Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

Relative Mediastinal Displacement Index (RMDI): A Prenatal MRI Indicator of Adverse Events in Fetuses With Isolated Left Congenital Diaphragmatic Hernia.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO), has partly improved congenital diaphragmatic hernia (CDH) outcomes, yet the overall morbidity and mortality remain high. Existing prenatal indicators for CDH fetuses are operator-dependent, time-consuming, or less accurate, a new simple and accurate indicator to indicate adverse events in CDH patients is needed. PURPOSE: To propose and assess the association of a new MRI parameter, the relative mediastinal displacement index (RMDI), with adverse events including in-hospital deaths or the need for ECMO in fetuses with isolated left CDH (iLCDH). STUDY TYPE: Retrospective analysis. SUBJECTS: One hundred thirty-nine fetuses were included in the iLCDH group (24 with adverse events and 115 without) and 257 fetuses were included in the control group from two centers in Guangzhou. FIELD STRENGTH/SEQUENCE: 3.0 T, T2WI-TRUFI; 1.5 T, T2WI-FIESTA. ASSESSMENT: Three operators independently measured the → DL $$ \underset{\mathrm{DL}}{\to } $$ , → DR $$ \underset{\mathrm{DR}}{\to } $$ , and DH on the axial images. The calculation formula of the RMDI was ( → DL $$ \underset{\mathrm{DL}}{\to } $$ + → DR $$ \underset{\mathrm{DR}}{\to } $$ )/DH . STATISTICAL TESTS: The independent sample t test, Mann-Whitney U test, Chi-square test, Chi-square test continuity correction, Fisher's test, linear regression analysis, logistic regression analysis, intraclass correlation coefficient, receiver operating characteristic curve analysis, and Delong test. A P value <0.05 was considered statistically significant. RESULTS: The RMDI did not change with gestational age in the iLCDH group (with [P = 0.189] and without [P = 0.567] adverse events) and the control group (P = 0.876). There were significant differences in RMDI between the iLCDH group (0.89 [0.65, 1.00]) and the control group (-0.23 [-0.34, -0.16]). In the iLCDH group, RMDI was the only indicator left for indicating adverse events, and the best cutoff value was 1.105. Moreover, there was a significant difference in diagnostic accuracy between the RMDI (AUC = 0.900) and MSA (AUC = 0.820), LHR (AUC = 0.753), o/e LHR (AUC = 0.709), and o/e TFLV (AUC = 0.728), respectively. DATA CONCLUSION: The RMDI is expected to be a simple and accurate tool for indicating adverse events in fetuses with iLCDH. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 1.

Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model.

The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephron in vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identifying novel genes associated with kidney development and disease. A rapid, efficient, and scalable organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.

Developing Hypoimmunogenic Human iPSC-Derived Oligodendrocyte Progenitor Cells as an Off-The-Shelf Cell Therapy for Myelin Disorders.

Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N-acetyl-l-aspartate (NAA), and consequently demyelination and vacuolation in the brain. In this study, hypoimmunogenic human induced pluripotent stem cell (iPSC)-derived oligodendrocyte progenitor cells (OPC) are developed from a healthy donor as an "off-the-shelf" cell therapy. Hypoimmunogenic iPSCs are generated through CRISPR/Cas9 editing of the human leukocyte antigen (HLA) molecules in healthy donor-derived iPSCs and differentiated into OPCs. The OPCs are engrafted into the brains of CD (nur7) mice and exhibit widespread distribution in the brain. The engrafted OPCs mature into oligodendrocytes that express the endogenous wildtype ASPA gene. Consequently, the transplanted mice exhibit elevated human ASPA expression and enzymatic activity and reduced NAA level in the brain. The transplanted OPCs are able to rescue major pathological features of CD, including defective myelination, extensive vacuolation, and motor function deficits. Moreover, the hypoimmunogenic OPCs exhibit low immunogenicity both in vitro and in vivo. The hypoimmunogenic OPCs can be used as "off-the-shelf" universal donor cells to treat various CD patients and many other demyelinating disorders, especially autoimmune demyelinating diseases, such as multiple sclerosis.

