Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia.

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.

Identifying Medical Diagnoses and Treatable Diseases by Image-Based Deep Learning.

The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.

The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Proteomics Defines Plasma Biomarkers for the Early Diagnosis of Biliary Atresia.

Early diagnosis of biliary atresia (BA) is crucial for improving the chances of survival and preserving the liver function of pediatric patients with BA. Herein, we performed proteomics analysis using data-independent acquisition (DIA) and parallel reaction monitoring (PRM) to explore potential biomarkers for the early diagnosis of BA compared to other non-BA jaundice cases. Consequently, we detected and validated differential protein expression in the plasma of patients with BA compared to the plasma of patients with intrahepatic cholestasis. Bioinformatics analysis revealed the enriched biological processes characteristic of BA by identifying the differential expression of specific proteins. Signaling pathway analysis revealed changes in the expression levels of proteins associated with an alteration in immunoglobulin levels, which is indicative of immune dysfunction in BA. The combination of polymeric immunoglobulin receptor expression and immunoglobulin lambda variable chain (IGL c2225_light_IGLV1-47_IGLJ2), as revealed via machine learning, provided a useful early diagnostic model for BA, with a sensitivity of 0.8, specificity of 1, accuracy of 0.89, and area under the curve value of 0.944. Thus, our study identified a possible effective plasma biomarker for the early diagnosis of BA and could help elucidate the underlying mechanisms of BA.

MAPK signaling pathway induced LOX-1+ polymorphonuclear myeloid-derived suppressor cells in biliary atresia.

Biliary atresia (BA) is a severe pediatric liver disease characterized by progressive bile duct destruction and fibrosis, leading to significant liver damage and frequently necessitating liver transplantation. This study elucidates the role of LOX-1+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in BA pathogenesis and assesses their potential as non-invasive early diagnostic biomarkers. Using flow cytometry, immunofluorescence, and molecular profiling, we analyzed the expression and activity of these cells in peripheral blood and liver tissues from BA patients and controls. Our findings reveal a significant increase in the frequencies and function of LOX-1+PMN-MDSCs in BA patients, along with MAPK signaling pathway upregulation, indicating their involvement in disease mechanisms. Additionally, the frequencies of LOX-1+PMN-MDSC in peripheral blood significantly positively correlate with liver function parameters in BA patients, demonstrating diagnostic performance comparable to traditional serum markers. These findings suggest that LOX-1+PMN-MDSCs contribute to the immunosuppressive environment in BA and could serve as potential diagnostic targets.

Early Radiographic Characteristics of the Lateral Talocalcaneal Angle and its Predictive Significance for Relapse in Patients With Idiopathic Clubfoot Treated With the Ponseti Method.

In order to evaluate the early radiographic characteristics of the lateral talocalcaneal (L-TC) angle in patients with idiopathic clubfoot (ICF) and to investigate its prognostic significance for relapse after initial treatment with the Ponseti method. We retrospectively included 151 patients (96 males and 55 females; 227 feet) with ICF treated at our Institution between January 2005 and December 2014. The age at initial treatment was less than 6 months, and radiographs were obtained within 3 months of the Achilles tenotomy (mean age: 2.3 months; range: 0.77-6.8). All patients were followed up for at least 7 years (range, 7-18). The participants' feet were classified into 3 groups: relapsed (Group A), not relapsed (Group B), and normal foot groups which consisted of healthy feet in patients with unilateral ICF (Group C). All angle measurements were expressed in degrees. Forty-seven ICF feet in 33 patients relapsed, while 180 feet in 118 patients did not, and the age at relapse was 5.92 ± 1.91 years. Seventy-five normal feet were included in Group C. The average L-TC angle in Group A and B patients was 33.57° ± 12.05° and 39.37° ± 12.55°, respectively, while Group C was 49.61° ± 9.11°. A significant difference was found among the 3 groups of patients (F = 31.48, p < .001). The L-TC angle cut-off value below which a recurrence could be predicted was 36.1° (sensitivity, 74.47%). The L-TC angle of ICF patients treated using the Ponseti method were reduced compared to normal feet. An L-TC angle of <36.1° has relative value in predicting ICF relapse.

Suppression of innate and acquired immunity in severe hand foot and mouth disease caused by EV71 infections in children.

