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Microorganisms are important sources of lipolytic enzymes with characteristics for wide promising usages in the specific industrial biotechnology. The cellulolytic myxobacterium Sorangium cellulosum is rich of lipolytic enzymes in the genome, but little has been investigated. Here, we discerned 406 potential lipolytic enzymes in 13 sequenced S. cellulosum genomes. These lipolytic enzymes belonged to 12 families, and most are novel with low identities (14–37%) to those reported. We characterized a new carboxylesterase, LipB, from the alkaline-adaptive So0157-2. This enzyme, belonging to family VIII, hydrolyzed glyceryl tributyrate and p-nitrophenyl esters with short chain fatty acids (≤C12), and exhibited the highest activity against p-nitrophenyl butyrate. It retained over 50% of the activities in a broad temperature range (from 20°C to 60°C), alkaline conditions (pH 8.0–9.5), and the enzymatic activity was stable with methanol, ethanol and isopropanol, and stimulated significantly in the presence of 5 mM Ni2+. LipB also exhibited β-lactamase activity on nitrocefin, but not ampicillin, cefotaxime and imipenem. The bioinformatic analysis and specific enzymatic characteristics indicate that S. cellulosum is a promising resource to explore lipolytic enzymes for industrial adaptations.

Introduction: Anterior cervical discectomy and fusion (ACDF) is a standard procedure for treating symptomatic cervical degenerative disease. The cage and plate constructs (CPCs) are widely employed in ACDF to maintain spinal stability and to provide immediate support. However, several instrument-related complications such as dysphagia, cage subsidence, and adjacent segment degeneration have been reported in the previous literature. This study aimed to design a novel individualized zero-profile (NIZP) cage and evaluate its potential to enhance the biomechanical performance between the instrument and the cervical spine.Methods: The intact finite element models of C3-C7 were constructed and validated. A NIZP cage was designed based on the anatomical parameters of the subject’s C5/6. The ACDF procedure was simulated and the CPCs and NIZP cage were implanted separately. The range of motion (ROM), intradiscal pressure (IDP), and peak von Mises stresses of annulus fibrosus were compared between the two surgical models after ACDF under four motion conditions. Additionally, the biomechanical performance of the CPCs and NIZP cage were evaluated.Results: Compared with the intact model, the ROM of the surgical segment was significantly decreased for both surgical models under four motion conditions. Additionally, there was an increase in IDP and peak von Mises stress of annulus fibrosus in the adjacent segment. The NIZP cage had a more subtle impact on postoperative IDP and peak von Mises stress of annulus fibrosus in adjacent segments compared to CPCs. Meanwhile, the peak von Mises stresses of the NIZP cage were reduced by 90.0–120.0 MPa, and the average von Mises stresses were reduced by 12.61–17.56 MPa under different motion conditions. Regarding the fixation screws, the peak von Mises stresses in the screws of the NIZP cage increased by 10.0–40.0 MPa and the average von Mises stresses increased by 2.37–10.10 MPa.Conclusion: The NIZP cage could effectively reconstruct spinal stability in ACDF procedure by finite element study. Compared with the CPCs, the NIZP cage had better biomechanical performance, with a lower stress distribution on the cage and a more moderate effect on the adjacent segmental discs. Therefore, the NIZP cage could prevent postoperative dysphagia as well as decrease the risk of subsidence and adjacent disc degeneration following ACDF. In addition, this study could serve as a valuable reference for the development of personalized instruments.

IntroductionGonadotropin-releasing hormone antagonist (GnRH-ant) protocol is widely used in the world for controlled ovarian hyperstimulation (COH). However, previous studies have shown that pregnancy outcomes of fresh embryo transfer with GnRH-ant protocol are not ideal. Current studies have demonstrated the value of growth hormone (GH) in improving the pregnancy outcome of elderly women and patients with diminished ovarian reserve, but no prospective studies have confirmed the efficacy of GH in fresh embryo transfer with GnRH-ant protocol, and its potential mechanism is still unclear. This study intends to evaluate the impact of GH on IVF/ICSI outcomes and endometrial receptivity of patients undergoing GnRH-ant protocol with fresh embryo transfer, and preliminarily explore the possible mechanism.MethodsWe designed a randomized controlled trial of 120 infertile patients with normal ovarian response (NOR) who will undergo IVF/ICSI from April 2023 to April 2025, at Department of Reproductive Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients will be divided into the depot gonadotropin-releasing hormone agonist (GnRH-a) protocol group, GnRH-ant protocol control group, and GnRH-ant protocol plus GH intervention group at a ratio of 1:1:1 by block randomization design. Patients will be followed on enrollment day, trigger day, embryo transfer day, 7 days after oocytes pick-up, 15 days after embryo transfer, 28 days after embryo transfer, and 12 weeks of gestation. The primary outcome is the ongoing pregnancy rate. Secondary outcomes include the gonadotropin dosage, duration of COH, endometrial thickness and pattern, luteinizing hormone, estradiol, progesterone level on trigger day, numbers of retrieved oocytes, high-quality embryo rate, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, early miscarriage rate, multiple pregnancy rate and incidence of moderate and severe ovarian hyperstimulation syndrome. The endometrium of certain patients will be collected and tested for endometrial receptivity.Ethics and disseminationThe study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology [approval number: TJ-IRB20230236; approval date: February 10, 2023]. The research results will be presented at scientific/medical conferences and published in academic journals.Clinical trial registrationChinese Clinical Trial Registry; identifier: ChiCTR2300069397.