Effect of sevoflurane anesthesia to neonatal rat hippocampus by RNA-seq.

BACKGROUND: Sevoflurane is an inhalational anesthetic for the induction and maintenance of general anesthesia in pediatric surgery. However, few studies have paid attention to the multiple organ toxicity and the mechanism behind it. METHODS: Inhalation anesthesia neonatal rat model were realized by exposing to 3.5% sevoflurane. RNA-seq was performed to find out how inhalation anesthesia affects the lung, cerebral cortex, hippocampus, and heart. Validation of RNA-seq results by QPCR after animal model establishment. Tunel assay detects cell apoptosis in each group. CCK-8, cell apoptosis assay and western blot assay validation of the role of siRNA-Bckdhb in the action of sevoflurane on rat hippocampal neuronal cells. RESULTS: There are significant differences between different groups, especially the hippocampus and cerebral cortex. Bckdhb was significantly up-regulated in the hippocampus with sevoflurane-treated. Pathway analysis revealed several abundant pathways related to DEGs, e.g., protein digestion and absorption and PI3K-Akt signaling pathway. A series of cellular and animal experiments showed that siRNA-Bckdhb can inhibit the reduction of cellular activity caused by sevoflurane. CONCLUSION: Bckdhb interference experiments indicated that sevoflurane induces hippocampal neuronal cells apoptosis by regulating Bckdhb expression. Our study provided new insights into the molecular mechanism of sevoflurane-induced brain damage in pediatrics.

[Chemical constituents in different parts of Ixeris sonchifolia based on UPLC-LTQ-Orbitrap-MS~n].

The chemical constituents in stem leaf, root, and flower of Ixeris sonchifolia were identified by the ultra performance li-quid chromatography coupled with linear ion trap quadrupole-orbitrap mass spectrometry(UPLC-LTQ-Orbitrap-MS~n). The separation was performed on an Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) with a mobile phase of water(containing 0.1% formic acid, A)-acetonitrile(B) with gradient elution. With electrospray ionization source, the data of 70% methanol extract from stem leaf, root and flower of I. sonchifolia were collected by high-resolution full-scan Fourier transform spectroscopy, data dependent acquisition, precursor ion scan, and selected ion monitoring in the negative and positive ion modes. The compounds were identified based on accurate molecular weight, retention time, fragment ions, comparison with reference standard, Clog P and references. A total of 131 compounds were identified from the 70% methanol extract of I. sonchifolia, including nucleosides, flavonoids, organic acids, terpenoids, and phenylpropanoids, and 119, 110, and 126 compounds were identified from the stem leaf, root and flower of I. sonchifolia, respectively. In addition, isorhamnetin, isorhamnetin-7-O-sambubioside and caffeylshikimic acid were discovered from I. sonchifolia for the first time. This study comprehensively analyzed and compared the chemical constituents in different parts of I. sonchifolia, which facilitated the discovery of effective substances and the development and application of medicinal material resources of I. sonchifolia.

Epigenetic Regulation of NGF-Mediated Osteogenic Differentiation in Human Dental Mesenchymal Stem Cells.

Nerve growth factor (NGF) is the best-characterized neurotrophin and is primarily recognized for its key role in the embryonic development of the nervous system and neuronal cell survival/differentiation. Recently, unexpected actions of NGF in bone regeneration have emerged as NGF is able to enhance the osteogenic differentiation of mesenchymal stem cells. However, little is known regarding how NGF signaling regulates osteogenic differentiation through epigenetic mechanisms. In this study, using human dental mesenchymal stem cells (DMSCs), we demonstrated that NGF mediates osteogenic differentiation through p75NTR, a low-affinity NGF receptor. P75NTR-mediated NGF signaling activates the JNK cascade and the expression of KDM4B, an activating histone demethylase, by removing repressive H3K9me3 epigenetic marks. Mechanistically, NGF-activated c-Jun binds to the KDM4B promoter region and directly upregulates KDM4B expression. Subsequently, KDM4B directly and epigenetically activates DLX5, a master osteogenic gene, by demethylating H3K9me3 marks. Furthermore, we revealed that KDM4B and c-Jun from the JNK signaling pathway work in concert to regulate NGF-mediated osteogenic differentiation through simultaneous recruitment to the promoter region of DLX5. We identified KDM4B as a key epigenetic regulator during the NGF-mediated osteogenesis both in vitro and in vivo using the calvarial defect regeneration mouse model. In conclusion, our study thoroughly elucidated the molecular and epigenetic mechanisms during NGF-mediated osteogenesis.