Hand, foot, and mouth disease (HFMD) is a common children infectious disease caused by human enteroviruses. Most of the cases have minimal symptoms, however, some patients may develop serious neurological, cardiac complications, or even death. The pathological mechanism leading to severe HFMD is not clearly understood, and the immunological status of the individual patient may play an important role. Transcriptomes of peripheral blood mononuclear cells from EV71-infected patients (n = 45) and healthy controls (n = 36) were examined. Immune pathways were up-regulated in patients with mild disease symptoms (n = 11, M) compared to the healthy controls (n = 36, H), demonstrating an effective anti-viral response upon EV71 infection. However, in patients with severe symptoms (n = 23, S) as well as severe patients following treatment (n = 11, A), their innate and acquired immune pathways were down-regulated, indicating a global immunity suppression. Such immune suppression characteristics could thus provide an opportunity for early EV-71 infection prognosis prediction. Based on our cohort, an SVM model using RNA-seq expression levels of five genes (MCL1, ZBTB37, PLEKHM1P, IFNAR2 and YEATS2) was developed and achieved a high ROC-AUC (91·3%) in predicting severe HFMD. Meanwhile, qPCR fold-changes method was performed based three genes (MCL1, IFNAR2 and YEATS2) on additional cohort. This qPCR method achieved a ROC-AUC of 78.6% in predicting severe HFMD, which the patients could be distinguished in 2-3 h. Therefore, our models demonstrate the possibility of HFMD severity prediction based on the selected biomarkers that predict severe HFMD effectively.

Establishment and identification of an animal model of Hirschsprung disease in suckling mice.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital intestinal malformation. Previous HSCR animal model needs invasive operation on adult animal. The aim of this study is to establish an early-onset animal model which is consistent with the clinical manifestation of HSCR patients. METHODS: The neonatal mice were randomly divided into the benzalkonium chloride (BAC) group, treated with BAC via enema, and the control group, treated with saline. Weight changes, excretion time of carmine, CT scan, hematoxylin-eosin staining and immunofluorescence staining were used to evaluate the effect of the model. Differentially expressed genes (DEGs) in the HSCR mice were analyzed by using DAVID 6.8 database and compared with DEGs from HSCR patients. RESULTS: The weight of mice was lower and the excretion time of carmine was longer in the BAC group. Moreover, distal colon stenosis and proximal colon enlargement appeared in the BAC group. Neurons in the distal colon decreased significantly after 4 weeks of BAC treatment and almost disappeared completely after 12 weeks. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression. CONCLUSIONS: An economical and reliable HSCR animal model which has similar clinical characteristics to HSCR patients was successfully established. IMPACT: The animal model of Hirschsprung disease was first established in BALB/c mice. This model is an animal model of early-onset HSCR that is easy to operate and consistent with clinical manifestations. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression.

Plasma anti-myosin autoantibodies in the diagnosis of necrotizing enterocolitis.

We aimed to assess whether autoantibodies can be used as biomarkers for necrotizing enterocolitis (NEC) and applied for its early diagnosis. A prospective observational study was conducted in neonates with suspected NEC abdominal distension (the developmental study), which consisted of 50 neonates finally divided into NEC (n = 24) and non-NEC (n = 26) cohorts based on follow-up results. Serum samples were collected within 48 h of illness onset and used for screening NEC-associated plasma autoantibodies by autoantigen microarray. Additionally, we validated anti-myosin autoantibodies by enzyme-linked immunosorbent assay (ELISA) in an independent validation study, for which we selected plasma samples within 48 h of onset of NEC (n = 38) and samples of gestational age- and weight-matched controls (n = 13). Autoantigen microarray revealed that both IgG and IgM anti-myosin autoantibodies in plasma from neonates with NEC were significantly higher than those in neonates with other diagnoses. ELISA showed that plasma anti-myosin autoantibodies increased in the NEC cohort, with 1.5-fold higher levels than in the non-NEC cohort. Anti-myosin autoantibodies were able to distinguish NEC from non-NEC, achieving an area under the curve (AUC) of 0.8856 (95% confidence interval (CI): 0.7918-0.9795), with sensitivity of 81.58% and specificity of 76.93%. Plasma anti-myosin autoantibodies were significantly higher in all three subtypes of NEC (P < 0.0001 for NEC I; P = 0.0018 for NEC II; P = 0.0011 for NEC III), especially in NEC stage I than that in the non-NEC controls. CONCLUSION: Anti-myosin autoantibodies may be applied as a promising diagnostic marker for NEC, especially for NEC stage I. WHAT IS KNOWN: • Intestinal damage and self-antigen exposure may lead to increased autoantibodies, and they are widely used as biomarkers for diagnosing inflammatory bowel disease. • Necrotizing enterocolitis (NEC) is a devastating disease with overwhelming inflammation and immune dysregulation. WHAT IS NEW: • Increased autoantibodies were present in patients with NEC, even before typical X-ray manifestations. • Anti-myosin autoantibodies may be applied as a promising diagnostic marker for NEC.

