine receptor family, and interfere with the natural regulation of dopamine synthesis and release in the neural system. Iron deficiency is also indicated to contribute to RLS augmentation, as low iron levels can affect the function of the dopamine system. Furthermore, genetic risk factors, such as variations in the BTBD9 and MEIS1 genes, have been linked to an increased risk of RLS initiation and augmentation. Additionally, circadian rhythm, which controls the sleep–wake cycle, may also contribute to the worsening of RLS symptoms and the development of augmentation. Recently, Vitamin D deficiency has been suggested to be involved in RLS augmentation. Based on these findings, we propose that the progressive reduction of selective receptors, influenced by various pathological factors, reverses the overcompensation of the dopamine intensity promoted by short-term, low-dose dopaminergic therapy in the development of augmentation. More research is needed to uncover a deeper understanding of the mechanisms underlying the RLS symptom and to develop effective RLS augmentation treatments.

Introduction: Reliable biomarkers are in need to predict the prognosis of hepatocellular carcinoma (HCC). Whilst recent evidence has established the critical role of copper homeostasis in tumor growth and progression, no previous studies have dealt with the copper-related genes (CRGs) signature with prognostic potential in HCC.Methods: To develop and validate a CRGs prognostic signature for HCC, we retrospectively included 353 and 142 patients as the development and validation cohort, respectively. Copper-related Prognostic Signature (Copper-PSHC) was developed using differentially expressed CRGs with prognostic value. The hazard ratio (HR) and the area under the time-dependent receiver operating characteristic curve (AUC) during 3-year follow-up were utilized to evaluate the performance. Additionally, the Copper-PSHC was combined with age, sex, and cancer stage to construct a Copper-clinical-related Prognostic Signature (Copper-CPSHC), by multivariate Cox regression. We further explored the underlying mechanism of Copper-PSHC by analyzing the somatic mutation, functional enrichment, and tumor microenvironment. Potential drugs for the high-risk group were screened.Results: The Copper-PSHC was constructed with nine CRGs. Patients in the high-risk group demonstrated a significantly reduced overall survival (OS) (adjusted HR, 2.65 [95% CI, 1.83–3.84] and 3.30, [95% CI, 1.27–8.60] in the development and validation cohort, respectively). The Copper-PSHC achieved a 3-year AUC of 0.74 [95% CI, 0.67–0.82] and 0.71 [95% CI, 0.56–0.86] for OS in the development and validation cohort, respectively. Copper-CPSHC yield a 3-year AUC of 0.73 [95% CI, 0.66–0.80] and 0.72 [95% CI, 0.56–0.87] for OS in the development and validation cohort, respectively. Higher tumor mutation burden, downregulated metabolic processes, hypoxia status and infiltrated stroma cells were found for the high-risk group. Six small molecular drugs were screened for the treatment of the high-risk group.Conclusion: Copper-PSHC services as a promising tool to identify HCC with poor prognosis and to improve disease outcomes by providing potential clinical decision support in treatment.

As a thin fibrous layer covering the bone surface, the periosteum plays a significant role in bone physiology during growth, development and remodeling. Over the past several decades, the periosteum has received considerable scientific attention as a source of mesenchymal stem cells (MSCs). Periosteum-derived cells (PDCs) have emerged as a promising strategy for tissue engineering due to their chondrogenic, osteogenic and adipogenic differentiation capacities. Starting from the history of PDCs, the present review provides an overview of their characterization and the procedures used for their isolation. This study also summarizes the chondrogenic, osteogenic, and adipogenic abilities of PDCs, serving as a reference about their potential therapeutic applications in various clinical scenarios, with particular emphasis on the comparison with other common sources of MSCs. As techniques continue to develop, a comprehensive analysis of the characterization and regulation of PDCs can be conducted, further demonstrating their role in tissue engineering. PDCs present promising potentials in terms of their osteogenic, chondrogenic, and adipogenic capacities. Further studies should focus on exploring their utility under multiple clinical scenarios to confirm their comparative benefit over other commonly used sources of MSCs.

