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Objective: Expand genetic screening for atypical Type I sialidosis (ST-1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population., Methods: We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation., Results: A total of 31 patients from 23 unrelated families were genetically diagnosed with ST-1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST-1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic-clonic seizures. Mobility and independence varied greatly across the cohort. Cherry-red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians., Interpretation: ST-1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry-red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Prostate cancer (PCa) is threatening the health of millions of people, the pathological mechanism of prostate cancer has not been fully elaborated, and needs to be further explored. Here, we found that the expression of DUSP26 is dramatically suppressed, and a positive connection of its expression with PCa prognosis was also observed. In vitro, overexpression of DUSP26 significantly inhibited the proliferative, migrative, and invasive capacities of PC3 cells, DUSP26 silencing presented opposite results. Tumor formation experiments in subcutaneous nude mice demonstrated that DUSP26 overexpression could significantly suppress PC3 growth in vivo. Moreover, the mechanism of DUSP26 gene and PCa was discovered by RNA-Seq analysis. We found that DUSP26 significantly inhibited MAPK signaling pathway activation, and further experiments displayed that DUSP26 could impair TAK1, p38, and JNK phosphorylation. Interestingly, treatment with the TAK1 inhibitor (iTAK1) attenuated the effect of DUSP26 on PC3 cells. Together, these results suggested that DUSP26 may serve as a novel therapeutic target for PC3 cell type PCa, the underlying mechanism may be through TAK1-JNK/p38 signaling., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients., Methods: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila., Results: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K + currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes., Interpretation: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024;96:758-773., (© 2024 American Neurological Association.)

Sarcopenia is characterized by accelerated muscle mass and function loss, which burdens and challenges public health worldwide. Several studies indicated that selenium deficiency is associated with sarcopenia; however, the specific mechanism remains unclear. Here, we demonstrated that selenoprotein W (SELENOW) containing selenium in the form of selenocysteine functioned in sarcopenia. SELENOW expression is up-regulated in dexamethasone (DEX)-induced muscle atrophy and age-related sarcopenia mouse models. Knockout (KO) of SELENOW profoundly aggravated the process of muscle mass loss in the two mouse models. Mechanistically, SELENOW KO suppressed the RAC1-mTOR cascade by the interaction between SELENOW and RAC1 and induced the imbalance of protein synthesis and degradation. Consistently, overexpression of SELENOW in vivo and in vitro alleviated the muscle and myotube atrophy induced by DEX. SELENOW played a role in age-related sarcopenia and regulated the genes associated with aging. Together, our study uncovered the function of SELENOW in age-related sarcopenia and provides promising evidence for the prevention and treatment of sarcopenia.

This experiment aimed to evaluate the effects of using sugarcane bagasse (SB) as a substitute for soybean hulls and wheat bran in the diet of pregnant sows on their reproductive performance and gut microbiota. A total of seventy-two primiparous sows were randomly divided into four treatment groups, with eighteen replicates of one sow each. The sows were fed a basal diet supplemented with 0% (CON), 5%, 10%, and 15% SB to replace soybean hulls from day 57 of gestation until the day of the end of the gestation period. The results showed that SB contains higher levels of crude fiber (42.1%) and neutral detergent fiber (81.3%) than soybean hulls, and it also exhibited the highest volumetric expansion when soaked in water (50 g expanding to 389.8 mL) compared to the other six materials we tested (vegetable scraps, soybean hulls, wheat bran, rice bran meal, rice bran, and corn DDGS). Compared with the CON, 5% SB significantly increased the litter birth weight of piglets. Meanwhile, 10% and 15% SB significantly increased the rates of constipation and reduced the contents of isobutyric acid and isovaleric acid in feces. Furthermore, 10% and 15% SB significantly disturbed gut microbial diversity with increasing Streptococcus and decreasing Prevotellaceae_NK3B31-group and Christensenellaceae_R-7-group genera in feces. Interestingly, Streptococcus had a significant negative correlation with isobutyric acid, isovaleric acid, and fecal score, while Prevotellaceae_NK3B31-group and Christensenellaceae_R-7-group had a positive correlation with them. In conclusion, our study indicates that 5% SB can be used as an equivalent substitute for soybean hulls to improve the reproductive performance of sows without affecting their gut microbiota.

Objective: The purpose of this study is to develop and assess a nomogram risk prediction model for central precocious puberty (CPP) in obese girls., Methods: We selected 154 cases of obese girls and 765 cases of non-obese girls with precocious puberty (PP) who underwent the gonadotropin-releasing hormone stimulation test at the Jiangxi Provincial Children's Hospital. Univariate analysis and multivariate analysis were conducted to identify predictors of progression to CPP in girls with PP. A predictive model was developed and its predictive ability was preliminarily evaluated. The nomogram was used to represent the risk prediction model for CPP in girls with obesity. The model was validated internally using the Bootstrap method, and its efficacy was assessed using calibration curves and clinical decision analysis curves., Results: In obese girls with PP, basal luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels, as well as uterine volume, were identified as independent risk factors for progression to CPP. In non-obese girls, the basal LH level, bone age, and uterine volume were identified as independent risk factors for progression to CPP. With an AUC of 0.896, the risk prediction model for obese girls, was found to be superior to that for non-obese girls, which had an AUC of 0.810. The model displayed strong predictive accuracy. Additionally, a nomogram was used to illustrate the CPP risk prediction model for obese girls. This model performs well in internal validation and is well calibrated, providing a substantial net benefit for clinical use., Conclusion: A medical nomogram model of CPP risk in obese girls comprised of basal LH value, basal FSH value, and uterine volume, which can be used to identify those at high risk for progression of CPP in obese girls and develop individualized prevention programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Huang, Yang, Yang, Xu, Xie and Cao.)

Background: Prostate cancer (PCa) is a malignant tumor of the male reproductive system, and its incidence has increased significantly in recent years. This study aimed to further identify candidate biomarkers with prognostic and diagnostic significance by integrating gene expression and DNA methylation data from PCa patients through association analysis., Material and Methods: To this end, this paper proposes a sparse partial least squares regression algorithm based on hypergraph regularization (HR-SPLS) by integrating and clustering two kinds of data. Next, module 2, with the most significant weight, was selected for further analysis according to the weight of each module related to DNA methylation and mRNAs. Based on the DNA methylation sites in module 2, this paper uses multiple machine learning methods to construct a PCa diagnosis-related model of 10-DNA methylation sites., Results: The results of Receiver Operating Characteristic (ROC) analysis showed that the DNA methylation-related diagnostic model we constructed could diagnose PCa patients with high accuracy. Subsequently, based on the mRNAs in module 2, we constructed a prognostic model for 7-mRNAs (MYH11, ACTG2, DDR2, CDC42EP3, MARCKSL1, LMOD1, and MYLK) using multivariate Cox regression analysis. The prognostic model could predict the disease free survival of PCa patients with moderate to high accuracy (area under the curve (AUC) =0.761). In addition, Gene Set EnrichmentAnalysis (GSEA) and immune analysis indicated that the prognosis of patients in the risk group might be related to immune cell infiltration., Conclusions: Our findings may provide new methods and insights for identifying disease-related biomarkers by integrating DNA methylation and gene expression data.