A Preliminary Cadaveric MRI Study of Fetal Hip Development.

PURPOSE: The earlier the detection of the hip joint is discovered, the better the final result. The purpose of this study aimed to investigate the fetal hip development using magnetic resonance imaging (MRI), so as to alert clinicians to possible abnormal development during intrauterine life. METHOD: Measurements of 34 cadaver fetuses (68 hips) were obtained regarding acetabular width and depth, anterior bony acetabular index (ABAI), anterior cartilaginous acetabular index (ACAI), posterior bony acetabular index (PBAI), and posterior cartilaginous acetabular index (PCAI). The standard values of each acetabular measurement index were obtained, and the gestational age-measurement index change trend chart was drawn to comprehensively analyze the normal development law of the fetal hip joint. RESULTS: With the development of fetuses, the width and depth of acetabular increase linearly, and the slope of acetabular width was larger than that of depth. In addition, two change points during the 24th and 34th weeks of gestation were detected with regard to width. ABAI and PBAI also decreased. ABAI demonstrated an approximately linear trend, while PBAI shows a non-linear trend. During the 36th week, the change point in PBAI was observed. ACAI and PCAI exhibited slow increases, indicating a non-linear trend. During the 21st and 36th weeks of gestation, the change points regarding ACAI were observed. During the 22nd week of gestation, the change point for PCAI was observed. CONCLUSION: Plots of the parameters obtained via MRI examinations of cadaver fetuses across gestational age comprehensively illustrated the fetal hip development. This developmental information about the hip joint has the potential to guide clinicians in the early detection of abnormal hip joint development during intrauterine life.

The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells.

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins (BMPs). The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B (KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen's pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

The metabolite profiling of 3,4-dicaffeoylquinic acid in Sprague-Dawley rats using ultra-high performance liquid chromatography equipped with linear ion trap-Orbitrap MS.

3,4-Dicaffeoylquinic acid (3,4-DiCQA) is a dicaffeoylquinic acid that possesses antioxidant, anti-inflammatory, antibacterial, antiviral, anticancer, hypoglycemic, hypotensive, and hepatoprotective activities. This study developed a rapid and reliable method using ultra-high performance liquid chromatography equipped with linear ion trap-Orbitrap MS to identify the metabolites of 3,4-DiCQA in rat plasma, urine, feces, and tissues. The metabolic profile of 3,4-DiCQA was determined after an oral administration of 200 mg/kg to rats. A strategy of full scan-parent ions list acquisition coupled to diagnostic product ion analysis for screening and identification of target metabolites was used. A total of 67 metabolites, combined with accurate mass measurement, diagnostic ions, neutral losses, and reference standards, were observed and characterized for the first time. The results indicated that hydrolysis, methylation, hydrogenation, hydration, dehydroxylation, dehydrogenation, sulfate conjugation, and glucuronide conjugation were the major metabolic reactions of 3,4-DiCQA in vivo.

Effect of thoracic paravertebral block on intraoperative hypotension and postoperative pain in patients undergoing breast cancer surgery under general anesthesia: a retrospective study.