BackgroundFalls are serious health events that can cause life-threatening injuries, especially among specific populations. This study assessed the risk factors associated with falls among inpatients with hematological diseases and explored the predictive value of fall risk assessment models.MethodsClinical data from 275 eligible hematology disease patients who visited Mianyang Central Hospital with or without falls from September 2019 to August 2022 were retrospectively analyzed. Fall risk scores were determined in all included patients. Clinical characteristics were compared between patients with and without falls. Binary logistic regression models were used to screen for potential fall-specific risk factors among hospitalized patients with hematology diseases.ResultsFalls occurred in 79 cases. Patients in the fall group had a higher Charlson Comorbidity Index (CCI), a higher incidence of diabetes mellitus, visual impairment, hematological malignancies, and maintenance of stable disease stage, higher glucose levels, and a greater proportion of dizziness, nocturnal defecation, and receipt of intensive chemotherapy than those in the non-fall group (all P < 0.05). Fall patients were also more likely to have used diuretics, laxatives, sedative-sleeping drugs, analgesics, albumin, and calcium, and to have had catheters placed. The Barthel Index, grade of nursing care, support of chaperones, body temperature, nutrition score, and pain score also differed significantly between the two groups (all P < 0.05). Multivariable logistic regression analysis showed that the maintenance of stable disease stage (OR = 4.40, 95% CI 2.11–9.18, P < 0.001), use of sedative and sleeping drugs (OR = 4.84, 95% CI 1.09–21.49, P = 0.038), use of diuretics (OR = 5.23, 95% CI 2.40–11.41, P < 0.001), and intensive chemotherapy (OR = 10.41, 95% CI 3.11–34.87, P < 0.001) were independent risk factors for falls. A high Barthel Index (OR = 0.95, 95% CI 0.93–0.97, P < 0.001), a high level of nursing care (OR = 0.19, 95% CI 0.04–0.98, P = 0.047), and availability of family accompaniment (OR = 0.15, 95% CI 0.06–0.34, P < 0.001) were protective factors for falls. A ROC curve analysis was used to evaluate the predictive value of different fall-specific risk scales among inpatients with hematological diseases. The Johns Hopkins Fall Risk Rating Scale had high sensibility and specificity with an area under the curve of 0.73 (95% CI 0.66–0.80, P < 0.001).ConclusionThe Johns Hopkins Fall Risk Scale had a strong predictive value for falls among hospitalized patients with hematology diseases and can be recommended as a valid tool for clinical use.

In clinical practice, laminectomy is a commonly used procedure for spinal decompression in patients suffering from spinal disorders such as ossification of ligamentum flavum, lumbar stenosis, severe spinal fracture, and intraspinal tumors. However, the loss of posterior column bony support, the extensive proliferation of fibroblasts and scar formation after laminectomy, and other complications (such as postoperative epidural fibrosis and iatrogenic instability) may cause new symptoms requiring revision surgery. Implantation of an artificial lamina prosthesis is one of the most important methods to avoid post-laminectomy complications. Artificial lamina is a type of synthetic lamina tissue made of various materials and shapes designed to replace the resected autologous lamina. Artificial laminae can provide a barrier between the dural sac and posterior soft tissues to prevent postoperative epidural fibrosis and paravertebral muscle compression and provide mechanical support to maintain spinal alignment. In this paper, we briefly review the complications of laminectomy and the necessity of artificial lamina, then we review various artificial laminae from clinical practice and laboratory research perspectives. Based on a combination of additive manufacturing technology and finite element analysis for spine surgery, we propose a new designing perspective of artificial lamina for potential use in clinical practice.

Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people’s health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

Precocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl–tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid–biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice.