Prostate cancer (PCa) is the most common malignancy of the male urinary system. Mitophagy, as a type of autophagy, can remove damaged mitochondria in cells. Mitophagy-related genes (MRGs) have been shown to play critical roles in the development of PCa. To this end, based on the comprehensive analysis of RNA-seq and scRNA-seq data of PCa samples and their controls, this paper identified PCa subtypes and constructed a prognostic model. In this paper, we downloaded scRNA-seq and RNA-seq data from Gene Expression Omnibus (GEO) and TCGA database. Based on the R package "Seurat" to process the scRNA-seq data, a total of five cell types were identified. Each cell population was scored based on the R package "AUCell" and using the intersection genes between MRGs and each cell population. The B cell population was then identified as a high-scoring cell population. Differentially expressed genes in RNA-seq data were identified based on the R package "limma" and intersected with previously intersected genes. Then, based on univariate Cox regression analysis and Lasso-Cox regression analysis, the prognostic genes were screened, and the risk model was constructed (composed of ADH5, CAT, BCAT2, DCXR, OGT, and FUS). The model is validated on internal and external test sets. Independent prognostic analysis identified age, N stage, and risk score as independent prognostic factors. This paper's risk models and prognostic genes can provide a reference for developing novel therapeutic targets for PCa., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ruohui Huang reports was provided by First Affiliated Hospital of Gannan Medical University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Hematopoietic stem cell transplantation provides an effective cure for various hematological diseases, especially malignant hematological diseases, its treatment system has been continuously optimized, the source of donors has been expanding, the indications have been expanding, and the therapeutic effect has also made breakthroughs to a certain extent. At present, the status of hematopoietic stem cell transplantation technology in most hematological diseases is still unshakable, but the recurrence of the primary disease and complications related to hematopoietic stem cell transplantation are still two major clinical challenges that affect the long-term survival and quality of life of patients. Cell therapy represented by chimeric antigen receptor T (CAR-T) has made breakthrough progress in the treatment of refractory/recurrent B-cell malignancies. Compared with traditional drugs, cell therapy has unique in vivo metabolic characteristics, relying on immune specific recognition and the repair ability of stem cells. It is currently emerging in the treatment of blood tumors and the management of transplant complications. Multiple clinical studies have preliminarily demonstrated a new diagnostic and therapeutic model combining cell therapy with hematopoietic stem cell transplantation.

Objective: To evaluate the status of, differences in, and factors influencing quality of life (QoL) in patients with chronic graft-versus-host disease (GVHD). Methods: From September 2021 to February 2023, a cross-sectional study of 140 patients with chronic GVHD was conducted at our center. Symptom burden was assessed by the Lee Symptomatology Scale (LSS), and QoL was assessed by the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) (version 1) and five-level EuroQoL five-dimensional questionnaire (EQ-5D-5L). Results: Data from 140 respondents, including 32 (22.9%) with mild chronic GVHD, 87 (62.1%) with moderate chronic GVHD, and 21 (15.0%) with severe chronic GVHD, were analyzed. Of the respondents, 61.4% were male, and the median transplantation age was 34 (15-68) years. The primary diagnoses were acute myeloid leukemia (50.0%), acute lymphoblastic leukemia (20.0%), and myelodysplastic syndrome (15.0%). The common chronic GVHD-affected organs included the skin in 74 patients (52.9%), the eyes in 57 patients (40.7%), and the liver in 50 patients (35.7%). Among the whole cohort, the eye (20.48±23.75), psychological (16.13±17.00), and oral (13.66±20.55) scores were highest in the LSS group. The physiological function (36.07±11.13), social function (36.10±10.68), and role-emotional functioning (38.36±11.88) scores were lowest in the SF-36 group. The EQ-5D index was 0.764. The total LSS scores for mild, moderate, and severe chronic GVHD were 6.51±6.15, 10.07±5.61, and 20.90±10.09, respectively. The SF-36 physical component scores (PCSs) were 43.12±6.38, 40.73±7.14, and 36.97±6.97, respectively, and the mental component scores (MCSs) were 43.00±8.47, 38.90±9.52, and 28.96±9.63, respectively. The EQ-5D values were 0.810±0.124, 0.762±0.179, and 0.702±0.198, respectively. The multivariate analysis showed that the overall symptom burden ( β =-0.517), oral symptom burden ( β =-0.456), National Institute of Health (NIH) criteria for the eyes ( β =-0.376), and nutrition-related symptom burden ( β =-0.211) were significantly negatively correlated with the PCS. The NIH score ( β =-0.260) was negatively correlated with the MCS score. Oral symptom burden ( β =-0.400), joint/fascia NIH criteria ( β =-0.332), number of involved systems ( β =-0.253), overall NIH criteria ( β =-0.205), and number of immunosuppressants taken ( β =-0.171) were significantly negatively correlated with the EQ-5D score (all P <0.05). Medium to strong correlations were found between the EQ-5D score and the SF-36 score (| r |=0.384-0.571, P <0.001). Conclusions: The QoL of patients with chronic GVHD is impaired, and the more severe the disease, the poorer the QoL. Overall symptom burden, severity of eyes, and oral symptom burden were the most important factors affecting QoL.

The higher order structure (HOS) of a protein is vital to its function and activity, making it a critical component in the development of protein-based therapeutics. Characterization of HOS can be performed using various biophysical techniques, but many of these methods have limitations such as low throughput, complicated workflow, narrow concentration range, and low sensitivity. Microfluidic Modulation Spectroscopy (MMS) is an emerging technology that addresses these limitations, offering high sensitivity and automated analysis for protein secondary structure. This study evaluates and compares the different well plate formats and scan modes of two MMS instruments. The newer Apollo system features a high throughput 96-well plate format and sweep scan mode that allows a 50% reduction in sample volume consumption and measurement time compared to the previous system. By measuring two proteins with drastically different secondary structures, the results demonstrated that the measurements were highly repeatable (>99% repeatability by area of overlap) regardless of the well plate formats or the scan modes. The limit of quantitation (LOQ) for determining structural impurity using the sweep scan mode was 3.2% and significantly better than that of FTIR at 23% from previous studies. This work highlighted the advancement of MMS as a highly sensitive technique to detect small changes of protein structures due to aggregation or misfolding., Competing Interests: Declaration of competing interest Authors Dipanwita Batabyal and Mats Wikström are employees and stockholders of Amgen Inc. Authors Tianhui Maria Ma, Richard H. Huang, Valerie I. Collins are employees and stockholders of Redshift BioAnalytics Inc., (Published by Elsevier Inc.)

Matrix metalloproteinases (MMP) are enzymes that degrade the extracellular matrix and regulate essential normal cell behaviors. Inhibition of these enzymes has been a strategy for anti-cancer therapy since the 1990s, but with limited success. A new type of MMP-targeting strategy exploits the innate selective hydrolytic activity and consequent catalytic signal amplification of the proteinases, rather than inhibiting it. Using nanomaterials, the enzymatic chemical reaction can trigger the temporal and spatial activation of the anti-cancer effects, amplify the associated response, and cause mechanical damage or report on cancer cells. We analyzed nearly 60 literature studies that incorporate chemical design strategies that lead to spatial, temporal, and mechanical control of the anti-cancer effect through four modes of action: nanomaterial shrinkage, induced aggregation, formation of cytotoxic nanofibers, and activation by de-PEGylation. From the literature analysis, we derived chemical design guidelines to control and enhance MMP activation of nanomaterials of various chemical compositions (peptide, lipid, polymer, inorganic). Finally, the review includes a guide on how multiple characteristics of the nanomaterial, such as substrate modification, supramolecular structure, and electrostatic charge should be collectively considered for the targeted MMP to result in optimal kinetics of enzyme action on the nanomaterial, which allow access to amplification and additional levels of spatial, temporal, and mechanical control of the response. Although this review focuses on the design strategies of MMP-responsive nanomaterials in cancer applications, these guidelines are expected to be generalizable to systems that target MMP for treatment or detection of cancer and other diseases, as well as other enzyme-responsive nanomaterials.

