Development and validation of an explainable machine learning model for predicting multidimensional frailty in hospitalized patients with cirrhosis.

We sought to develop and validate a machine learning (ML) model for predicting multidimensional frailty based on clinical and laboratory data. Moreover, an explainable ML model utilizing SHapley Additive exPlanations (SHAP) was constructed. This study enrolled 622 patients hospitalized due to decompensating episodes at a tertiary hospital. The cohort data were randomly divided into training and test sets. External validation was carried out using 131 patients from other tertiary hospitals. The frail phenotype was defined according to a self-reported questionnaire (Frailty Index). The area under the receiver operating characteristics curve was adopted to compare the performance of five ML models. The importance of the features and interpretation of the ML models were determined using the SHAP method. The proportions of cirrhotic patients with nonfrail and frail phenotypes in combined training and test sets were 87.8% and 12.2%, respectively, while they were 88.5% and 11.5% in the external validation dataset. Five ML algorithms were used, and the random forest (RF) model exhibited substantially predictive performance. Regarding the external validation, the RF algorithm outperformed other ML models. Moreover, the SHAP method demonstrated that neutrophil-to-lymphocyte ratio, age, lymphocyte-to-monocyte ratio, ascites, and albumin served as the most important predictors for frailty. At the patient level, the SHAP force plot and decision plot exhibited a clinically meaningful explanation of the RF algorithm. We constructed an ML model (RF) providing accurate prediction of frail phenotype in decompensated cirrhosis. The explainability and generalizability may foster clinicians to understand contributors to this physiologically vulnerable situation and tailor interventions.

Upregulated Tß4 expression in inflammatory bowel disease impairs the intestinal mucus barrier by inhibiting autophagy in mice.

Disrupted intestinal barrier homeostasis is fundamental to inflammatory bowel disease. Thymosin ß4 (Tß4) improves inflammation and has beneficial effects in dry-eye diseases, but its effects on the intestinal mucus barrier remain unknown. Therefore, this study evaluated the underlying regulatory mechanisms and effects of Tß4 by examining Tß4 expression in a mouse model with dextran sodium sulfate (DSS)-induced colitis and colonic barrier damage. Additionally, we intraperitoneally injected C57BL/6 mice with Tß4 to assess barrier function, microtubule-associated protein 1 light chain 3 (LC3II) protein expression, and autophagy. Finally, normal human colon tissue and colon carcinoma cells (Caco2) were cultured to verify Tß4-induced barrier function and autophagy changes. Mucin2 levels decreased, microbial infiltration increased, and Tß4 expression increased in the colitis mouse model versus the control mice, indicating mucus barrier damage. Moreover, Tß4-treated C57BL/6 mice had damaged intestinal mucus barriers and decreased LC3II levels. Tß4 also inhibited colonic mucin2 production, disrupted tight junctions, and downregulated autophagy; these results were confirmed in Caco2 cells and normal human colon tissue. In summary, Tß4 may be implicated in colitis by compromising the integrity of the intestinal mucus barrier and inhibiting autophagy. Thus, Tß4 could be a new diagnostic marker for intestinal barrier defects.

SNHG1 knockdown promotes osteogenic differentiation of hDFSCs through anti-oxidative stress mediated by autophagy.

The long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a crucial role in tumorigenesis and is frequently employed as a prognostic biomarker. However, its involvement in the osteogenic differentiation of oral stem cells, particularly human dental follicle stem cells (hDFSCs), remains unclear. Our investigation revealed that the absence of SNHG1 enhances the osteogenic differentiation of hDFSCs. Furthermore, the downregulation of SNHG1 induces autophagy in hDFSCs, leading to a reduction in intracellular oxidative stress levels. Notably, this effect is orchestrated through the epigenetic regulation of EZH2. Our study unveils a novel function of SNHG1 in governing the osteogenic differentiation of hDFSCs, offering fresh insights for an in-depth exploration of the molecular mechanisms underlying dental follicle development. These findings not only provide a foundation for advancing the understanding of SNHG1 but also present innovative perspectives for promoting the repair and regeneration of periodontal supporting tissue, ultimately contributing to the restoration of periodontal health and tooth function.