Background and objectives: Laminectomy is a common surgical procedure in spine surgery. However, disruption of the posterior ligamentous complex of the spine may lead to a range of postoperative complications. Artificial lamina as a kind of bionic implant can well restore the posterior spinal structure. In this study, an individualized artificial titanium alloy lamina was designed to reconstruct the posterior spinal structure after laminectomy and explored its biomechanical effects, which could provide a theoretical basis for the clinical application of the artificial lamina.Methods: Three finite element models were constructed, namely the nonlinear and non-homogeneous intact model of the whole lumbar spine, the lumbar decompression alone surgical model, and the artificial lamina implantation surgical model. The range of motion, intradiscal pressure, and annulus fibrosus peak stress were compared between the three models at the surgical and adjacent segments. The stresses of the artificial lamina and fixation screws were also analyzed for the four movement states.Results: Compared with the intact model, the lumbar decompression alone surgical model showed an increase in range of motion, intradiscal pressure, and annulus fibrosus peak stresses at the surgical segment and adjacent segments under all conditions. The artificial lamina implantation surgical model showed an increase in these measurements only in flexion, increasing by 7.5%–22.5%, 7.6%–17.9%, and 6.4%–19.3%, respectively, over the intact model, while there was little difference under other conditions. The peak stresses in both the screw and the artificial lamina were highest in axial rotation, i. e. 46.53 MPa and 53.84 MPa, respectively. Screw stresses were concentrated on the connection between the screw and the artificial lamina, and artificial lamina stresses were concentrated on the spinous root, around the screw hole, and the contact with the vertebral body.Conclusion: An individualized artificial titanium alloy lamina can effectively reduce the range of motion, intradiscal pressure, and annulus fibrosus stress at the surgical segment and adjacent segments. The application of artificial lamina could better preserve the biomechanical properties of the intact lumbar spine and reduce the risk of adjacent segmental disease.

Women with hereditary breast cancer factors are more likely to be infertile and tend to receive fertility treatments. The safety of fertility treatments that contain hormone-related medications for ovarian stimulation has gained wide attention; however, evidence of the safety of fertility treatments is limited. This study aims to assess the association between fertility treatments and the incidence rate of breast cancer in women with a family history of breast cancer or BRCA mutations. A literature search was conducted in PubMed, Cochrane Library, and Embase. Studies concerning the effect of fertility treatments on breast cancer risk in genetically susceptible women were included. The fixed and random effects models were used to estimate the summary effects. Risk Of Bias In Non-randomized Studies - of Interventions instrument was used to assess the risk of bias in the included studies. A total of 5,282 studies were screened. Five cohort studies and three case-control studies were included. Breast cancer risk was not significantly increased by fertility treatments in general genetically susceptible women [pooled odds ratio (OR) 1.18, 95% confidence interval (CI) 0.96–1.45], women with a family history of breast cancer (pooled OR 1.35, 95% CI 0.97–1.89), or women with BRCA mutations (pooled OR 1.02, 95% CI 0.74–1.4). In subgroup analyses, there was no significant increase in breast cancer risk whether in BRCA1 mutation carriers (pooled OR 1.18, 95% CI 0.81–1.72), BRCA2 mutation carriers (pooled OR 0.54, 95% CI 0.09–3.34), or in the women treated with in vitro fertilization (pooled OR 0.75, 95% CI 0.51–1.1), clomiphene citrate (pooled OR 1.07, 95% CI 0.78–1.45) or gonadotropins (pooled OR 1.32, 95% CI 0.8–2.18). This is the first meta-analysis concerning the impact of fertility treatments on breast cancer risk in genetically susceptible women. Despite the finding that fertility treatment did not significantly increase breast cancer risk in genetically susceptible women, large prospective cohorts with more detailed information are required. Further investigations are needed to explore subtypes of breast cancer, genetic background of hormone-related breast cancer, and the association between BRCA mutations and the incidence of hormone receptor-positive breast cancer. Registration numberPROSPERO(CRD42021281336).

BackgroundAlthough most acute promyelocytic leukemia(APL) with low-intermediate risk could survive the induction treatment, early death still a big problem to have effects on overall survival in real world.This study aimed to analyze the clinical characteristics and possible predictors of early death in newly diagnosed patients with low-intermediate-risk acute promyelocytic leukemia.MethodsSixty patients with newly diagnosed low/intermediate-risk APL admitted to Mianyang Central Hospital from January 2013 to December 2021 were retrospectively analyzed.ResultsSixty patients with a median age of 46 years (range, 17-75 years) were included. Fourteen patients (23.3%) were in low-risk group, and 46 patients (76.7%) were in intermediate-risk group. Fourteen patients (23.3%) died during induction treatment. Five patients died of hemorrhage, 5 of severe infection and 4 of differentiation syndrome. Multivariate analysis showed that HGB