Background: COVID-19 caused mild to severe infections in humans. The long-term epidemic environment harms people's mental health. To explore the impact of the epidemic on people's mental and psychological conditions, we surveyed in Wenzhou., Methods: We collected the data of people who visited the First Affiliated Hospital of Wenzhou Medical University for five types of mental and psychological diseases from January 2018 to December 2021. Then, taking December 2019 as the cut-off point, the 48-month data were divided into the pre-epidemic group and the dur-epidemic group. Based on the above data, statistical analysis was done., Results: From 2018 to 2021, the number of initial diagnoses, the number of disease visits, and drug consumption for these five types of mental and psychological diseases were all on the rise. Compared with the number of disease visits for all disorders in both psychiatry and neurology departments, it was found that the growth rate of these five diseases was higher than the growth rate of all disorders. We found that the number of disease visits, drug consumption, and scale scores after the COVID-19 outbreak were significantly different from those before the outbreak (P < 0.05). And the number of disease visits positively correlated with drug consumption (P < 0.0001, r = 0.9503), which verified the stability of the data., Conclusion: The epidemic environment has had a long-term and negative impact on people's mental and psychological conditions. Therefore, whether or not the epidemic is receding, we still need to be concerned about the impact of COVID-19 on mental and psychological health., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Atherosclerosis is a chronic inflammatory disease with its molecular basis incompletely understood. Here, we determined whether the Golgi phosphoprotein 73 (GP73), a novel protein highly related to inflammation and disrupted lipid metabolism, was involved in the development of atherosclerosis., Methods: Public microarray databases of human vascular samples were analyzed for expression patterns. Apolipoprotein-E-gene-deficient (ApoE-/-) mice (8-week-old) were randomly assigned to either a chow diet group or a high-fat diet group. The levels of serum GP73, lipid profiles and key inflammatory cytokines were determined by ELISA. The aortic root plaque was isolated and used for by Oil Red O staining. PMA-differentiated THP-1 macrophages were transfected with GP73 small interfering RNA (siRNA) or infected with adenovirus expressing GP73, and then stimulated with oxidized low density lipoprotein (ox-LDL). The expressions of pro-inflammatory cytokines and signal pathway key targets were determined by ELISA kit and Western blot respectively. In addition, ichloro-dihydro-fluorescein diacetate (DCFH-DA) was used to measure the intracellular ROS levels., Results: The expressions of GP73 and NLRP3 were substantially upregulated in human atherosclerotic lesions. There were significant linear correlations between GP73 and inflammatory cytokines expressions. High-fat diet-induced atherosclerosis and increased levels of plasma inflammatory mediators (IL-1β, IL-18, and TNF-α) were observed in ApoE-/- mice. Besides, the expressions of GP73 in the aorta and serum were significantly upregulated and positively correlated with the NLRP3 expression. In the THP-1 derived macrophages, ox-LDL treatment upregulated the expressions of GP73 and NLRP3 proteins and activated the inflammatory responses in a concentration-dependent and time-dependent manner. Silencing of GP73 attenuated the inflammatory response and rescued the decreased migration induced by ox-LDL, inhibiting the NLRP3 inflammasome signaling and the ROS and p-NF-κB activation., Conclusions: We demonstrated that GP73 promoted the ox-LDL-induced inflammation in macrophages by affecting the NF-κB/NLRP3 inflammasome signaling, and may play a role in atherosclerosis., Competing Interests: Declaration of Competing Interest The authors declared no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Angio-associated migratory cell protein (AAMP) is a protein that participates in cell migration and is reported to be involved in cancer progression. However, the molecular mechanism of AAMP in pan-cancer is not known., Methods: We used multi-omics data, such as TIMER, TCGA, GTEx, CPTAC, HPA, and cBioPortal to analyze AAMP expression, and gene alteration in pan-cancer. Univariate Cox regression and Kaplan-Meier were utilized to explore prognostic significance of AAMP expression level. We applied Spearman analysis to investigate the correlation between AAMP and TMB, MSI, immune cell infiltration, immune checkpoints. Moreover, we mainly studied liver hepatocellular carcinoma(LIHC) to explore AAMP expression, clinical significance, and prognosis. Cox regression analysis was used to study independent factor to predict prognosis for AAMP in LIHC. GSEA was utilized to investigate the biological function for AAMP in LIHC., Results: AAMP was overexpressed in most cancers, and high AAMP expression was associated with worse overall survival (OS), disease-specific survival (DSS), and progress-free interval (PFI) for LIHC and adrenocortical carcinoma (ACC). Moreover, AAMP had the highest mutation frequency in uterine corpus endometrial carcinoma (UCEC). AAMP was correlated with TMB and MSI in esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), lung squamous cell carcinoma (LUSC), and thyroid carcinoma (THCA). Then, we focus on LIHC to investigate the expression and prognosis of AAMP. AAMP overexpression was related to histological grade and pathological stage in LIHC. Multivariate Cox regression analysis revealed that AAMP overexpression was an independent adverse prognostic marker for LIHC. AAMP expression was correlated with immune cell infiltration and immune checkpoints in LIHC. Function enrichment analysis indicated the participation of AAMP in the cell cycle and DNA replication., Conclusions: AAMP was a latent prognostic indicator for pan-cancer and had high potential as a biomarker for the diagnosis and prognosis of LIHC., (© 2023. The Author(s).)

Stroke is an acute cerebrovascular condition causing damage to cranial nerves and requires subsequent rehabilitation treatment. In clinical practice, the effectiveness of rehabilitation is usually subjectively assessed by experienced physicians or using global prognostic scales. Several brain imaging techniques, such as positron emission tomography, functional magnetic resonance imaging, and computed tomography angiography, can be applied in rehabilitation effectiveness evaluation, but their complexity and long measurement times limit the activity of patients during measurement. This paper proposes an intelligent headband system based on near-infrared spectroscopy. An optical headband continuously and noninvasively monitors changes in hemoglobin parameters in the brain. The system's wearable headband and wireless transmission provide convenience of use. According to the change of hemoglobin parameters during rehabilitation exercise, several indexes were also defined to evaluate the state of cardiopulmonary function and further build the neural network model of the cardiopulmonary function evaluation. Finally, the relationship between the defined indexes and the cardiopulmonary function state were investigated and the neural network model for the cardiopulmonary function evaluation was also applied in the rehabilitation effect evaluation. The experimental results show the cardiopulmonary function state could reflect on most of the defined indexes and the output of neural network model, and the rehabilitation therapy could also improve the cardiopulmonary function.