The Tree Shrew Model of Parkinson Disease: A Cost-Effective Alternative to Nonhuman Primate Models.

The surge in demand for experimental monkeys has led to a rapid increase in their costs. Consequently, there is a growing need for a cost-effective model of Parkinson disease (PD) that exhibits all core clinical and pathologic phenotypes. Evolutionarily, tree shrews (Tupaia belangeri) are closer to primates in comparison with rodents and could be an ideal species for modeling PD. To develop a tree shrew PD model, we used the 1-methyl-4-phenylpyridinium (MPP+), a metabolite derived from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to induce lesions in dopaminergic neurons of the unilateral substantia nigra. The induced tree shrew model consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms included bradykinesia, rest tremor, and postural instability, and ∼50% individuals showed apomorphine-induced rotations, a classic phenotype of unilateral PD models. All these are closely resembled the ones observed in PD monkeys. Meanwhile, this model was also sensitive to L-dopa treatment in a dose-dependent manner, which suggested that the motor deficits are dopamine dependent. Immunostaining showed a significant loss of dopaminergic neurons (∼95%) in the lesioned substantia nigra, which is a crucial PD pathological marker. Moreover, a control group of nigral saline injection did not show any motor deficits and pathological changes. Cytomorphologic analysis revealed that the size of nigral dopaminergic neurons in tree shrews is much bigger than that of rodents and is close to that of macaques. The morphologic similarity may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, in this study, we have successfully developed a PD model in a small animal species that faithfully recapitulated the classic clinical symptoms and key pathological indicators of PD monkeys, providing a novel and low-cost avenue for evaluation of PD treatments and underlying mechanisms.

Duck STING mediates antiviral autophagy directing the interferon signaling pathway to inhibit duck plague virus infection.

Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal model for waterfowl among migratory birds, studying and dissecting the antiviral immunity and viral evasion in duck cells may pave a path to deciphering these puzzles. Here, we studied the mechanism of antiviral autophagy mediated by duck STING in DEF cells. The results collaborated that duck STING could significantly enhance LC3B-II/I turnover, LC3B-EGFP puncta formation, and mCherry/EGFP ratio, indicating that duck STING could induce autophagy. The autophagy induced by duck STING is not affected by shRNA knockdown of ATG5 expression, deletion of the C-terminal tail of STING, or TBK1 inhibitor BX795 treatment, indicating that duck STING activated non-classical selective autophagy is independent of interaction with TBK1, TBK1 phosphorylation, and interferon (IFN) signaling. The STING R235A mutant and Sar1A/B kinase mutant abolished duck STING induced autophagy, suggesting binding with cGAMP and COPII complex mediated transport are the critical prerequisite. Duck STING interacted with LC3B through LIR motifs to induce autophagy, the LIR 4/7 motif mutants of duck STING abolished the interaction with LC3B, and neither activated autophagy nor IFN expression, indicating that duck STING associates with LC3B directed autophagy and dictated innate immunity activation. Finally, we found that duck STING mediated autophagy significantly inhibited duck plague virus (DPV) infection via ubiquitously degraded viral proteins. Our study may shed light on one scenario about the control and evasion of diseases transmitted by migratory birds.

Photocatalyzed Imino-Difluoromethylation of Alkenes with Bifunctional Oxime Esters.

Herein, we report a simple and versatile difluoromethylene-imide reaction in which a series of olefins can undergo a difluoromethylenimine reaction under photocatalytic conditions through an energy transfer (EnT) process. The reaction has mild conditions and a wide range of applicability. We successfully synthesized 27 molecules containing difluoromethylene units, featuring easily accessible starting materials and operational simplicity.

Risk factors for post-cerebral infarction cognitive dysfunction in older adults: a retrospective study.