Seed germination is an important agronomic trait that affects crop yield and quality. Rapid and uniform seed germination traits are required in agricultural production. Although several genes are involved in seed germination and have been identified in Arabidopsis and rice, the genetic basis governing seed germination in maize remains unknown. Herein, we conducted a genome-wide association study to determine the genetic architecture of two germination traits, germination speed, and consistency, in a diverse panel. We genotyped 321 maize inbred populations with tropical, subtropical, or temperate origins using 1219401 single-nucleotide polymorphism markers. We identified 58 variants that were associated with the two traits, and 12 of these were shared between the two traits, indicating partial genetic similarity. Moreover, 36 candidate genes were involved in seed germination with functions including energy metabolism, signal transduction, and transcriptional regulation. We found that favorable variants had a greater effect on the tropical subpopulation than on the temperate. Accumulation of favorable variants shortened germination time and improved uniformity in maize inbred lines. These findings contribute significantly to understanding the genetic basis of maize seed germination and will contribute to the molecular breeding of maize seed germination.

Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.

Meniere's disease (MD) is a clinical syndrome characterized by spontaneous recurrent vertigo, usually accompanied by hearing loss, tinnitus, and aural fullness. The cause of MD remains unclear and is generally considered to be associated with endolymphatic hydrops. Studies showed that patients with MD could have eustachian tube dysfunction (ETD). ETD can disrupt the pressure balance between the middle and inner ear and impair the inner ear's function. In recent years, several studies have attempted to identify MD by using wideband tympanometry (WBT). However, there are limited studies in this area. There is no consensus on how to use WBT to diagnose Meniere's disease. Therefore, we endeavored to conduct a narrative review in this aspect based on the latest research findings. Reduction in resonance frequency and absorbance are characteristic of MD and can identify Meniere's disease. The use of an increase in the integrated area of absorbance as an indicator for identifying MD is controversial. WBT seems to be ineffective as a diagnostic tool during the acute episodes of Meniere's disease. Patients with MD may benefit from WBT. WBT has excellent potential for future use in Meniere's disease. However, further large sample sizes, multicenter studies are needed.

The biosynthetic genes for secondary metabolites are often clustered into giant operons with no transcription terminator before the end. The long transcripts are frangible and the transcription efficiency declines along with the process. Internal promoters might occur in operons to coordinate the transcription of individual genes, but their effects on the transcription of operon genes and the yield of metabolites have been less investigated. Epothilones are a kind of antitumor polyketides synthesized by seven multifunctional enzymes encoded by a 56-kb operon. In this study, we identified multiple internal promoters in the epothilone operon. We performed CRISPR-dCas9–mediated transcription activation of internal promoters, combined activation of different promoters, and activation in different epothilone-producing M. xanthus strains. We found that activation of internal promoters in the operon was able to promote the gene transcription, but the activation efficiency was distinct from the activation of separate promoters. The transcription of genes in the operon was influenced by not only the starting promoter but also internal promoters of the operon; internal promoters affected the transcription of the following and neighboring upstream/downstream genes. Multiple interferences between internal promoters thus changed the transcriptional profile of operon genes and the production of epothilones. Better activation efficiency for the gene transcription and the epothilone production was obtained in the low epothilone-producing strains. Our results highlight that interactions between promoters in the operon are critical for the gene transcription and the metabolite production efficiency.

BackgroundChronic cough is a common complaint which affects a large number of patients worldwide. Increased cough sensitivity is a very important cause of chronic persistent cough. However, there are limited clinical diagnosis and treatment for increased cough sensitivity. Transient receptor potential vanilloid-1 (TRPVl) is a member of the transient receptor potential (TRP) family of channels which is very closely associated with respiratory diseases. However, the mechanism through which TRPV1 that influences downstream events is still poorly understood.ResultsCapsaicin induced increase in cough sensitivity by upregulating the protein level of TRPV1, leading to the secretions of Substance P and neurokinin A which stimulated neurogenic inflammation. However, sinomenine, a component of traditional Chinese medicine, significantly attenuated the capsaicin-induced cough by inhibiting the expression of TRPV1 in guinea pigs. In addition, capsaicin increased the expression of SOX5 which mediated the transcriptional upregulation of TRPV1. However, pretreatment with sinomenine reduced the expression of SOX5.ConclusionThese results indicate that capsaicin induced increase in cough sensitivity by activating neurogenic inflammation, while sinomenine attenuated the increase in cough sensitivity by inhibiting the expressions of SOX5 and TRPV1 in guinea pigs. This finding may provide a novel target for the treatment of aggravated cough sensitivity.