Recent studies have identified DNA replication stress as an important feature of advanced prostate cancer (PCa). The identification of biomarkers for DNA replication stress could therefore facilitate risk stratification and help inform treatment options for PCa. Here, we designed a robust machine learning-based framework to comprehensively explore the impact of DNA replication stress on prognosis and treatment in 5 PCa bulk transcriptomic cohorts with a total of 905 patients. Bootstrap resampling-based univariate Cox regression and Boruta algorithm were applied to select a subset of DNA replication stress genes that were more clinically relevant. Next, we benchmarked 7 survival-related machine-learning algorithms for PCa recurrence using nested cross-validation. Multi-omic and drug sensitivity data were also utilized to characterize PCa with various DNA replication stress. We found that the hyperparameter-tuned eXtreme Gradient Boosting model outperformed other tuned models and was therefore used to establish a robust replication stress signature (RSS). RSS demonstrated superior performance over most clinical features and other PCa signatures in predicting PCa recurrence across cohorts. Lower RSS was characterized by enriched metabolism pathways, high androgen activity, and a favorable prognosis. In contrast, higher RSS was significantly associated with TP53, RB1, and PTEN deletion, exhibited increased proliferation and DNA replication stress, and was more immune-suppressive with a higher chance of immunotherapy response. In silico screening identified 13 potential targets (e.g. TOP2A, CDK9, and RRM2) from 2249 druggable targets, and 2 therapeutic agents (irinotecan and topotecan) for RSS-high patients. Additionally, RSS-high patients were more responsive to taxane-based chemotherapy and Poly (ADP-ribose) polymerase inhibitors, whereas RSS-low patients were more sensitive to androgen deprivation therapy. In conclusion, a robust machine-learning framework was used to reveal the great potential of RSS for personalized risk stratification and therapeutic implications in PCa., (© 2023. The Author(s).)

Multiple-pathogen periodontal disease necessitates a local release and concentration of antibacterial medication to control inflammation in a particular location of the mouth cavity. Therefore, it is necessary to effectively load and deliver medicine/antibiotics to treat numerous complex bacterial infections. This study developed chlorhexidine (CHX)/polycaprolactone (PCL) nanofiber membranes with controlled release properties as periodontal dressings to prevent or treat oral disorders. Electrostatic spinning was adopted to endow the nanofiber membranes with a high porosity, hydrophilicity, and CHX loading capability. The release of CHX occurred in a concentration-dependent manner. The CHX/PCL nanofiber membranes exhibited good biocompatibility with human periodontal ligament stem cells, with cell viability over 85% in each group via CCK-8 assay and LIVE/DEAD staining; moreover, the good attachment of the membrane was illustrated by scanning electron microscopy imaging. Through the agar diffusion assay, the nanofiber membranes with only 0.075 wt% CHX exhibited high antibacterial activity against three typical oral infection-causing bacteria: Porphyromonas gingivalis , Enterococcus faecalis , and Prevotella intermedia . The results indicated that the CHX/PCL nanofiber holds great potential as a periodontal dressing for the prevention and treatment periodontal disorders associated with bacteria.

Clear cell renal cell carcinoma (ccRCC) is the most aggressive and deadly cancer of the urinary system and is regulated by multiple signaling pathways. However, the specific molecular mechanisms underlying ccRCC have not been fully studied or demonstrated. This study aimed to elucidate the function of lysosomal-associated transmembrane protein 5 (LAPTM5) in ccRCC cell lines and animal models and determine the potential underlying mechanisms. Our results demonstrated that LAPTM5 expression in patients with ccRCC was significantly higher in the tumor group than that in the adjacent nontumor group. Moreover, LAPTM5 promoted proliferation, migration, and invasion of ccRCC cells through the gain and loss of the function of LAPTM5 in 786-0 and Caki-1 cell lines. Similar results regarding LAPTM5 overexpression were obtained in BALB/c nude mice. In addition, LAPTM5 activated the Jun N-terminal kinase (JNK)/p38 signaling cascade by interacting with Ras-related C3 botulinum toxin substrate 1 (RAC1). Treatment with an RAC1 inhibitor eliminated the effects of LAPTM5 in ccRCC. In conclusion, these results indicate that LAPTM5 may be a new therapeutic target for ccRCC via activation of the RAC1-JNK/p38 axis., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Ruo-Hui Huang et al.)

ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells was correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein-stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to the dissociation of ACE2 from its E3 ligase UBR4. Reduction in UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, and ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: The purpose was to compare the accuracy of extraprostatic extension (EPE) grade on MRI predicting EPE with Partin tables, Memorial Sloan Kettering Cancer Center nomogram (MSKCCn), and combined models and to analyze the clinical incremental value of EPE grade., Materials and Methods: 105 prostate cancer patients confirmed by pathology after radical prostatectomy in our hospital from 2017 to 2021 were selected. The clinical stage, PSA, Gleason score, number of positive biopsy cores, and percentage of positive biopsy cores were recorded. Evaluate EPE grade according to EPE grade criteria, and calculate the probability of predicting EPE with Partin tables and MSKCCn. EPE grade is combined with Partin tables and MSKCCn to construct EPE grade+Partin tables and EPE grade+MSKCCn models. Calculate the area under the curve (AUC), sensitivity, and specificity of EPE grade, Partin tables, MSKCCn, EPE grade+Partin tables, and EPE grade+MSKCCn and compare their diagnostic efficacy. The clinical decision curve was used to analyze the clinical net income of each prediction scheme., Results: The AUC of EPE grade was 0.79, Partin tables was 0.50, MSKCCn was 0.78, the EPE grade+Partin table model was 0.79, and the EPE grade+MSKCCn model was 0.83. After EPE grade was combined with Partin tables and MSKCCn, the diagnostic efficiency of clinical model was significantly improved ( P < 0.05). There was no significant difference in the diagnostic efficacy of the combined model compared with the single EPE grade ( P > 0.05). The calibration curve of the combined model shows that it has a good calibration degree for EPE. In the analysis of the decision curve, the net income of the EPE grade is higher than that of Partin tables and MSKCCn and is equal to the EPE grade+Partin tables and is slightly lower than that of EPE grade+MSKCCn. The clinical net income of the combined model is obviously higher than that of individual clinical models., Conclusion: The accuracy of EPE classification in predicting prostate cancer EPE is high, and combined with the clinical model, it can significantly improve the diagnostic efficiency of the clinical model and increase the clinical benefit., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Jun-Yi Xiang et al.)

It is known that metabolic reprogramming (MR) contributes to tumorigenesis through the activation of processes that support survival of cells, proliferation, and grow in the tumor microenvironment. In order to keep the tumor proliferating at a high rate, metabolic pathways must be upregulated, and tumor metabolism must be adapted to meet this requirement. Additionally, immune cells engage in metabolic remodeling to maintain body and self-health. With the advent of immunotherapy, the fate of individuals suffering from non-small cell lung cancer (NSCLC) has been transformed dramatically. MR may have a profound influence on their prognosis. The aim of this review is to summarize current research advancements in metabolic reprogramming and their impact on immunotherapy in NSCLC. Moreover, we talk about promising approaches targeting and manipulating metabolic pathways to improve cancer immunotherapy's effectiveness in NSCLC., (© 2022. The Author(s).)

RtcB is involved in transfer RNA (tRNA) splicing in archaeal and eukaryotic organisms. However, most RtcBs are found in bacteria, whose tRNAs have no introns. Because tRNAs are the substrates of archaeal and eukaryotic RtcB, it is assumed that bacterial RtcBs are for repair of damaged tRNAs. Here, we show that a subset of bacterial RtcB, denoted RtcB2 herein, specifically repair ribosomal damage in the decoding center. To access the damage site for repair, however, the damaged 70S ribosome needs to be dismantled first, and this is accomplished by bacterial PrfH. Peptide-release assays revealed that PrfH is only active with the damaged 70S ribosome but not with the intact one. A 2.55-Å cryo-electron microscopy structure of PrfH in complex with the damaged 70S ribosome provides molecular insight into PrfH discriminating between the damaged and the intact ribosomes via specific recognition of the cleaved 3'-terminal nucleotide. RNA repair assays demonstrated that RtcB2 efficiently repairs the damaged 30S ribosomal subunit but not the damaged tRNAs. Cell-based assays showed that the RtcB2-PrfH pair reverse the damage inflicted by ribosome-specific ribotoxins in vivo. Thus, our combined biochemical, structural, and cell-based studies have uncovered a bacterial defense system specifically evolved to reverse the lethal ribosomal damage in the decoding center for cell survival.