Weight progression and adherence to weight gain target in women with vs. without gestational diabetes: a retrospective cohort study.

BACKGROUND: Weight management has been an important component of the service in obstetric care offered to pregnant women. Current gestational weight gain recommendations were primarily for the general obstetric population, raising concern about the applicability to women with gestational diabetes mellitus (GDM). We aimed to assess the difference in weight progression and adherence to the recommended gestational weight gain targets between women with gestational diabetes mellitus (GDM) and women with normal glucose tolerance (NGT). METHODS: This was a hospital-based retrospective study of 56,616 pregnant women (9,430 GDM women and 47,186 NGT women) from Guangzhou between 2017 and 2021. The average change in weight progression was estimated based on serial weight measurements throughout pregnancy, using a mixed effects model with a random intercept to account for repeated measures of the same individual. RESULTS: Women with GDM gained less weight (12.07 [SD 5.20] kg) than women with NGT (14.04 [SD 5.04] kg) throughout pregnancy. Before OGTT, a small difference was observed in the average change in weight progression between the two groups (GDM, 0.44 kg/week vs. NGT, 0.45 kg/week, p < 0.001), however, this gap widened significantly after the test (0.34 vs. 0.50 kg/week, p < 0.001). GDM individuals were identified with an approximately 4-fold increased proportion of insufficient weight gain (41.1% vs. 10.4%) and a 2-fold decreased proportion of excessive weight gain (22.6% vs. 54.2%) compared to NGT individuals. These results were consistently observed across different BMI categories, including underweight (insufficient: 52.7% vs. 19.9%; excessive: 15.6% vs. 35.3%), normal weight (insufficient 38.2% vs. 7.4%; excessive: 22.2% vs. 57.3%), and overweight/obese (insufficient: 43.1% vs. 9.8%; excessive: 30.1% vs. 68.8%). CONCLUSION: Weight progression varied significantly between GDM and NGT individuals, resulting in a substantial difference in identifying insufficient and excessive weight gain between the two groups under current gestational weight gain guidelines.

Prognostic Value of Serum Cholinesterase Levels for In-Hospital Mortality among Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Cholinesterase (ChE) is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD), including chronic airway inflammation and oxidation/antioxidant imbalance. However, the relationship between serum ChE levels and survival outcomes of patients hospitalized with acute exacerbations of COPD (AECOPD) is unknown. In this retrospective single-center study, we investigated the ability of the serum ChE level to predict in-hospital death in patients hospitalized with AECOPD. The clinicopathological data, including serum ChE levels as well as clinical and biochemical indicators were extracted for 477 patients from the hospital records and analyzed. Our results demonstrated that AECOPD patients with lower serum ChE levels were associated with increased mortality, frequent hospitalization due to acute exacerbations (AE) in the past year, and longer hospital stay. The optimal cutoff value for the serum ChE level was 4323 U/L. The area under the ROC curve (AUC) values for predicting in-hospital mortality based on the serum ChE level was 0.79 (95% confidence interval (CI), 0.72-0.85). Multivariate logistic regression analysis demonstrated that serum ChE level ≤ 4323 U/L (odds ratio (OR) 9.09, 95% CI 3.43-28.3, p < 0.001), age-adjusted Charlson comorbidity index (aCCI), and the number of hospitalizations due to AE in the past year were independent risk factors for predicting the in-hospital mortality of AECOPD patients. In conclusion, our study demonstrated that low serum ChE levels were associated with significantly higher in-hospital mortality rates of patients hospitalized with AECOPD. Therefore, serum ChE level is a promising prognostic predictor of hospitalized AECOPD patients.

[Diterpenoid constituents in Pseudolarix amabilis and their antitumor activities in vitro].