As a relatively successful pathogen, several parasites can establish long-term infection in host. This “harmonious symbiosis” status relies on the “precise” manipulation of host immunity and metabolism, however, the underlying mechanism is still largely elusive. Immunometabolism is an emerging crossed subject in recent years. It mainly discusses the regulatory mechanism of metabolic changes on reprogramming the key transcriptional and post-transcriptional events related to immune cell activation and effect, which provides a novel insight for understanding how parasites regulate the infection and immunity in hosts. The present study reviewed the current research progress on metabolic reprogramming mechanism exploited by parasites to modulate the function in various immune cells, highlighting the future exploitation of key metabolites or metabolic events to clarify the underlying mechanism of anti-parasite immunity and design novel intervention strategies against parasitic infection.

Bariatric surgery including duodenal-jejunal bypass surgery (DJB) improves insulin sensitivity and reduces obesity-associated inflammation. However, the underlying mechanism for such an improvement is still incompletely understood. Our objective was to investigate the role of the gut microbiota in DJB-associated improvement of hepatic steatosis in high fat diet (HFD)-fed rats. To study this, hepatic steatosis was induced in male adult Sprague-Dawley rats by feeding them with a 60% HFD. At 8 weeks after HFD feeding, the rats were subjected to either DJB or sham operation. HFD was resumed 1 week after the surgery for 3 more weeks. In additional groups of animals, feces were collected from HFD-DJB rats at 2 weeks after DJB. These feces were then transplanted to HFD-fed rats without DJB at 8 weeks after HFD feeding. Hepatic steatosis and fecal microbiota were analyzed at 4 weeks after surgery or fecal transplantation. Our results showed that DJB alleviated hepatic steatosis in HFD-fed rats. Fecal microbiota analysis showed that HFD-fed and standard diet-fed rats clustered differently. DJB induced substantial compositional changes in the gut microbiota. The fecal microbiota of HFD-fed rats received fecal transplant from DJB rats overlapped with that of HFD-DJB rats. Treatment of rats with HFD-induced liver lesions by fecal transplant from DJB-operated HFD-fed rats also attenuated hepatic steatosis. Thus, alterations in the gut microbiota after DJB surgery are sufficient to attenuate hepatic steatosis in HFD-fed rats. Targeting the gut microbiota could be a promising approach for preventing or treating human NAFLD.

Background: Electronic screen media play an increasingly vital role in children's entertainment; however, excessive screen time may negatively influence child development. The purpose of this study was to investigate the relationship between the screen time of children with autism spectrum disorder (ASD) and their autistic symptoms and development quotients (DQs).Methods: We compared the screen time of 101 children with ASD and 57 typically developing (TD) children. Then, we performed a correlation analysis to determine the correlations between the screen time and the ASD-related scale scores and developmental quotients of the Gesell Developmental Schedules (GDS) of ASD children. We further divided the ASD group into subgroups according to the screen time and age and then separately conducted the above correlation analyses by subgroup.Result: The results showed that the screen time of the children with ASD was longer than that of the TD children (3.34 ± 2.64 h vs. 0.91 ± 0.93 h). The screen time of the children with ASD was positively correlated with the Childhood Autism Rating Scale (CARS) score (r = 0.242, P = 0.021) and “taste, smell and touch” item of CARS(r = 0.304, P = 0.005), and negatively correlated with the language DQ of the GDS (r = −0.236, P = 0.047). The subgroup analysis showed that in the longer screen time subgroup of ASD children, the screen time was positively correlated with the CARS score (r = 0.355, P = 0.026) and negatively correlated with the DQs of all domains of the GDS (P < 0.05). In addition, in the younger age group of ASD children, the screen time was positively correlated with the CARS score (r = 0.314, P = 0.021) and negatively correlated with the DQs of all domains of the GDS, except for the personal-social behavior domain (P < 0.05).Conclusion: Compared with TD children, children with ASD have a longer screen time. The screen time is related to autism-like symptoms and the DQs of children with ASD. The longer the screen time, the more severe the symptoms of ASD (especially sensory symptoms), and the more obvious the developmental delay, especially in ASD children with a longer screen time and younger age, particularly in the language domain.