OBJECTIVE: Our research aims to elucidate the significance of type 2 diabetes (T2D) and provides an insight into a novel risk model for post-cerebral infarction cognitive dysfunction (PCICD). METHODS: Our study recruited inpatients hospitalized with cerebral infarction in Xijing hospital, who underwent cognitive assessment of Mini-Mental State Examination (MMSE) from January 2010 to December 2021. Cognitive status was dichotomized into normal cognition and cognitive impairment. Collected data referred to Demographic Features, Clinical Diseases, scale tests, fluid biomarkers involving inflammation, coagulation function, hepatorenal function, lipid and glycemic management. RESULTS: In our pooled dataset from 924 eligible patients, we included 353 in the final analysis (age range 65-91; 30.31% female). Multivariate logistic regression analysis was performed to show that Rural Areas (OR = 1.976, 95%CI = 1.111-3.515, P = 0.020), T2D (OR = 2.125, 95%CI = 1.267-3.563, P = 0.004), Direct Bilirubin (OR = 0.388, 95%CI = 0.196-0.769, P = 0.007), Severity of Dependence in terms of Barthel Index (OR = 1.708, 95%CI = 1.193-2.445, P = 0.003) that were independently associated with PCICD, constituting a model with optimal predictive efficiency. CONCLUSION: To the best of our knowledge, this study provides a practicable map of strategical predictors to robustly identify cognitive dysfunction at risk of post-cerebral infarction for clinicians in a broad sense. Of note, our findings support that the decline in serum direct bilirubin (DBil) concentration is linked to protecting cognitive function.

Isolation and antioxidant activity of peptides from Chinese hairy tofu.

Hairy tofu is a famous Chinese snack that is made from soybeans and rich in various nutrients. In order to further explore the antioxidant peptides of hairy tofu hydrolysates, seven proteases were used to hydrolyze hairy tofu. The results of in vitro radical scavenging activity showed that hairy tofu hydrolysates obtained by pancreatin exhibited the highest antioxidant activity. After Sephadex G-25 gel filtration and reversed-phase high-performance liquid chromatography (RP-HPLC), 97 peptides were identified in the most antioxidant fraction using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Among them, nine peptides were synthesized and their antioxidant activities were assessed using a H2O2-induced oxidative 293T cell model. Finally, four peptides (QCESHK, LAWNEGR, NLQGENEWDQK, and FTEMWR) at concentrations of < 50 µg/ml significantly decreased the malondialdehyde content compared with the model group, displaying in vivo antioxidant activity and low cytotoxicity. Overall, this research provided the choice of using hairy tofu peptides as antioxidant products in the pharmaceutical and food industries.

Fructose-1, 6-Bisphosphate Aldolase B Suppresses Glycolysis and Tumor Progression of Gastric Cancer.

OBJECTIVE: Gastric cancer (GC) is believed to be one of the most common digestive tract malignant tumors. However, mounting evidence indicates a link between the glycolysis and tumorigenesis, including gastric cancer. METHODS: Our research identified 5508 differently expressed mRNAs in gastric cancer. Then, the genes highly associated with tumorigenesis were identified through weighted correlation network analysis (WGCNA). Bioinformatics analysis observed that these hub genes were significantly linked to the regulation of cell cycle, drug metabolism, and glycolysis. Among these hub genes, there is a critical gene involved in glycolysis regulation, namely fructose-bisphosphate B (ALDOB). RESULTS: Analysis based on The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets revealed that ALDOB was significantly downregulated in GC compared with normal tissues. In addition, cell viability assay confirmed that ALDOB acted as a tumor suppressor. Finally, drug sensitivity analysis revealed that ALDOB increased the sensitivity of gastric cancer cells to most antitumor drugs, especially talazoparib, XAV939, and FTI-277. Our results showed that the expression of ALDOB was significantly lower in GC tissues than in normal tissues. And ALDOB significantly inhibited proliferation and migration, delayed glycolysis in GC cells. Consequently, our study suggests that ALDOB may be a potential target for the clinical treatment of gastric cancer.

The mediating role of loneliness between psychological resilience and health-related quality of life among patients with nasopharyngeal carcinoma: a cross-sectional study using structural equation modeling.