By various chromatographic techniques and extensive spectroscopic methods, 17 abietane diterpenoids were isolated from the dichloromethane fraction of the 95% ethanol cold-soak extracts of the seeds of Pseudolarix amabilis, namely pseudoamaol A(1), 12α-hydroxyabietic acid(2), 12-methoxy-7,13-abietadien-18-oic acid(3), 13-hydroxy-8,11,13-podocarpatrien-18-oic acid(4), 15-hydroxy-7,13-abietadien-12-on-18-oic acid(5), 8(14)-podocarpen-13-on-18-oic acid(6), holophyllin K(7), metaglyptin B(8), 7α-hydroxydehydroabietinsaure-methylester(9), 7-oxodehydroabietic acid(10), 15-hydroxy-7-oxodehydroabietinsaure-methy-lester(11), 15-methoxydidehydroabietic acid(12), 7-oxo-15-hydroxy-dehydroabietic acid(13), 15-hydroxydehydroabietic acid(14), 8,11,13-abietatriene-15,18-diol(15), 8,11,13-abietatriene-15-hydroxy-18-succinic acid(16), and 7ß-hydroxydehydroabie-tic acid(17). Compound 1 was a new compound. The isolated compounds were evaluated for their antitumor activities(HepG2, SH-SY5Y, K562), and compounds 8 and 17 showed potential cytotoxic activity against K562 cells, with IC_(50) values of 26.77 and 37.35 µmol·L~(-1), respectively.

Variant rs8400 enhances ALKBH5 expression through disrupting miR-186 binding and promotes neuroblastoma progression.

Objective: AlkB homolog 5 (ALKBH5) has been proven to be closely related to tumors. However, the role and molecular mechanism of ALKBH5 in neuroblastomas have rarely been reported. Methods: The potential functional single-nucleotide polymorphisms (SNPs) in ALKBH5 were identified by National Center for Biotechnology Information (NCBI) dbSNP screening and SNPinfo software. TaqMan probes were used for genotyping. A multiple logistic regression model was used to evaluate the effects of different SNP loci on the risk of neuroblastoma. The expression of ALKBH5 in neuroblastoma was evaluated by Western blotting and immunohistochemistry (IHC). Cell counting kit-8 (CCK-8), plate colony formation and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays were used to evaluate cell proliferation. Wound healing and Transwell assays were used to compare cell migration and invasion. Thermodynamic modelling was performed to predict the ability of miRNAs to bind to ALKBH5 with the rs8400 G/A polymorphism. RNA sequencing, N6-methyladenosine (m6A) sequencing, m6A methylated RNA immunoprecipitation (MeRIP) and a luciferase assay were used to identify the targeting effect of ALKBH5 on SPP1. Results: ALKBH5 was highly expressed in neuroblastoma. Knocking down ALKBH5 inhibited the proliferation, migration and invasion of cancer cells. miR-186-3p negatively regulates the expression of ALKBH5, and this ability is affected by the rs8400 polymorphism. When the G nucleotide was mutated to A, the ability of miR-186-3p to bind to the 3'-UTR of ALKBH5 decreased, resulting in upregulation of ALKBH5. SPP1 is the downstream target gene of the ALKBH5 oncogene. Knocking down SPP1 partially restored the inhibitory effect of ALKBH5 downregulation on neuroblastoma. Downregulation of ALKBH5 can improve the therapeutic efficacy of carboplatin and etoposide in neuroblastoma. Conclusions: We first found that the rs8400 G>A polymorphism in the m6A demethylase-encoding gene ALKBH5 increases neuroblastoma susceptibility and determines the related mechanisms. The aberrant regulation of ALKBH5 by miR-186-3p caused by this genetic variation in ALKBH5 promotes the occurrence and development of neuroblastoma through the ALKBH5-SPP1 axis.

CD177+ cells produce neutrophil extracellular traps that promote biliary atresia.