Objective: This study aimed to investigate whether cytokine profiles and virological markers might add value in monitoring the effects of peginterferon (PEG-IFN) therapy for hepatitis B e-antigen (HBeAg) positive chronic hepatitis B (CHB)., Methods: HBeAg positive patients with CHB were treated with PEG-IFN for 48 weeks. Clinical biochemical, and HBV serological indexes, as well as cytokines, were detected at baseline and every 12 weeks., Results: A total of 116 patients with CHB were enrolled in this study; 100 patients completed the 48-week treatment and follow-up, of whom 38 achieved serum HBeAg disappearance, 25 achieved HBeAg seroconversion, 37 showed HBsAg decreases ≥ 1 log 10 IU/mL, 9 showed HBsAg disappearance, and 8 became HBsAb positive. The cytokine levels at baseline and during treatment were similar between the HBeAg disappearance group and non-disappearance group. The disappearance of HBeAg was independently associated with HBeAg levels at weeks 12 and 24, and with the HBeAg decline at week 24 ( P < 0.05). The HBsAg response was independently associated with HBsAg, the HBsAg decline, HBeAg, the HBeAg decline at week 12, and HBsAg at week 24 ( P < 0.05)., Conclusion: There was no significant correlation between the response to interferon (IFN) and cytokines during PEG-IFN treatment. The changes in virological markers predicted the response to IFN after 48 weeks., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Endophytic fungi of medicinal plants are abundant, and their metabolites often have antioxidant, antibacterial, and antitumor effects and can produce secondary metabolites identical or similar to those of their hosts, which can mitigate the problem of insufficient supply of medicinal plants. In this study, we screened endophytic fungi for strains that produce the same diterpene lactones as Andrographis paniculata based on their biological activity. Firstly, the dominant group of endophytic fungi of Andrographis paniculata was screened and pathogenicity was studied using Koch's rule. Secondly, DPPH, ABTS, OH, PTIO radical scavenging, and FRAP assays were used to detect the antioxidant activity of the extracellular extracts of the strains, and total phenol and total flavonoid contents of the strains with high antioxidant capacity were determined. S. aureus , B. subtilis , E. coli , and P. aeruginosa were used to determine the antibacterial activity of the mycelial extracts of the strains. Finally, the secondary metabolites of the mycelial extracts of the strains were examined by high-performance liquid chromatography. The results showed that 32 strains of Andrographis paniculata were relatively isolated > 70% and non-pathogenic. Extracellular extracts of strains AP-1 and AP-4 showed vigorous antioxidant activity, and AP-4, AP-12, AP-47, and AP-48 showed antibacterial activity against four strains of bacteria. The HPLC results indicated that the mycelial extracts of AP-4 and AP-12 contained diterpene lactones. The two endophytic fungi were recognized as Colletotrichum sp. The study successfully obtained diterpene lactones from the endophytic fungus of Andrographis paniculata and confirmed the feasibility of using endophytic fungal strains to produce active substances consistent with the host. It was also useful for exploring endophytic fungi and medicinal plants. The relationship provides theoretical guidance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Xu, Huang, Zheng, Liu, Hu, Gu and Du.)

Background: Studies have reported conflicting evidence regarding whether chemotherapy leads to dementia. This study aimed to determine whether chemotherapy increases dementia risk in Taiwanese patients with colorectal cancer (CRC)., Methods: Data from the Taiwan Cancer Registry and National Health Insurance Research Database were used. Patients newly diagnosed as having CRC between 2007 and 2015 without prior history of dementia or neurodegenerative disorders were identified. Based on whether they underwent chemotherapy, patients were divided into chemotherapy and non-chemotherapy groups. Those who later developed dementia were identified using validated diagnostic codes. The Fine and Gray subdistribution hazard model for all-cause dementia with competing risk of death was applied for all patients or each stratified group., Results: A total of 76,130 patients with CRC were included, with 45,872 (60.25%) in the chemotherapy group and 30,258 (39.75%) in the non-chemotherapy group. A higher incidence of dementia was observed in the non-chemotherapy group compared with the chemotherapy group (3.75% vs. 2.40%, p < 0.0001), but the risk of dementia did not differ between the groups (adjusted subdistribution hazard ratio [HR SD ] = 0.97, 95% confidence interval [CI]: 0.88-1.06, p = 0.492). In the stratified analysis, chemotherapy was a risk factor for dementia in patients aged > 80 years (adjusted HR SD = 1.20, 95% CI: 1.03-1.40, p = 0.0190), whereas gender, clinical cancer stage, comorbidities, surgery, and radiation therapy had no impact on the risk of dementia., Conclusion: Chemotherapy increased the risk of dementia in elderly patients with CRC, highlighting the necessity to monitor their cognitive function after chemotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has had a considerable impact on US hospitalizations, affecting processes and patient population., Objective: To evaluate the impact of COVID-19 pandemic on central-line-associated bloodstream infections (CLABSIs) and catheter associated urinary tract infections (CAUTIs) in hospitals., Methods: We performed a retrospective study of CLABSIs and CAUTIs in 78 US 12 months before COVID-19 and 6 months during COVID-19 pandemic., Results: During the 2 study periods, there were 795,022 central-line days and 817,267 urinary catheter days. Compared to the period before the COVID-19 pandemic, CLABSI rates increased by 51.0% during the pandemic period from 0.56 to 0.85 per 1,000 line days (P < .001) and by 62.9% from 1.00 to 1.64 per 10,000 patient days (P < .001). Hospitals with monthly COVID-19 patients representing >10% of admissions had a National Health Safety Network (NHSN) device standardized infection ratio for CLABSI that was 2.38 times higher than hospitals with <5% prevalence during the pandemic period (P = .004). Coagulase-negative Staphylococcus CLABSIs increased by 130% from 0.07 to 0.17 events per 1,000 line days (P < .001), and Candida spp by 56.9% from 0.14 to 0.21 per 1,000 line days (P = .01). In contrast, no significant changes were identified for CAUTI (0.86 vs 0.77 per 1,000 catheter days; P = .19)., Conclusions: The COVID-19 pandemic was associated with substantial increases in CLABSIs but not CAUTIs. Our findings underscore the importance of hardwiring processes for optimal line care and regular feedback on performance to maintain a safe environment.

Supramolecular self-assembly in biological systems holds promise to convert and amplify disease-specific signals to physical or mechanical signals that can direct cell fate. However, it remains challenging to design physiologically stable self-assembling systems that demonstrate tunable and predictable behavior. Here, the use of zwitterionic tetrapeptide modalities to direct nanoparticle assembly under physiological conditions is reported. The self-assembly of gold nanoparticles can be activated by enzymatic unveiling of surface-bound zwitterionic tetrapeptides through matrix metalloprotease-9 (MMP-9), which is overexpressed by cancer cells. This robust nanoparticle assembly is achieved by multivalent, self-complementary interactions of the zwitterionic tetrapeptides. In cancer cells that overexpress MMP-9, the nanoparticle assembly process occurs near the cell membrane and causes size-induced selection of cellular uptake mechanism, resulting in diminished cell growth. The enzyme responsiveness, and therefore, indirectly, the uptake route of the system can be programmed by customizing the peptide sequence: a simple inversion of the two amino acids at the cleavage site completely inactivates the enzyme responsiveness, self-assembly, and consequently changes the endocytic pathway. This robust self-complementary, zwitterionic peptide design demonstrates the use of enzyme-activated electrostatic side-chain patterns as powerful and customizable peptide modalities to program nanoparticle self-assembly and alter cellular response in biological context., (© 2021 Wiley-VCH GmbH.)