BACKGROUND: Cancer patients' health-related quality of life (HRQoL) has always been a hot discussion spot. Loneliness and psychological resilience are considered to be significant psychosocial factors impacting the HRQoL of the cancer population. However, there is a lack of studies on the interrelationship among loneliness, resilience, and HRQoL in patients with nasopharyngeal carcinoma (NPC). This study aims to explore the relationship between resilience and HRQoL among NPC patients and to recognize the potential mediating role of loneliness in this relationship. METHODS: A cross-sectional study was performed in this study. A convenience sampling method was conducted to recruit participants. A total of 155 patients with nasopharyngeal carcinoma were required to complete the socio-demographic questionnaire, the Cancer Loneliness Scale (CLS), the 10-item Connor-Davidson Resilience Scale (CD-RISC-10), and the European Organization for Research and Treatment of Quality of Life Questionnaire C-30 (EORTC QLQ-C30) from April 2022 to August 2022 in a tertiary grade A hospital in Guangzhou, China. The multiple linear regression analysis was used to identify influencing factors, and structural equation modeling with the bootstrap method was performed to test the mediating role of loneliness. This study complied with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: HRQoL was at a median level among NPC patients, with a mean score of 64.19 (24.38) on the Global health status/quality of life (GHS/QoL) scale. Monthly household income (B = 4.973, P < 0.001), cancer stage (B=-4.342, P = 0.004), psychological resilience (B = 0.914, P < 0.001), and loneliness (B =-1.083, P < 0.001) were independent factors related to HRQoL, explaining 36.7% of the variance of HRQoL. Psychological resilience exerted its direct negative impact on loneliness (ß = -0.199, BC95%CI = -0.318/-0.089), and it also had a both direct and indirect positive impact on HRQoL (ß = 0.653, BC95%CI = 0.423/0.912; ß = 0.142, BC95%CI = 0.046/0.296). Loneliness exerted a partially mediating impact on the relationship between psychological resilience and HRQoL. CONCLUSIONS: NPC patients with higher monthly household, early stages of cancer, higher resilience, and lower loneliness show a better HRQoL. Resilience has an indirect positive impact on HRQoL by influencing loneliness in NPC patients. It is suggested that healthcare staff should strive to enhancing resilience and reducing loneliness as new strategies to promote NPC patients' HRQoL further.

Result of a Pilot External Quality Assessment Scheme for Clinical Diagnosis of Inherited Metabolic Disorders in China.

BACKGROUND: We aimed to evaluate the diagnostic capabilities of Chinese laboratories for inherited metabolic disorders (IMDs) using gas chromatography-mass spectrometry (GC-MS) on urine samples. Meanwhile, based on the result of the pilot external quality assessment (EQA) scheme, we hope to establish a standardized and reliable procedure for future EQA practice. METHODS: We recruited laboratories that participated in the EQA of quantitative analysis of urinary organic acids with GC-MS before joining the surveys. In each survey, a set of five real urine samples was distributed to each participant. The participants should analyze the sample by GC-MS and report the "analytical result", "the most likely diagnosis", and "recommendation for further tests" to the NCCL before the deadline. RESULTS: A total of 21 laboratories participated in the scheme. The pass rates were 94.4% in 2020 and 89.5% in 2021. For all eight IMDs tested, the analytical proficiency rates ranged from 84.7% - 100%, and the interpretational performance rate ranged from 88.2% - 97.0%. The performance on hyperphenylalaninemia (HPA), 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), and ethylmalonic encephalopathy (EE) samples were not satisfactory. CONCLUSIONS: In general, the participants of this pilot EQA scheme are equipped with the basic capability for qualitative organic acid analysis and interpretation of the results. Limited by the small size of laboratories and samples involved, this activity could not fully reflect the state of clinical practice of Chinese laboratories. NCCL will improve the EQA scheme and implement more EQA activities in the future.

Results of a Pilot External Quality Assessment Scheme for Genetic Testing of Newborns with Spinal Muscular Atrophy.