BACKGROUND: To retrospectively compare the effects of general anesthesia (GA) and thoracic paravertebral block (TPVB) combined with general anesthesia on the incidence of hypotension and postoperative pain in breast cancer (BC) surgery. METHODS: We retrospectively collected the medical records of patients who underwent BC surgery under general anesthesia from January 2018 to December 2020, and divided them into 2 groups according to the patient's anesthesia management method: GA group (Group G) and TPVB combined with GA group (Group T). During the operation, the use of boosting drugs and ephedrine, amount of fluid infusion, amount of bleeding, and operation time of the 2 participant groups were recorded, as well as the pain score in the resting state. RESULTS: During anesthesia, the bispectral index (BIS) value of Group G was significantly lower than that of Group T, the use of sufentanil and the use rate of ephedrine were significantly higher than that of Group T, and the difference was statistically significant (P<0.05). At the T4 time point, the blood pressure [systolic blood pressure/diastolic blood pressure (SBP/DBP)] of Group G was higher than that of Group T; at time point T3, the blood pressure (SBP/DBP) of Group G was lower than that of Group T. At the T4 time point, the heart rate of G group was higher than that of Group T, and the heart rate of G group was lower than that of Group T at the time points T2 and T3. The difference between the 2 groups was statistically significant. The change trend of the visual analogue scale (VAS) scores of the 2 participant groups was basically the same when they were resting peacefully, and there were statistical differences in the VAS scores at 1, 2, 4, and 8 h after surgery (P<0.05). CONCLUSIONS: When TPVB is combined with GA, there is a lower incidence of hypotension, more stable circulatory state, and better postoperative analgesic effect.

Effect of intravenous oxycodone on the physiologic responses to extubation following general anesthesia.

BACKGROUND: Endotracheal intubation and extubation may cause undesirable hemodynamic changes. Intravenous oxycodone has recently been introduced and used for relieving hemodynamic alterations in response to intubation, but there is insufficient information regarding its application in stabilizing hemodynamics during extubation in the patients emerging from general anesthesia. METHODS: One hundred patients, who had undergone assorted laparoscopic surgeries under general anesthesia, were randomly assigned to Control group (saline injection, 50 cases) and Study group (intravenous injection of 0.08 mg/kg oxycodone immediately after completion of the surgical procedure, 50 cases). Blood pressure, heart rate, blood oxygen saturation (SpO2) as well as blood concentrations of epinephrine, norepinephrine, and cortisol were recorded or measured immediately before extubation (T0), during extubation (T1), as well as one minute (T2), 5 min (T3), and 10 min after extubation (T4). In addition, coughing and restlessness, time of eye-opening, and duration from completing surgery to extubation as well as Ramsay Sedation Scale were analyzed. RESULTS: Blood pressure and heart rate as well as blood concentrations of epinephrine, norepinephrine, and cortisol were significantly higher in the Control group compared with the Study group at the time of extubation as well as 1, 5, and 10 min after extubation (P < 0.05). When the patients emerged from general anesthesia, 70 % of the Control group had cough, which was significantly higher than that of Study group (40 %, P < 0.05). Significantly higher number of patients manifested restlessness in the Control group before (40 %) and after extubation (20 %) compared with that in the Study group (20 and 2 %, respectively, P < 0.05). In addition, patients of Control group had lower Ramsay score at extubation (1.7 ± 0.7) as well as 30 min after extubation (2.4 ± 0.9) compared to that of the patients of Study group (2.2 ± 0.9, and 3.0 ± 0.8, respectively, P = 0.003 and 0.001). CONCLUSIONS: Intravenous oxycodone attenuated alterations of hemodynamics and blood hormones associated with extubation during emergence from general anesthesia. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000040370 (registration date: 11-28-2020) "'retrospectively registered".

Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging.

Skeletal aging is a complex process, characterized by a decrease in bone formation, an increase in marrow fat, and stem cell exhaustion. Loss of H3K9me3, a heterochromatin mark, has been proposed to be associated with aging. Here, we report that loss of KDM4B in mesenchymal stromal cells (MSCs) exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. KDM4B epigenetically coordinated ß-catenin/Smad1-mediated transcription by removing repressive H3K9me3. Importantly, KDM4B ablation impaired MSC self-renewal and promoted MSC exhaustion by inducing senescence-associated heterochromatin foci formation, providing a mechanistic explanation for stem cell exhaustion with aging. Moreover, while KDM4B was required for parathyroid hormone-mediated bone anabolism, KDM4B depletion accelerated bone loss and marrow adiposity induced by a high-fat diet. Our results suggest that the epigenetic rejuvenation and reversing bone-fat imbalance might be new strategies for preventing and treating skeletal aging and osteoporosis by activating KDM4B in MSCs.