Background: More than ten special scales are available to predict the risk of pressure ulcers in children. However, the performances of those scales have not yet been compared in China., Aim: To compare the Waterlow, Braden Q, and Glamorgan scales, and identify more suitable pressure ulcer evaluation scale for the pediatric intensive care unit (PICU)., Methods: Trained nurses used the Waterlow, Braden Q, and Glamorgan scales to assess pediatric patients at Sun Yat-sen Memorial Hospital (China) within 24 h of admission from May 2017 to December 2020 in two stages. Skin examination was carried out to identify pressure ulcers every 3 d for 3 wk., Results: The incidence of pressure ulcers was 3/28 (10.7%) in the PICU and 5/314 (1.6%) in the general pediatric ward. For children in the general ward, the Waterlow, Braden Q, and Glamorgan scales had comparable area under the operating characteristic curve (AUC) of 0.870, 0.924, and 0.923, respectively, and optimal cut-off values of 14, 14, and 29 points. For PICU, the Waterlow, Braden Q, and Glamorgan scales had slightly lower AUC of 0.833, 0.733, and 0.800, respectively, and optimal cut-off values of 13, 16, and 27 points. Braden Q demonstrated a satisfactory specificity, and during the second stage of the study for PICU patients, the AUC of the Braden Q scale was 0.810, with an optimal cut-off value of 18.35 points., Conclusion: The Waterlow, Braden Q, and Glamorgan scales have comparable performance, while the Braden Q scale demonstrates a better specificity and can be successfully used by pediatric nurses to identify patients at high risk of pressure ulcers in PICU., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Cancer is an intricate disease with inherent intra-tumor heterogeneity at the cellular level because of genetic changes and environmental differences. Cellular heterogeneity exists even within the same tumor type. Small deviations in a genome or transcriptome can lead to significant differences in function. Conventional bulk population sequencing, which produces admixed populations of cells, can only provide an average expression signal for one cell population, ignoring differences between individual cells. Important advances in sequencing have been made in recent years. Single cell sequencing starts in a single cell, thereby increasing our capability to characterize intratumor heterogeneity. This technology has been used to analyze genetic variation, specific metabolic activity, and evolutionary processes in tumors, which may help us understand tumor occurrence and development and improve our understanding of the tumor microenvironment. In addition, it provides a theoretical basis for the development of clinical treatments, especially for personalized medicine. In this article, we briefly introduce Single cell sequencing technology, summarize the application of Single cell sequencing to study the tumor microenvironment, as well as its therapeutic application in different clinical procedures., (© 2021. The Author(s).)

Cyclic-oligonucleotide-based antiphage signaling systems (CBASS) are diverse and abundant in bacteria. Here, we present the biochemical and structural characterization of two CBASS systems, composed of CdnG and Cap5, from Asticcacaulis sp. and Lactococcus lactis. We show that CdnG from Asticcacaulis sp. synthesizes 3',2'-cGAMP in vitro, and 3',2'-cGAMP is the biological signaling molecule that activates Cap5 for DNA degradation. Crystal structures of Cap5, together with the SAVED domain in complex with 3',2'-cGAMP, provide insight into the architecture of Cap5 as well as molecular recognition of 3',2'-cGAMP by the SAVED domain of Cap5. Amino acid conservation of the SAVED domain of Cap5, together with mutational studies, led us to propose a mechanism of Back-to-Front stacking of two SAVED domains, mediated by 3',2'-cGAMP, to activate HNH nuclease domain for DNA degradation. This study of the most abundant CBASS system provides insights into the mechanisms employed by bacteria in their conflicts against phage., (© 2021. The Author(s).)

Intramuscular fat content (IFC) is an essential quantitative trait of meat, affecting multiple meat quality indicators. A certain amount of IFC could not only improve the sensory score of pork but also increase the flavour, tenderness, juiciness and shelf-life. To dissect the genetic determinants of IFC, two methods, including genome-wide efficient mixed-model analysis (GEMMA) and linkage disequilibrium adjusted kinships (LDAKs), were used to carry out genome-wide association studies for IFC in Suhuai pig population. A total of 14 and 18 significant single nucleotide polymorphisms (SNPs) were identified by GEMMA and LDAK, respectively. The results of these two methods were highly consistent and all 14 significant SNPs in GEMMA were detected by LDAK. Seven of the 18 SNPs reached the genome-wide significance level (P < 9.85E-07) while 11 cases reached the suggestive significance level (P < 1.77E-05). These significant SNPs were mainly distributed on Sus scrofa chromosome (SSC) 5, 3, and 7. Moreover, one locus resides in a 2.27 Mb (71.37-73.64 Mb) region on SSC5 harbouring 13 significant SNPs associated with IFC, and the lead SNP (rs81302978) also locates in this region. Linkage disequilibrium (LD) analysis showed that there were four pairs of complete LD (r 2  = 1) among these 13 SNPs, and the remaining 9 SNPs with incomplete LD (r 2  ≠ 1) were selected for subsequent analyses of IFC. Association analyses showed that 7 out of 9 SNPs were significantly associated with IFC (P < 0.05) in 330 Suhuai pigs, and the other 2 SNPs tended to reach a significant association level with IFC (P < 0.1). The phenotypic variance explained (PVE) range of these 9 SNPs was 0.92-3.55%. Meanwhile, the lead SNP was also significantly associated (rs81302978) with IFC (P < 0.05) in 378 commercial hybrid pigs (Pietrain × Duroc) × (Landrace × Yorkshire) (PDLY), and the PVE was 1.38%. Besides, two lipid metabolism-relevant candidate genes, the leucine rich repeat kinase 2 (LRRK2) and PDZ domain containing ring finger 4 (PDZRN4) were identified in the 2.27 Mb region on SSC5. In conclusion, our results may provide a set of markers useful for genetic improvement of IFC in pigs and will advance the genome selection process of IFC on pig breeding programmes., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Oxygenated volatile organic compounds (OVOCs) are important intermediates in the troposphere and the most important sources of ozone. Proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS) was used to measure VOCs in the Chengdu Plain, Southwestern China. The diurnal variations, photochemical reactivity, O 3 formation potential, and sources were also investigated. The mixing ratios of ten kinds of VOCs (acetaldehyde, acetone, isoprene, Methyl ethyl ketone, Methyl vinyl ketone and Methacrolein, benzene, toluene, styrene, C8 aromatics, and C9 aromatics) were (10.97±4.69)×10 -9 . The concentrations of OVOCs, aromatic hydrocarbons, and biogenic VOCs were (8.54±3.44)×10 -9 , (1.53±0.93)×10 -9 , and (0.90±0.32)×10 -9 , respectively. Isoprene, acetaldehyde, and m-xylene were the top three photochemically active species with the greatest O 3 formation potentials. The dominant three OVOCs species (acetaldehyde, acetone, and MEK) were mainly derived from local biogenic sources and anthropogenic secondary sources, and acetone had a strong regional background level, indicating that pollution in this area is significantly affected by regional transmission. This study deepens the understanding of regional O 3 formation mechanisms in southwest China and provides a basis for the scientifically informed control of O 3 pollution.