BACKGROUND: This study aims to evaluate the ability of laboratories to perform spinal muscular atrophy (SMA) genetic testing in newborns based on dried blood spot (DBS) samples, and to provide reference data and advance preparation for establishing the pilot external quality assessment (EQA) scheme for SMA genetic testing of newborns in China. METHODS: The pilot EQA scheme contents and evaluation principles of this project were designed by National Center for Clinical Laboratories (NCCL), National Health Commission. Two surveys were carried out in 2022, and 5 batches of blood spots were submitted to the participating laboratory each time. All participating laboratories conducted testing upon receiving samples, and test results were submitted to NCCL within the specified date. RESULTS: The return rates were 75.0% (21/28) and 95.2% (20/21) in the first and second surveys, respectively. The total return rate of the two examinations was 83.7% (41/49). Nineteen laboratories (19/21, 90.5%) had a full score passing on the first survey, while in the second survey twenty laboratories (20/20, 100%) scored full. CONCLUSIONS: This pilot EQA survey provides a preliminary understanding of the capability of SMA genetic testing for newborns across laboratories in China. A few laboratories had technical or operational problems in testing. It is, therefore, of importance to strengthen laboratory management and to improve testing capacity for the establishment of a national EQA scheme for newborn SMA genetic testing.

Prenatal Diagnosis of Fetal Micrognathia at 11-20 Weeks of Gestation: A Prospective Observation Study.

OBJECTIVE: To prospectively evaluate the prognosis of fetuses diagnosed with micrognathia using prenatal ultrasound screening. METHODS: Between January 2019 and December 2022, a normal range of IFA to evaluate the facial profile in fetuses with micrognathia in a Chinese population between 11 and 20 gestational weeks was established, and the pregnancy outcomes of fetal micrognathia were described. The medical records of these pregnancies were collected, including family history, maternal demographics, sonographic findings, genetic testing results, and pregnancy outcomes. RESULTS: Ultrasound identified 25 patients with fetal micrognathia, with a mean IFA value of 43.6°. All cases of isolated fetal micrognathia in the initial scans were non-isolated in the following scans. A total of 78.9% (15/19) cases had a genetic cause confirmed, including 12 with chromosomal abnormalities and 3 with monogenic disorders. Monogenic disorders were all known causes of micrognathia, including two cases of campomelic dysplasia affected by SOX9 mutations and one case of mandibulofacial dysostosis with an EFTUD2 mutation. In the end, 19 cases were terminated, 1 live birth was diagnosed as Pierre Robin syndrome, and 5 cases were lost to follow-up. CONCLUSION: IFA is a useful indicator and three-dimensional ultrasound is a significant support technique for fetal micrognathia prenatal diagnosis. Repeat ultrasound monitoring and genetic testing are crucial, with CMA recommended and Whole exome sequencing performed when normal arrays are reported. Isolated fetal micrognathia may be an early manifestation of monogenic disorders.

Nutritional screening and assessment tools for patients with cirrhosis based on the Global Leadership Initiative on Malnutrition criteria.

BACKGROUND: Malnutrition is highly prevalent and associated with complications and mortality in patients with cirrhosis. METHODS: This was a prospective observational study. Patients with cirrhosis were screened using the Nutritional Risk Screening 2002, the Royal Free Hospital-Nutritional Prioritizing Tool and the Skeletal Muscle Index. Then, the sensitivity, specificity, positive and negative predictive values, and consistency with the Global Leadership Initiative on Malnutrition criteria results were calculated. We also analysed the association between nutritional status and short-term prognosis. RESULTS: We enrolled 125 patients with cirrhosis, of whom 59.20% and 60.00% were malnourished based on the Global Leadership Initiative on Malnutrition criteria and Skeletal Muscle Index. Some 53.60% and 65.60%, respectively, were classified medium-to-high nutritional risk by Nutritional Risk Screening 2002 and the Royal Free Hospital-Nutritional Prioritizing Tool. The Royal Free Hospital-Nutritional Prioritizing Tool had the best predictive value, and it was more sensitive and had a better negative predictive value than the Nutritional Risk Screening 2002 Tool. The Skeletal Muscle Index also had good sensitivity and predictive value. The Royal Free Hospital-Nutritional Prioritizing Tool, Skeletal Muscle Index and Global Leadership Initiative on Malnutrition criteria showed high concordance. The 3- and 6-month mortality rates were significantly higher for patients with moderate-to-high nutritional risk or malnutrition, regardless of the tool. CONCLUSIONS: When assessing cirrhosis with the Global Leadership Initiative on Malnutrition criteria, the Royal Free Hospital-Nutritional Prioritizing Tool is best for nutritional screening and the Skeletal Muscle Index is also a good nutritional assessment tool.