Long noncoding RNA NEAT 1 and its target microRNA-125a in sepsis: Correlation with acute respiratory distress syndrome risk, biochemical indexes, disease severity, and 28-day mortality.

BACKGROUND: Sepsis is one of the main contributors to in-hospital deaths. This study aimed to evaluate the clinical roles of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) and microRNA (miR)-125a in sepsis. METHODS: LncRNA NEAT1 and miR-125a in plasma samples from 102 sepsis patients and 100 healthy controls (HCs) were detected by reverse transcription-quantitative polymerase chain reaction. In sepsis patients, general disease severity was assessed by acute physiology and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score. Meanwhile, acute respiratory distress syndrome (ARDS) occurrence and mortality during 28 days were recorded. RESULTS: LncRNA NEAT1 was increased, but miR-125a was decreased in sepsis patients compared to HCs, and in ARDS sepsis patients compared to non-ARDS sepsis patients. The receiver's operative characteristic (ROC) curves revealed that higher lncRNA NEAT1 or lower miR-125a had certain predictive value for ARDS risk. Further multivariate logistic regression revealed miR-125a but not lncRNA NEAT1 was correlated with ARDS risk independently in sepsis patients. Additionally, lncRNA NEAT1 was positively, but miR-125a was negatively correlated with APACHE II score and SOFA score in sepsis patients. Moreover, higher lncRNA NEAT1 and lower miR-125a were observed in 28-day deaths compared to 28-day survivors and were correlated with increased accumulating mortality in sepsis patients. CONCLUSION: LncRNA NEAT1 high expression and miR-125a low expression correlate with increased ARDS risk, enhanced disease severity, higher 28-day mortality, and negatively associate with each other in sepsis patients.

Thromboelastography in Patients with Inflammatory Bowel Disease.

PURPOSE: Patients with inflammatory bowel disease (IBD) frequently suffer from venous thromboembolic events, and the risk of thromboembolism increases along with disease activity. This study was conducted to discover novel thrombophilic markers using thromboelastography (TEG) and to evaluate the relation between the predisposing factors and the activity of disease in Chinese patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Thirty-four patients with CD, 29 patients with UC, and 53 healthy volunteers were enrolled into this study. Blood levels of R, K, α Angle, G, maximal amplitude (MA), and LY30 with TEG were determined. RESULTS: Mean values of R, K, α Angle, G, and MA were significantly different in patients with CD and UC compared with the healthy individuals. Patients with active CD had different K, α Angle, G, and MA levels compared with patients in remission (P < 0.05, P < 0.001, P < 0.001, and P < 0.001). Levels of R, α Angle, G, and MA were also significantly different in active UC patients compared with those in remission (P < 0.01, P < 0.001, P < 0.001, and P < 0.001). Except for the G level in the CD group, differences in all TEG levels between healthy individuals and IBD patients in remission were not statistically significant. No statistical differences were observed in LY30 among patients with active phase, patients in remission, and the healthy individuals. CONCLUSION: Thrombophilic defects are common in Chinese patients with IBD, and TEG can be considered a new direction to anticoagulant thromboprophylaxis in IBD.

Epigenetic regulation of kidney progenitor cells.

The reciprocal interactions among the different embryonic kidney progenitor populations lay the basis for proper kidney organogenesis. During kidney development, three types of progenitor cells, including nephron progenitor cells, ureteric bud progenitor cells, and interstitial progenitor cells, generate the three major kidney structures-the nephrons, the collecting duct network, and the stroma, respectively. Epigenetic mechanisms are well recognized for playing important roles in organism development, in fine-tuned control of physiological activities, and in responses to environment stimuli. Recently, evidence supporting the importance of epigenetic mechanisms underlying kidney organogenesis has emerged. In this perspective, we summarize the research progress and discuss the potential contribution of novel stem cell, organoid, and next-generation sequencing tools in advancing this field in the future.