Intensive efforts have been undertaken in the fields of prevention, diagnosis, and therapy of lung cancer. Fucoidans exhibit a wide range of biological activities, which are dependent on the degree of sulfation, sulfation pattern, glycosidic branches, and molecular weight of fucoidan. The determination of oversulfation of fucoidan and its effect on anti-lung cancer activity and related signaling cascades is challenging. In this investigation, we used a previously developed fucoidan (SCA), which served as a native fucoidan, to generate two oversulfated fucoidan derivatives (SCA-S1 and SCA-S2). SCA, SCA-S1, and SCA-S2 showed differences in compositions and had the characteristic structural features of fucoidan by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) analyses. The anticancer properties of SCA, SCA-S1, and SCA-S2 against human lung carcinoma A-549 cells were analyzed in terms of cytotoxicity, cell cycle, Bcl-2 expression, mitochondrial membrane potential (MMP), expression of caspase-3, cytochrome c release, Annexin V/propidium iodide (PI) staining, DNA fragmentation, and the underlying signaling cascades. Our findings indicate that the oversulfation of fucoidan promotes apoptosis of lung cancer cells and the mechanism may involve the Akt/mTOR/S6 pathway. Further in vivo research is needed to establish the precise mechanism whereby oversulfated fucoidan mitigates the progression of lung cancer.

Background/aim: To characterize the potential roles of CEP55 in colorectal cancer development and assess its eligibility as a prognostic diagnosis tool for colorectal cancer., Patients and Methods: Immunohistochemical (IHC) analysis of CEP55 immunoreactivity in 166 cancer specimens from colorectal cancer patients., Results: CEP55 was not found to statistically significantly affect different patient clinical parameters. Multivariate analysis illustrated that patients with N stage (1+2) colorectal cancer and high CEP55 expression had a significantly lower five-year survival rate than patients with N stage (1+2) colorectal cancer and low CEP55 expression., Conclusion: There is a correlation between CEP55 and advanced N-stage colorectal cancer. Thus, CEP55 may be a potential diagnostic biomarker for colorectal cancer patients., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Periprosthetic joint infection (PJI) is one of the main causes for the failure of joint arthroplasty. In view of the limited clinical effect of oral/injectable antibiotics and the drug resistance problem, there is a pressing need to develop antibacterial implants with therapeutic antimicrobial properties. In this work, we prepared a highly antibacterial ultrahigh molecular weight polyethylene (UHMWPE) implant by incorporating tea polyphenols. The presence of tea polyphenols not only improved the oxidation stability of irradiated UHMWPE, but also gave it the desirable antibacterial property. The potent antibacterial activity was attributed to the tea polyphenols that produced excess intracellular reactive oxygen species and destroyed the bacterial membrane structure. The tea polyphenol-blended UHMWPE had no biological toxicity to human adipose-derived stem cells and effectively reduced bacteria-induced inflammation in vivo. These results indicate that tea polyphenol-blended UHMWPE is promising for joint replacement prostheses with multifunctionality to meet patient satisfaction.

Supramolecular materials have gained substantial interest for a number biological and nonbiological applications. However, for optimum utilization of these dynamic self-assembled materials, it is important to visualize and understand their structures at the nanoscale, in solution and in real time. Previous approaches for imaging these structures have utilized super-resolution optical imaging methods such as STORM, which has provided important insights, but suffers from drawbacks of complex sample preparation and slow acquisition times, thus limiting real-time in situ imaging of dynamic processes. We demonstrate a noncovalent fluorescent labeling design for STED-based super-resolution imaging of self-assembling peptides. This is achieved by in situ, electrostatic binding of anionic sulfonates of Alexa-488 dye to the cationic sites of lysine (or arginine) residues exposed on the peptide nanostructure surface. A direct, multiscale visualization of static structures reveals hierarchical organization of supramolecular fibers with sub-60 nm resolution. In addition, the degradation of nanofibers upon enzymatic hydrolysis of peptide could be directly imaged in real time, and although resolution was compromised in this dynamic process, it provided mechanistic insights into the enzymatic degradation process. Noncovalent Alexa-488 labeling and subsequent imaging of a range of cationic self-assembling peptides and peptide-functionalized gold nanoparticles demonstrated the versatility of the methodology for the imaging of cationic supramolecular structures. Overall, our approach presents a general and simple method for the electrostatic fluorescent labeling of cationic peptide nanostructures for nanoscale imaging under physiological conditions and probe dynamic processes in real time and in situ.

Colloidal perovskite barium titanate (BaTiO 3 , or BT) nanoparticles (NPs), conventionally used for applications in electronics, can also be considered for their potential as biocompatible computed tomography (CT) contrast agents. NPs of BT produced by traditional solid-state methods tend to have broad size distributions and poor dispersibility in aqueous media. Furthermore, uncoated BT NPs can be cytotoxic because of leaching of the heavy metal ion, Ba 2+ . Here, we present and compare three approaches for surface modification of BT NPs (8 nm) synthesized by the gel collection method to improve their aqueous stability and dispersibility. The first approach produced citrate-capped BT NPs that exhibited extremely high aqueous dispersibility (up to 50 mg/mL) and a small hydrodynamic size (11 nm). Although the high dispersibility was found to be pH-dependent, such aqueous stability sufficiently enabled a feasibility analysis of BT NPs as CT contrast agents. The second approach, a core/shell design, aimed to encapsulate BT nanoaggregates with a silica layer using a modified Stöber method. A cluster of 7-20 NPs coated with a thick layer (20-100 nm) of SiO 2 was routinely observed, producing larger NPs in the 100-200 nm range. A third approach was developed using a reverse-microemulsion method to encapsulate a single BT core within a thin (10 nm) silica layer, with an overall particle size of 29 nm. The -OH groups on the silica layer readily enabled surface PEGylation, allowing the NPs to remain highly stable in saline solutions. We report that the silica-coated BT NPs in both methods exhibited a low level of Ba 2+ leaching (≤3% of total barium in NPs) in phosphate-buffered saline for 48 h compared to the unmodified BT NPs (14.4%).

Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40-50 ms at 1.5 T, 20-35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dual-specificity phosphatase 11 (DUSP11, also named as PIR1) is a member of the atypical DUSP protein tyrosine phosphatase family. DUSP11 is only known to be an RNA phosphatase that regulates noncoding RNA stability. To date, the role of DUSP11 in immune cell signaling and immune responses remains unknown. In this study, we generated and characterized the immune cell functions of DUSP11-deficient mice. We identified TGF-β-activated kinase 1 (TAK1) as a DUSP11-targeted protein. DUSP11 interacted directly with TAK1, and the DUSP11-TAK1 interaction was enhanced by LPS stimulation in bone marrow-derived macrophages. DUSP11 deficiency enhanced the LPS-induced TAK1 phosphorylation and cytokine production in bone marrow-derived macrophages. Furthermore, DUSP11-deficient mice were more susceptible to LPS-induced endotoxic shock. The LPS-induced serum levels of IL-1β, TNF-α, and IL-6 were significantly elevated in DUSP11-deficient mice compared with those of wild-type mice. The data indicate that DUSP11 inhibits LPS-induced macrophage activation by targeting TAK1., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Aim: To review and clarify the strengths and directions of associations between nephrolithiasis and hypertension (HTN), diabetes mellitus (DM) and gallstones (GS) given the inconsistent results reported in cohort studies., Methods: Relevant literature was searched in PubMed and EMBASE from inception to July 2019, for cohort studies that examined the relationships between kidney stones and these three diseases among adults. Pooled relative risks (RRs) were calculated by maximally adjusted risk estimates using a random effect model. Subgroup analysis, meta-regression and sensitivity analysis were conducted whenever appropriate., Results: Of 3537 papers, 21 articles with each including 1 to 3 cohorts were identified. In this meta-analysis, nephrolithiasis was reciprocally linked to HTN, DM and GS. Kidney stones were significantly associated with 31%, 33% and 46% higher risks of incident HTN, DM and GS whereas GS was associated with a significantly higher risk of nephrolithiasis (RR: 1.49; 95% CI, 1.28-1.73), followed by HTN (RR: 1.30; 95% CI, 1.11-1.52) and DM (RR: 1.18; 95% CI, 1.07-1.29). Also, females with DM (RR: 1.29; 95% CI, 1.08-1.55) were more likely to develop kidney stones than diabetic male patients (RR: 0.91; 95% CI, 0.75-1.10)., Conclusion: Although additional studies are needed to confirm these findings and elucidate the mechanisms, this study revealed possible bidirectional associations between nephrolithiasis and HTN, diabetes and GS, which reinforced the notion of nephrolithiasis as a systemic disease that requires comprehensive investigations., (© 2020 Asian Pacific Society of Nephrology.)

Importance: While current reports suggest that a disproportionate share of US coronavirus disease 2019 (COVID-19) cases and deaths are among Black residents, little information is available regarding how race is associated with in-hospital mortality., Objective: To evaluate the association of race, adjusting for sociodemographic and clinical factors, on all-cause, in-hospital mortality for patients with COVID-19., Design, Setting, and Participants: This cohort study included 11 210 adult patients (age ≥18 years) hospitalized with confirmed severe acute respiratory coronavirus 2 (SARS-CoV-2) between February 19, 2020, and May 31, 2020, in 92 hospitals in 12 states: Alabama (6 hospitals), Maryland (1 hospital), Florida (5 hospitals), Illinois (8 hospitals), Indiana (14 hospitals), Kansas (4 hospitals), Michigan (13 hospitals), New York (2 hospitals), Oklahoma (6 hospitals), Tennessee (4 hospitals), Texas (11 hospitals), and Wisconsin (18 hospitals)., Exposures: Confirmed SARS-CoV-2 infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample., Main Outcomes and Measures: Death during hospitalization was examined overall and by race. Race was self-reported and categorized as Black, White, and other or missing. Cox proportional hazards regression with mixed effects was used to evaluate associations between all-cause in-hospital mortality and patient characteristics while accounting for the random effects of hospital on the outcome., Results: Of 11 210 patients with confirmed COVID-19 presenting to hospitals, 4180 (37.3%) were Black patients and 5583 (49.8%) were men. The median (interquartile range) age was 61 (46 to 74) years. Compared with White patients, Black patients were younger (median [interquartile range] age, 66 [50 to 80] years vs 61 [46 to 72] years), were more likely to be women (2259 [49.0%] vs 2293 [54.9%]), were more likely to have Medicaid insurance (611 [13.3%] vs 1031 [24.7%]), and had higher median (interquartile range) scores on the Neighborhood Deprivation Index (-0.11 [-0.70 to 0.56] vs 0.82 [0.08 to 1.76]) and the Elixhauser Comorbidity Index (21 [0 to 44] vs 22 [0 to 46]). All-cause in-hospital mortality among hospitalized White and Black patients was 23.1% (724 of 3218) and 19.2% (540 of 2812), respectively. After adjustment for age, sex, insurance, comorbidities, neighborhood deprivation, and site of care, there was no statistically significant difference in risk of mortality between Black and White patients (hazard ratio, 0.93; 95% CI, 0.80 to 1.09)., Conclusions and Relevance: Although current reports suggest that Black patients represent a disproportionate share of COVID-19 infections and death in the United States, in this study, mortality for those able to access hospital care did not differ between Black and White patients after adjusting for sociodemographic factors and comorbidities.

Background: Dietary and lifestyle factors may play an important role in the increasing prevalence of nephrolithiasis. We aimed to review and quantify the associations between lifestyle factors and incident nephrolithiasis and suggest lifestyle changes for the primary prevention of nephrolithiasis., Methods: PubMed, EMBASE, and Cochrane Library were searched up to May 2019, for observational studies and randomized controlled trials (RCTs) that assessed modifiable lifestyle factors and risk of nephrolithiasis in adults. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed using a random effects model. The I 2 statistic was employed to evaluate heterogeneity. Subgroup analysis, sensitivity analysis and meta-regression were also conducted whenever possible., Results: Fifty relevant articles with 1,322,133 participants and 21,030 cases in total were identified. Prominent risk factors for incident stones were body mass index (1.39,1.27-1.52), dietary sodium (1.38, 1.21-1.56), fructose, meat, animal protein, and soda. In contrast, protective factors included fluid intake (0.55, 0.51-0.60), a Dietary Approaches to Stop Hypertension (DASH) style diet (0.69, 0.64-0.75), alcohol (0.69, 0.56-0.85), water, coffee, tea, vegetables, fruits, dietary fiber, dietary calcium (0.83, 0.76-0.90), and potassium. Vitamin D (1.22, 1.01-1.49) and calcium (1.16, 1.00-1.35) supplementation alone increased the risk of stones in meta-analyses of observational studies, but not in RCTs, where the cosupplementation conferred significant risk., Conclusions: Several modifiable factors, notably fluid intake, dietary patterns, and obesity, were significantly associated with nephrolithiasis. Long-term RCTs are required to investigate the cost-effectiveness of dietary patterns for stone prevention. The independent and combined effects of vitamin D and calcium supplementation on nephrolithiasis need further elucidation.

Background: New surgical innovations of nipple-sparing mastectomy (NSM), such as endoscopic NSM (E-NSM) or robotic NSM (R-NSM), were emerging. However, there was a lack of evidence comparing the effectiveness and safety in the management of breast cancer., Methods: A case-control comparison study was conducted for patients with breast cancer underwent E-NSM or R-NSM with immediate prosthesis breast reconstruction (IPBR) from July 2010 to February 2019 at a single institution to compare the clinical outcomes, learning curve, patient-reported cosmetic results, and medical cost., Results: A total of 91 E-NSM and 40 R-NSM procedures were retrieved and analyzed. The surgical margin involvement rate in both R-NSM (2.5%) and E-NSM (4.4%) procedures were relatively low (P = 0.52). The R-NSM group was associated with higher satisfaction rates in terms of scar appearance, scar length, and surgical wound position compared with the E-NSM group. Compared with E-NSM, the R-NSM operation time took longer (241 ± 61 vs. 215 ± 70 min, P = 0.01), less blood loss (32 ± 29 vs. 79 ± 62 ml, P < 0.01), and higher medical cost (10,587 ± 554 vs. 6855 ± 936 U.S. dollars, P < 0.01). There was no statistically significant difference in nipple ischemia/necrosis or overall complication between R-NSM and E-NSM. In the learning curve analysis, it took the 27th procedure in E-NSM and 10th procedure in R-NSM to decrease operation time significantly., Conclusions: R-NSM was associated with higher wound-related satisfaction, lesser blood loss, and shorter learning curve compared with E-NSM, however, at the price of longer operation time and higher medical cost.