Characteristics and effects on daily lives of pelvic girdle pain during early postpartum in Beijing women, China.

Pelvic girdle pain (PGP) is a common problem during pregnancy and postpartum and negatively affects women's well-being. Yet it is not well known in China. This study assessed PGP's intensity, location, and quality and the status of daily activities on postpartum women with pain, and explored the relationship between pain and the prevalence of depressive symptoms. A cross-sectional study recruiting 1,038 eligible women at 6 weeks postpartum from the obstetric clinic of a hospital was conducted in Beijing, China. Data were collected using self-reported questionnaires, including Introductory information form, Body chart, Number Rating Scale, McGill Pain Questionnaire-2, Pelvic Girdle Questionnaire, and Edinburgh Postnatal Depression Scale. In this study, 32.2 percent women experienced pain. The mean (SD) pain intensity score was 3.07 ± 1.60. About 50.6 percent women experienced sacroiliac joint pain, and 25.5 percent women experienced pain in a combination of locations. About 73.1 percent women experienced aching pain, and 57.5 percent experienced more than one kind of pain quality. The mean total score, which assesses activity and symptom limitations, was 21.93 ± 17.35 (percent), of which a normal sex life (1.29 ± 0.94) was made more challenging due to pain. In mental health, the prevalence of depressive symptoms coincided with the prevalence of pain (p = 0.008). Postpartum PGP still needs to be taken seriously, and women with pain require further support. The above knowledge offers information to manage pain, daily lives and depressive symptoms, contributes to think about strategies to better promote postpartum women physical and mental health in the future.

The clinical value of intelligent wound measurement devices in patients with chronic wounds: A scoping review.

Chronic wounds are common in clinical practice, with long treatment cycle and high treatment cost. Changes in wound area can well predict the effectiveness of treatment and the possibility of healing. Therefore, continuous wound monitoring and evaluation are particularly important. Traditional manual wound measurement tends to overestimate wound area. Recently, various intelligent wound measurement devices have been introduced into clinical practice. This review aims to summarise the reliability, validity, types and measurement principles of different intelligent wound measurement devices, so as to analyse the clinical value and application prospect. Articles numbering 2610 were retrieved from the database, and 14 articles met the inclusion criteria. The results showed that the intelligent wound measurement devices included in the study reported good reliability and validity. Contact devices can lead to wound bed damage, wound deformation, patient pain, and is not convenient for electronic wound recording; partial contact devices can complete continuous monitoring and recording of wounds, but are not sensitive to wound depth measurement. Non-contact devices are more accurate in capturing wound images. In addition to wound measurement, they also have the function of wound assessment. In general, handheld and portable non-contact devices have great clinical value and promotion prospects.

Biochemical component analysis of human myopic corneal stroma using the Raman spectrum.

PURPOSE: This study aimed to measure the Raman spectrum of the human corneal stroma lens obtained from small incision lenticule extraction surgery (SMILE) in Asian myopic eyes using a confocal Raman micro-spectrometer built in the laboratory. METHODS: Forty-three myopic patients who underwent SMILE with equivalent diopters between - 4.00 and - 6.00 D were selected, and the right eye data were collected. Corneal stroma lenses were obtained during surgery, and the Raman spectra were measured after air drying. The complete Raman spectrum of human myopic corneal stroma lens tissue was obtained within the range of 700-4000 cm-1. RESULTS: Thirteen characteristic peaks were found, with the stronger peaks appearing at 937 cm-1, corresponding to proline, valine, and the protein skeleton of the human myopic corneal stroma lens; 1243 cm-1, corresponding to collagen protein; 1448 cm-1, corresponding to the collagen protein and phospholipids; and 2940 cm-1, corresponding to the amino acid and lipids, which was the strongest Raman peak. CONCLUSION: These results demonstrated that Raman spectroscopy has much potential as a fast, cost-effective, and reliable diagnostic tool in the diagnosis and treatment of eye diseases, including myopia, keratoconus, and corneal infection.