Abstract Background According to the validation literature on items of Young’s Internet Addiction Test (IAT), this study rephrased disputable items to improve the psychometric properties of this Chinese version of IAT and identify the presence of differential item function (DIF) among demographic and Internet use factors; detect the effect of demographic and Internet use factors on IAT after adjusting for DIF. Methods An online questionnaire was distributed to college students in Zhe Jiang province in two stage. The 1st phase study collected 384 valid responses to examine the quality of IAT items by using Rasch Model analysis and exploring factor analysis (EFA). The online questionnaire was modified according to the 1st phase study and distributed online for the 2nd phase study which collected a total of 1131 valid responses. The 2nd phase study applied confirmatory factor analysis (CFA) and a multiple indicator multiple causes (MIMIC) model to verify the construct of IAT, potential effect of covariates on IAT latent factors, as well as the effect of differential item functioning (DIF). Results Rasch model analysis in the 1st phase study indicated a 5-point rating scale was performed better, no sever misfit was found on item. The overall property of Chinese version IAT with the 5-point scale was good to excellent person and item separation (2.66 and 6.86). A three-factor model was identified by EFA. In the 2nd phase study, IAT 13 were detected with DIF for gender in MIMIC model. After correcting DIF effect, the significant demographic and Internet use factors on IAT were time spent online per day, year 3, year 2, general users. Conclusion Item improvement was efficient that the problematic items found in literature was performed good in this study. The overall psychometric property of this Chinese version IAT was good with limited DIF effect in one item. Item improvement on IAT13 was encouraged in the future study to avoid gender bias and benefit for epidemiology on PIU.

Abstract Background Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain. Methods Neuropathic pain was induced by partial transection of the infraorbital nerve (p-IONX) or partial sciatic nerve ligation (PSL) in mice and evaluated by measuring nociceptive thresholds to mechanical and heat stimulation. Anxiety-like behaviors were assessed by elevated plus maze, light dark box and open field tests. Aversive or anti-aversive effect was detected by conditioned place preference test. Neuronal activity was evaluated by single-unit and patch clamp recordings. The contribution of mPFC pyramidal neurons to anxiety was further examined by selectively inhibiting them by optogenetics. HMGB1 expression was measured by immunohistochemistry and western blotting. Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal antibody (mAb) intracerebrally or intraperitoneally. Results Anxiety-like behaviors were presented earlier after p-IONX than after PSL. HMGB1 expression was upregulated in the mPFC temporally in parallel to anxiety onset, rather than in other regions associated with anxiety. The upregulation of HMGB1 expression and its translocation from the nucleus to cytoplasm in the mPFC occurred predominantly in neurons and were accompanied with activation of microglia and astrocytes. Infusion of anti-HMGB1 mAb into the mPFC during the early and late phases after either p-IONX or PSL alleviated anxiety-like behaviors and aversion without changing pain sensitization, while local infusion of exogenous ds-HMGB1, the proinflammatory form of HMGB1, into the mPFC induced anxiety and aversion but not pain sensitization in naïve mice. In addition to reversing established pain sensitization and anxiety simultaneously, intraperitoneal injection of anti-HMGB1 mAb reduced HMGB1 upregulation and suppressed the hyperexcitability of layer 2/3 pyramidal neurons in the mPFC after p-IONX. Moreover, optogenetic inhibition of mPFC pyramidal neurons alleviated anxiety in p-IONX mice. Conclusion These results demonstrate that HMGB1 in the mPFC drives and maintains anxiety comorbidity in neuropathic pain by increasing the excitability of layer 2/3 pyramidal neurons, and justify antagonism of HMGB1, e.g., neutralization by mAb, as a promising therapeutic strategy for neuropathic pain with anxiety comorbidity.