Electrical status epilepticus in sleep affects intrinsically connected networks in patients with benign childhood epilepsy with centrotemporal spikes.

BACKGROUND: Although outcomes of benign childhood epilepsy with centrotemporal spikes (BECTS) are frequently excellent, some atypical forms of BECTS, especially electrical status epilepticus in sleep (ESES), are characterized by worse outcomes and negative impacts on cognitive development. METHODS: To explore specific ESES-related brain networks in patients with BECTS, we used resting-state functional magnetic resonance imaging (fMRI) to scan patients with BECTS with ESES (n = 9), patients with BECTS without ESES (n = 17), and healthy controls (n = 36). Unbiased seed-based whole-brain functional connectivity (FC) was adopted to explore the connectivity mode of three resting-state cerebral networks: the default mode network (DMN), salience network (SN), and central executive network (CEN). RESULTS: Compared with the other two groups, patients with BECTS with ESES showed FC in the SN or in the CEN decreased, but not in the DMN. Moreover, we found the FC in the CEN in patients with BECTS without ESES decreased when compared with controls. Our currently intrinsically defined anticorrelated networks strength was disrupted in BECTS and connote greater deactivation than the results from FC for a seed region in children with BECTS. CONCLUSION: These results indicated that children with BECTS with ESES showed brain activity altered in the CEN and the SN. The difference of impairment in the SN and CEN may lead to improve the understanding of the underlying neuropathophysiology, and to assess the activity of patients with BECTS with ESES, which is crucial for measuring disease activity, improving patient care, and assessing the effect of antiepilepsy therapy.

KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization.

Epigenomic changes and stem cell deterioration are two hallmarks of aging. Accumulating evidence suggest that senescence of mesenchymal stromal cells (MSCs) perpetuates aging or age-related diseases. Here we report that two H3K9 demethylases, KDM3A and KDM4C, regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 during MSC senescence. Suppression of KDM3A or KDM4C by either genetic or biochemical approach leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 promotes heterochromatin reorganization and blunts DNA damage response. Moreover, MSCs derived from Kdm3a-/- mice exhibit defective chromosome organization and exacerbated DNA damage response, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database reveals inverse correlation of KDM3A/KDM4C and/or NCAPD2/NCAPG2 with aging. Taken together, the present finding unveils that H3K9 demethylases function as a surveillance mechanism to restrain DNA damage accumulation in stem cells during aging.

Oligodendroglial tumours: subventricular zone involvement and seizure history are associated with CIC mutation status.

BACKGROUND: CIC-mutant oligodendroglial tumours linked to better prognosis. We aim to investigate associations between CIC gene mutation status, MR characteristics and clinical features. METHODS: Imaging and genomic data from the Cancer Genome Atlas and the Cancer Imaging Archive (TCGA/TCIA) for 59 patients with oligodendroglial tumours were used. Differences between CIC mutation and CIC wild-type were tested using Chi-square test and binary logistic regression analysis. RESULTS: In univariate analysis, the clinical variables and MR features, which consisted 3 selected features (subventricular zone[SVZ] involvement, volume and seizure history) were associated with CIC mutation status (all p < 0.05). A multivariate logistic regression analysis identified that seizure history (no vs. yes odd ratio [OR]: 28.960, 95 confidence interval [CI]:2.625-319.49, p = 0.006) and SVZ involvement (SVZ- vs. SVZ+ OR: 77.092, p = 0.003; 95% CI: 4.578-1298.334) were associated with a higher incidence of CIC mutation status. The nomogram showed good discrimination, with a C-index of 0.906 (95% CI: 0.812-1.000) and was well calibrated. SVZ- group has increased (SVZ- vs. SVZ+, hazard ratio [HR]: 4.500, p = 0.04; 95% CI: 1.069-18.945) overall survival. CONCLUSIONS: Absence of seizure history and SVZ involvement (-) was associated with a higher incidence of CIC mutation.