BACKGROUND & AIMS: We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the pathogenesis of BA. METHODS: Immune cells from the livers of mice with rhesus rotavirus-induced BA were analysed. Single-cell RNA-sequencing was performed to specifically analyse Gr-1+ (Ly6C/Ly6G+) cells in the liver. Gene expression profiles of CD177+ cells were analysed using the Smart-Seq RNA-sequencing method, and the pathogenesis of BA was examined in Cd177-/- mice. Neutrophil extracellular trap (NET) inhibitors were used to determine the role of CD177+ cell-derived NETs in BA-associated bile duct damage, and a pilot clinical study evaluated the potential effects of N-acetylcysteine on NET release in BA. RESULTS: Increased levels of Gr-1+ cells were observed in the livers of mice with rhesus rotavirus-induced BA. RNA-sequencing analysis revealed that CD177+ cells were the main population of Gr-1+ cells and expressed elevated levels of both interferon-stimulated and neutrophil degranulation genes. Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality. High numbers of mitochondria were detected in CD177+ cells derived from mice with BA; these cells were associated with increased levels of reactive oxygen species and increased NET formation, which induced the apoptosis of biliary epithelial cells in cocultures. In a pilot clinical study, the administration of N-acetylcysteine to patients with BA reduced CD177+ cell numbers and reactive oxygen species levels, indicating a potential beneficial effect. CONCLUSIONS: Our data indicate that CD177+ cells play an important role in the initiation of BA pathogenesis via NET formation. CLINICAL TRIAL REGISTRATION: The pilot study of N-acetylcysteine treatment in patients with BA was registered on the Chinese Clinical Trial Registry (ChiCTR2000040505). LAY SUMMARY: Neutrophils (a type of innate immune cell, i.e. an immune cell that doesn't target a specific antigen) are thought to play a role in the development of biliary atresia (a rare but potentially lethal condition of the bile ducts that occurs in infants). Herein, we found that neutrophils expressing a particular protein (CD177) played an important role in bile duct damage by releasing a special structure (NET) that can trap and kill pathogens but that can also cause severe tissue damage. A pilot study in patients with biliary atresia showed that inhibiting NETs could have a beneficial effect.

Combined effects of air pollutants on gestational diabetes mellitus: A prospective cohort study.

Exposures to multiple air pollutants during pregnancy have been associated with the risk of gestational diabetes mellitus (GDM). However, their combined effects are unclear. We aimed to evaluate the combined associations of five air pollutants from pre-pregnancy to the 2nd trimester with GDM. This study included 20,113 participants from the Born in Guangzhou Cohort Study (BIGCS). The inverse distance-weighted models were used to estimate individual air pollutant exposure, namely ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter less than 10 µm in diameter (PM10), and less than 2.5 µm in diameter (PM2.5). We estimated stage-specific associations of air pollutants with GDM using generalized estimating equation, and departures from additive joint effects were assessed using the relative excess risk (RERI) and the joint relative risk (JRR). Of the 20,113 participants, 3440 women (17.1%) were diagnosed with GDM. In the adjusted model, increased concentrations of O3 and SO2 3-6 months before pregnancy were associated with GDM occurrence, as well as O3 and PM10 in the 1st trimester, the adjusted relative risk (95% confident intervals) [RRs (95%CI)] ranged from 1.05 (1.00, 1.09) to 1.21 (1.04, 1.40). The largest JRR for GDM was the combination of SO2, NO2, and PM10 in the 1st trimester (JRR = 1.32, 95% CI: 1.10, 1.59). The JRR for O3 and SO2 was less than their additive joint effects [RERI = -0.25 (-0.47, -0.04), P for interaction = 0.048]. Associations of air pollutants with GDM differed somewhat by pre-pregnancy BMI and season. This study added new evidence to the current understanding of the combined effects of multiple air pollutants on GDM. Public health strategies were needed to reduce the adverse effects of air pollution exposure on pregnant women.

The role of PTEN in puromycin aminonucleoside-induced podocyte injury.

Podocytes are specialized cells of the glomerulus that play important structural and functional roles in maintaining the filtration barrier. Loss and injury of podocytes are leading factors of glomerular disease and kidney failure. Recent studies found that phosphatase and tensin homolog (PTEN) may play a critical role in maintaining the normal structure and function in podocytes. However, we still understand very little about how PTEN is regulated under podocyte injury conditions. In this study, We therefore investigated whether PTEN could play a role in podocyte injury induced by puromycin aminonucleoside (PAN), and whether dexamethasone (DEX) alleviates podocyte injury by PTEN/PI3K/Akt signaling. Our results showed that PI3K/Akt pathway was activated in podocytes exposed to PAN conditions, accompanied by down-regulation of the PTEN and microtubule-associated light chain 3 (LC3) expression.podocyte-specific knockout of PTEN significantly promoted podocyte injury, The potential renoprotection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and the inhibition of apoptosis.These novel findings also suggest that targeting PTEN might be a novel and promising therapeutic strategy against podocyte injury.

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis.

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.

Association between ABHD1 and DOK6 polymorphisms and susceptibility to Hirschsprung disease in Southern Chinese children.