Objective: To measure levels of vitamin A (VA) and vitamin D (VD) and the symptomatic association of their co-deficiencies on attention deficit hyperactivity disorder (ADHD) in Chinese children (6–9 years).Methods: Eighty-two children (69 boys and 13 girls; mean age = 7.1 ± 0.9 years at the time of the diagnosis) with ADHD were recruited as ADHD group. A total of 106 healthy children were recruited as the healthy control (HC) group. Serum levels of retinol and 25-hydroxyvitamin D (25(OH)D) of all children were evaluated using high-performance liquid chromatography (HPLC) and HPLC-tandem mass spectrometry. The Swanson, Nolan, and Pelham IV Rating Scale (SNAP-IV) was employed to assess the clinical symptoms of ADHD.Results: Children suffering from ADHD had significantly reduced serum levels of retinol and 25(OH)D compared with those of HCs, and the prevalence of VA deficiency and VD deficiency were higher in children suffering from ADHD. Serum concentrations of 25(OH)D and retinol were linked closely with the presence or absence of ADHD after adjustment for age, body mass index, season of blood sampling, and sun exposure. Serum concentrations of 25(OH)D and retinol showed a negative correlation with the total scores of SNAP-IV. Children with ADHD as well as VA and VD co-deficiency had increased SNAP-IV total scores and ADHD inattention subscale scores.Conclusion: VA deficiency and VD deficiency in children with ADHD were increased in comparison with that in HCs. VA and VD co-deficiency associated with ADHD symptom severity. Attention should be paid to regular testing of VA levels and VD levels. However, the mechanism of VA and VD in ADHD needs to be further studied. Interventional studies on VA and VD supplementation are recommended to further verify the relationship between VA and VD co-deficiency and ADHD.

ObjectiveTargeting immune checkpoints, such as PD-1, represents a promising approach for cancer immunotherapy, achieving long-term disease remission rates in numerous types of cancer. T cell immunoglobulin and ITIM domain (TIGIT) is a checkpoint receptor associated with the antitumor roles of NK and T cells. Notably, the blockade of TIGIT has been revealed as a potential promising approach in cancer immunotherapy. However, the therapeutic potential of blocking TIGIT in myelodysplastic syndrome (MDS) remains unclear and further research is required to reveal their role.MethodsFresh peripheral blood (PB) and bone marrow (BM) were obtained from patients with MDS and healthy donors (HDs) at the Tianjin Medical University General Hospital between January 21 2018 and March 22 2019. The present study investigated the expression levels of TIGIT on NK and T cells using flow cytometry (FCM) and PCR. In addition, other checkpoint receptors, such as CD226 and PD-1, were also investigated. To determine the mechanisms of antitumor immunity, the functions of NK and T cells expressing TIGIT were determined.ResultsTIGIT was found to be highly expressed on NK and T cells of the PB, where it was involved in disease progression and the immune escape of MDS. The high expression levels of TIGIT were associated with decreased NK and T cell function, and significantly lower secretions of activation factors, such as CD107a, IFN-γ and TNF-α. Notably, blocking TIGIT enhanced the antitumor effects of NK and T cells.ConclusionThe results of the present study suggested that targeting TIGIT alone or in combination with PD-1 may be a promising anticancer therapeutic strategy in MDS.

Myxococcus xanthus DK1622 has two RecA genes, recA1 (MXAN_1441) and recA2 (MXAN_1388), with unknown functional differentiation. Herein, we showed that both recA genes were induced by ultraviolet (UV) irradiation but that the induction of recA1 was more delayed than that of recA2. Deletion of recA1 did not affect the growth but significantly decreased the UV-radiation survival, homologous recombination (HR) ability, and induction of LexA-dependent SOS genes. In contrast, the deletion of recA2 markedly prolonged the lag phase of bacterial growth and increased the sensitivity to DNA damage caused by hydrogen peroxide but did not change the UV-radiation resistance or SOS gene inducibility. Protein activity analysis demonstrated that RecA1, but not RecA2, catalyzed DNA strand exchange (DSE) and LexA autocleavage in vitro. Transcriptomic analysis indicated that RecA2 has evolved mainly to regulate gene expression for cellular transportation and antioxidation. This is the first report of functional divergence of duplicated bacterial recA genes. The results highlight the evolutionary strategy of M. xanthus cells for DNA HR and genome sophistication.

Photodynamic therapy (PDT) involves the uptake of photosensitizers by cancer cells and the irradiation of a light with a specific wavelength to trigger a series of photochemical reactions based on the generation of reactive oxygen, leading to cancer cell death. PDT has been widely used in various fields of biomedicine. However, the molecular events of the cancer cell nucleus during the PDT process are still unclear. In this work, a nuclear-targeted gold nanorod Raman nanoprobe combined with surface-enhanced Raman scattering spectroscopy (SERS) was exploited to investigate the dynamic intranuclear molecular changes of B16 cells (a murine melanoma cell line) treated with a photosensitizer (Chlorin e6) and the specific light (650 nm). The SERS spectra of the cell nucleus during the PDT treatment were recorded in situ and the spectroscopic analysis of the dynamics of the nucleus uncovered two main events in the therapeutic process: the protein degradation and the DNA fragmentation. We expect that these findings are of vital significance in having a better understanding of the PDT mechanism acting on the cancer cell nucleus and can further help us to design and develop more effective therapeutic platforms and methods.

Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C0) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (Cmax) of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P-glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P-gp expression and altering the activities of CES and UGT.

Background: Although most acute promyelocytic leukemia(APL) with lowintermediate risk could survive the induction treatment, early death still a big problem to have effects on overall survival in real world. This study aimed to analyze the clinical characteristics and possible predictors of early death in newly diagnosed patients with low-intermediate-risk acute promyelocytic leukemia. Methods: Sixty patients with newly diagnosed low/intermediate-risk APL admitted to Mianyang Central Hospital from January 2013 to December 2021 were retrospectively analyzed. Results: Sixty patients with a median age of 46 years (range, 17-75 years) were included. Fourteen patients (23.3%) were in low-risk group, and 46 patients (76.7%) were in intermediate-risk group. Fourteen patients (23.3%) died during induction treatment. Five patients died of hemorrhage, 5 of severe infection and 4 of differentiation syndrome. Multivariate analysis showed that HGB <65g/L at diagnosis (OR=38.474, 95%CI: 2.648~558.923, P=0.008) during induction treatment was an independent risk factors for early death in lowintermediate risk APL patients. In survival group, all patients achieved complete remission, the time to achieve remission was 25.87 ± 5.02 days, the average ATO dosage was 0.16 ± 0.03 mg/kg/day. In univariate analysis, there was no statistically significant difference in time span for remission when ATO dosage was in the 0.11~0.16mg/kg/day range. Compared with patients with low-risk APL, those with intermediate-risk APL had higher white blood cell counts (at diagnosis, day 3, day 5 and peak), higher level of lactate dehydrogenase, higher percentage of bone marrow promyelocytes, more platelet transfusions during treatment, and more early deaths (P<0.05). The overall survival of intermediate-risk APL patients seemed worse than those with low-risk APL (c=5.033, P =0.025). Conclusions: In patients with low-intermediate risk APL, HGB <65g/L at diagnosis was an independent risk factors for early death. Remission could still be achieved at low-dose ATO without affecting the required time for lowintermediate risk APL patients. Differences in clinical characteristics were found between low-risk and intermediate-risk APL. The intermediate-risk group had higher early mortality risk than the low-risk group. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC. [ABSTRACT FROM AUTHOR]

As a key histopathological characteristic of tumor invasion, perineural invasion (PNI) assists tumor dissemination, whereas the current definition of PNI by dichotomy is not accurate and the prognostic value of PNI has not reached consensus. To define PNI status in each patient when mixed types of PNI occurred simultaneously, we here further subclassified the traditional PNI in 183 patients with oral squamous cell carcinoma (OSCC). The spatial localization of nerves in OSCC microenvironment was thoroughly evaluated and successfully concluded into four types of PNI: 0, tumor cells away from nerves; 1, tumor cells encircling nerves less than 33%; 2, tumor cells encircling nerves at least 33%; and 3, tumor cells infiltrating into nerve sheathes. Sequentially, patients were stratified by single and mixed types of PNI. Traditionally, types 0 and 1 were defined as PNI−, while types 2 and 3 were PNI+, which predicted shorter survival time. When multiple types of PNI existed within one tumor, patients with higher score of PNI types tended to have a relatively worse prognosis. Therefore, to define the status of PNI more precisely, the new variable worst pattern of PNI (WPNI) was proposed, which was taken as the highest score of PNI types present in each patient no matter how focal. Results showed that patients with WPNI 1 had longest survival time, and WPNI 2 correlated with better overall survival (p = 0.02), local-regional recurrence-free survival (p = 0.03), and distant metastasis-free survival (p = 0.046) than WPNI 3. Multivariate Cox analysis confirmed that only WPNI 3 could independently predict patients' prognosis, which could be explained by a more damaged immune response in WPNI 3 patients with less CD3+CD8+ T cells and CD19+ B cells. Conclusively, WPNI by trichotomy provide more meticulous and precise pathological information for tumor-nerve interactions in OSCC patients. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The US FDA has approved several therapeutics and vaccines worldwide through the emergency use authorization in response to the rapid spread of COVID-19. Nevertheless, the efficacies of these treatments are being challenged by viral escape mutations. There is an urgent need to develop effective treatments protecting against SARS-CoV-2 infection and to establish a stable effect-screening model to test potential drugs. Polyclonal antibodies (pAbs) have an intrinsic advantage in such developments because they can target rapidly mutating viral strains as a result of the complexity of their binding epitopes. In this study, we generated anti–receptor-binding domain (anti-RBD) pAbs from rabbit serum and tested their safety and efficacy in response to SARS-CoV-2 infection both in vivo and ex vivo. Primary human bronchial epithelial two-dimensional (2-D) organoids were cultured and differentiated to a mature morphology and subsequently employed for SARS-CoV-2 infection and drug screening. The pAbs protected the airway organoids from viral infection and tissue damage. Potential side effects were tested in mouse models for both inhalation and vein injection. The pAbs displayed effective viral neutralization effects without significant side effects. Thus, the use of animal immune serum–derived pAbs might be a potential therapy for protection against SARS-CoV-2 infection, with the strategy developed to produce these pAbs providing new insight into the treatment of respiratory tract infections, especially for infections with viruses undergoing rapid mutation. [ABSTRACT FROM AUTHOR]