LncRNA HOTAIRM1 promotes dental follicle stem cell-mediated bone regeneration by regulating HIF-1α/KDM6/EZH2/H3K27me3 axis.

Large bone defect reconstruction undergoes hypoxia and remains a major practical challenge. Bone tissue engineering with a more promising stem cell source facilitates the development of better therapeutic outcomes. Human dental follicle stem cells (hDFSCs) with superior multipotency, osteogenic capacity, and accessibility have been proven a promising cell source for bone regeneration. We previously identified a novel long noncoding RNA (lncRNA), HOTAIRM1, to be highly expressed in hDFSCs. Here we found that HOTAIRM1 overexpressed hDFSCs promoted bone regeneration in rat critical-size calvarial defect model. Mechanically, HOTAIRM1 was induced in hDFSCs under hypoxic conditions and activated HIF-1α. RNA-sequencing analysis indicated that HOTAIRM1 upregulated oxygen-sensing histone demethylases KDM6A/B and suppressed methyltransferase EZH2 via targeting HIF-1α. The osteogenic differentiation of hDFSCs was accompanied with demethylation of H3K27, and HOTAIRM1 overexpression decreased the distribution of H3K27me3 in osteogenic genes, including ALP, M-CSF, Wnt-3a, Wnt-5a, Wnt-7a, and ß-catenin, thus promoted their transcription. Our study provided evidence that HOTAIRM1 upregulated KDM6A/B and inhibited EZH2 in a HIF-1α dependent manner to enhance the osteogenesis of hDFSCs. HOTAIRM1-mediated hDFSCs may serve as a promising therapeutic approach to promote bone regeneration in clinical practice.

Duck plague virus tegument protein vp22 plays a key role in the secondary envelopment and cell-to-cell spread.

Duck plague virus (DPV) is one of the major infectious and fatal diseases of geese, ducks, and other wild waterfowl. The DPV UL49 gene product VP22 is one of the most abundant tegument proteins. However, the role of the DPV VP22 is enigmatic to be clarified. In this study, we found deletion of the UL49 gene resulted in reduced viral growth curve and smaller plaque size in duck embryo fibroblast (DEF) cells, confirming that DPV VP22 is required for efficient viral growth in vitro. In addition, deletion of the UL49 gene inhibited the secondary envelopment of the virus, the release of viral particles, and the spread of viruses between cells. Our study signified the importance of VP22 for DPV secondary envelopment, release, cell-to-cell spread, and accumulation of viral RNA. These findings provide a basis for further study of the function of VP22 in DPV or other herpesviruses.

Mast cells disrupt the duodenal mucosal integrity: Implications for the mechanisms of barrier dysfunction in functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal (GI) disorder, but its pathophysiology is poorly understood. Mast cells (MCs) may play a critical role in the development of FD. Therefore, the aim of this study was to investigate the effect of MCs on barrier function, tight junction (TJ) proteins and related signaling pathways. METHODS: The expression of the TJ proteins claudin-8, ZO-1 and occludin in biopsy tissues from seven FD patients and five controls was assessed. Based on the in vivo results, we further investigated the effect of (1) MC degranulation in a coculture model of Caco-2/RBL-2H3 cells and tryptase in Caco-2 monolayers, (2) MC degranulation in the presence or absence of a PAR-2 antagonist and (3) MC degranulation in the presence or absence of an ERK1/2 signaling pathway inhibitor. The epithelial integrity of Caco-2 cell monolayers was assessed by measuring the transepithelial electrical resistance (TEER). The expression of TJ proteins was evaluated by western blotting, QT-PCR and immunostaining. RESULTS: Epithelial claudin-8, ZO-1 and occludin protein expression were significantly reduced in tissues from FD patients compared with controls. MC degranulation and tryptase decreased the TEER and reduced the expression of TJ proteins in Caco-2 cell monolayers. A PAR-2 antagonist and an ERK1/2 signaling pathway inhibitor significantly reduced the effect of MC degranulation on the TEER and TJ protein expression in Caco-2 cell monolayers. CONCLUSIONS: MCs disrupt duodenal barrier function by modulating the levels of TJ proteins, and the PAR-2 and ERK1/2 signaling pathways may mediate the pathogenesis of FD.