Hirschsprung disease (HSCR) is an infrequent congenital intestinal dysplasia. The known genetic variations are unable to fully explain the pathogenesis of HSCR. The α/ß-hydratase domain 1 (ABHD1) interferes with the proliferation and migration of intestinal stem cells. Docking protein 6 (DOK6) is involved in neurodevelopment through RET signalling pathway. We examined the association of ABHD1 and DOK6 genetic variants with HSCR using 1470 controls and 1473 HSCR patients from Southern Chinese children. The results clarified that DOK6 rs12968648 G allele significantly increased HSCR susceptibility, in the allelic model (p = 0.034; OR = 1.12, 95%CI = 1.01~1.24) and the dominant model (p = 0.038; OR = 1.12, 95%CI = 1.01~1.25). Clinical stratification analysis showed that rs12968648 G allele was associated with increased risk of short-segment HSCR (S-HSCR), in the allelic model (p = 0.028; OR = 1.14, 95%CI = 1.01~1.28) and the additive model (p = 0.030; OR = 1.14, 95%CI = 1.01~1.28). ABHD1 rs2304678 C allele had higher risk to develop total colonic aganglionosis (TCA) in the allelic model (p = 7.04E-03; OR = 1.67, 95%CI = 1.15~2.43) and the dominant model (p = 4.12E-03; OR = 1.93, 95%CI = 1.23~3.04). DOK6 rs12968648 and ABHD1 rs2304678 had significant intergenic synergistic effect according to logical regression (p = 0.0081; OR = 0.76, 95%CI = 0.63~0.93) and multifactor dimensionality reduction (MDR, p = 0.0045; OR = 1.25, 95%CI = 1.07~1.46). This study verified two susceptible variations of HSCR on ABHD1 and DOK6. Their roles in HSCR should be conducted in further studies.

Association between lncRNA-H19 polymorphisms and hepatoblastoma risk in an ethic Chinese population.

H19 polymorphisms are associated with increased susceptibility to several cancers; however, their role in hepatoblastoma remains unclear. In this study, we investigated the association between three H19 polymorphisms (rs2839698 G>A, rs3024270 C>G, rs217727 G>A) and hepatoblastoma susceptibility in 213 hepatoblastoma patients. The rs2839698 and rs3024270 polymorphisms were associated with significantly increased hepatoblastoma risk, with the GG genotype associated with a higher risk of hepatoblastoma than the CC genotype at the rs3024270 locus. The rs217727 polymorphism was associated with significantly decreased hepatoblastoma risk, with the AG genotype associated with a lower risk of hepatoblastoma than the GG genotype. These findings were confirmed by combined analysis, and stratification analysis revealed that age, gender and clinical stage were associated with increased hepatoblastoma susceptibility. The GGG and AGG haplotypes were significantly associated with increased hepatoblastoma risk compared with the GCA reference (rs2839698, rs3024270, rs217727). The rs2839698 and rs3024270 polymorphisms correlated with decreased MRPL23-AS1 expression, whereas the rs217727 polymorphism was associated with increased MRPL23-AS1 expression. Overall, the H19 rs2839698, rs3024270 and rs217727 polymorphisms were associated with hepatoblastoma susceptibility in a Chinese Han population.

Distinct Disease Severity Between Children and Older Adults With Coronavirus Disease 2019 (COVID-19): Impacts of ACE2 Expression, Distribution, and Lung Progenitor Cells.

BACKGROUND: Children and older adults with coronavirus disease 2019 (COVID-19) display a distinct spectrum of disease severity yet the risk factors aren't well understood. We sought to examine the expression pattern of angiotensin-converting enzyme 2 (ACE2), the cell-entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the role of lung progenitor cells in children and older patients. METHODS: We retrospectively analyzed clinical features in a cohort of 299 patients with COVID-19. The expression and distribution of ACE2 and lung progenitor cells were systematically examined using a combination of public single-cell RNA-seq data sets, lung biopsies, and ex vivo infection of lung tissues with SARS-CoV-2 pseudovirus in children and older adults. We also followed up patients who had recovered from COVID-19. RESULTS: Compared with children, older patients (>50 years.) were more likely to develop into serious pneumonia with reduced lymphocytes and aberrant inflammatory response (P = .001). The expression level of ACE2 and lung progenitor cell markers were generally decreased in older patients. Notably, ACE2 positive cells were mainly distributed in the alveolar region, including SFTPC positive cells, but rarely in airway regions in the older adults (P < .01). The follow-up of discharged patients revealed a prolonged recovery from pneumonia in the older (P < .025). CONCLUSIONS: Compared to children, ACE2 positive cells are generally decreased in older adults and mainly presented in the lower pulmonary tract. The lung progenitor cells are also decreased. These risk factors may impact disease severity and recovery from pneumonia caused by SARS-Cov-2 infection in older patients.