Background: Chronic cough is a common complaint which affects a large number of patients worldwide. Increased cough sensitivity is a very important cause of chronic persistent cough. However, there are limited clinical diagnosis and treatment for increased cough sensitivity. Transient receptor potential vanilloid-1 (TRPVl) is a member of the transient receptor potential (TRP) family of channels which is very closely associated with respiratory diseases. However, the mechanism through which TRPV1 that influences downstream events is still poorly understood. Results: Capsaicin induced increase in cough sensitivity by upregulating the protein level of TRPV1, leading to the secretions of Substance P and neurokinin A which stimulated neurogenic inflammation. However, sinomenine, a component of traditional Chinese medicine, significantly attenuated the capsaicin-induced cough by inhibiting the expression of TRPV1 in guinea pigs. In addition, capsaicin increased the expression of SOX5 which mediated the transcriptional upregulation of TRPV1. However, pretreatment with sinomenine reduced the expression of SOX5. Conclusion: These results indicate that capsaicin induced increase in cough sensitivity by activating neurogenic inflammation, while sinomenine attenuated the increase in cough sensitivity by inhibiting the expressions of SOX5 and TRPV1 in guinea pigs. This finding may provide a novel target for the treatment of aggravated cough sensitivity. [ABSTRACT FROM AUTHOR]

As a relatively successful pathogen, several parasites can establish long-term infection in host. This "harmonious symbiosis" status relies on the "precise" manipulation of host immunity and metabolism, however, the underlying mechanism is still largely elusive. Immunometabolism is an emerging crossed subject in recent years. It mainly discusses the regulatory mechanism of metabolic changes on reprogramming the key transcriptional and post-transcriptional events related to immune cell activation and effect, which provides a novel insight for understanding how parasites regulate the infection and immunity in hosts. The present study reviewed the current research progress on metabolic reprogramming mechanism exploited by parasites to modulate the function in various immune cells, highlighting the future exploitation of key metabolites or metabolic events to clarify the underlying mechanism of anti-parasite immunity and design novel intervention strategies against parasitic infection. [ABSTRACT FROM AUTHOR]

Purpose: It is very important to develop potential molecular associated with oral squamous cell carcinoma (OSCC) malignant transformation and progression. Thus, the aim of our study was to determine the amino acid metabolic characteristics of OSCC patients and test their diagnostic value. Experimental Design: Eight pairs of matched tumor and normal samples were collected for gas chromatography–mass spectrometry (GC-MS) high-throughput untargeted analysis. Another 20 cases (each case including tumor and normal tissues) were also enrolled for ultrahigh-performance liquid chromatography–tandem mass spectrometer (UHPLC-MS/MS) amino acid quantitative analysis. T -test and receiver operating characteristic (ROC) curve analysis were used to determine candidate markers. Principal component analysis, partial least squares discriminant analysis, and heat map analysis were used to verify the ability of candidate markers to distinguish tumors from normal tissues. Results: A total of 10 amino acids biomarker were selected as OSCC candidate diagnostic biomarkers by GC-MS high-throughput untargeted metabolomics analyses [area under the curve (AUC) >0.80]. We further measured the specific concentration of these candidate amino acids biomarkers in another batch of 20 cases by UHPLC-MS/MS quantitative analysis. The result validated that nine amino acids had been detected, which had statistically significant difference (t -test, p < 0.05). Moreover, three of nine amino acid markers (glutamate, aspartic acid, and proline) displayed high sensitivity and specificity (AUC >0.90) by ROC curve analysis and obtained optimal sensitivity and specificity by binary logistic regression in the Glmnet package (AUC = 0.942). Conclusions: In conclusion, a panel including three amino acids (glutamate, aspartic acid, and proline) was identified as potential diagnostic biomarkers of OSCC by a combination of non-targeted and targeted metabolomics methods. [ABSTRACT FROM AUTHOR]