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Background Although the overall effect of particulate matter (PM) on cardiovascular disease (CVD) has been previously documented, the effect of different PM sizes (PM10, PM2.5-10 and PM2.5) has not been well studied. This study estimates the effect of different PM sizes on the incidence of CVD in Taipei, Taiwan. Methods We collected outpatients with CVD from 2006 to 2010 and data on the concentrations of air pollutants such as PM10, PM2.5-10, PM2.5, sulfur dioxide, carbon monoxide, nitrogen dioxide, and ozone. A Distributed Lag Non-linear Model (DLNM) was used to explore the effect of different PM sizes on CVD risk. Results In high air pollution events, PM2.5 was significantly associated with elevated risk (4.9%) [95% confidence interval (CI): 1.010–1.089] for CVD with increasing interquartile range (IQR) in single air pollutant model. PM2.5-10 and PM10 did not show a significant positive association with CVD in this study. After adjusting for other air pollutants such as SO2, CO, NO2, and O3, the estimated effect of PM2.5 only decreased 0.2%. Moreover, patients under 40 years old did not show a significant association between PM2.5 and CVD. Conclusion This study demonstrates that only PM2.5 is significantly positively correlated with the number of daily outpatient visits for CVD during high air pollution events.

PathDIP was introduced to increase proteome coverage of literature-curated human pathway databases. PathDIP 4 now integrates 24 major databases. To further reduce the number of proteins with no curated pathway annotation, pathDIP integrates pathways with physical protein–protein interactions (PPIs) to predict significant physical associations between proteins and curated pathways. For human, it provides pathway annotations for 5366 pathway orphans. Integrated pathway annotation now includes six model organisms and ten domesticated animals. A total of 6401 core and ortholog pathways have been curated from the literature or by annotating orthologs of human proteins in the literature-curated pathways. Extended pathways are the result of combining these pathways with protein-pathway associations that are predicted using organism-specific PPIs. Extended pathways expand proteome coverage from 81 088 to 120 621 proteins, making pathDIP 4 the largest publicly available pathway database for these organisms and providing a necessary platform for comprehensive pathway-enrichment analysis. PathDIP 4 users can customize their search and analysis by selecting organism, identifier and subset of pathways. Enrichment results and detailed annotations for input list can be obtained in different formats and views. To support automated bioinformatics workflows, Java, R and Python APIs are available for batch pathway annotation and enrichment analysis. PathDIP 4 is publicly available at http://ophid.utoronto.ca/pathDIP.

International audience; Oligodendrocytes, the myelinating cells in the vertebrate central nervous system, produce myelin sheaths to enable saltatory propagation of action potentials. The process of oligodendrocyte myelination entails a stepwise progression from precursor specification to differentiation, which is coordinated by a series of transcriptional and chromatin remodeling events. ATP-dependent chromatin remodeling enzymes, which utilize ATP as an energy source to control chromatin dynamics and regulate the accessibility of chromatin to transcriptional regulators, are critical for oligodendrocyte lineage development and regeneration. In this review, we focus on the latest insights into the spatial and temporal specificity of chromatin remodelers during oligodendrocyte development, myelinogenesis, and regeneration. We will also bring together various plausible mechanisms by which lineage specific transcriptional regulators coordinate with chromatin remodeling factors for programming genomic landscapes to specifically modulate these different processes during developmental myelination and remyelination upon injury.

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas, the most common malignant pediatric brain tumor, remain elusive. Here, by utilizing single-cell analysis at different stages of tumorigenesis, we demonstrated a developmental hierarchy of diverse progenitor pools in sonic hedgehog (SHH)-medulloblastomas. Unexpectedly, we identified Olig2-expressing progenitors as transit-amplifying cells at the onset of tumorigenesis. Although Olig2+ cells become quiescent stem-like progenitors in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. High-level OLIG2 expression is associated with poor outcome in human SHH-medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2-ablation impeded tumorigenesis. Transcriptome and chromatin-occupancy profiling revealed that Olig2 modulates the chromatin landscape and activates oncogenic networks including HIPPO-Yap/Taz and Aurora-A/MycN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results raise the unanticipated possibility that glial lineage-associated Olig2-expressing progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting Olig2-driven oncogenic networks as potential therapeutic targets.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-derived sarcomas with strong metastatic proclivity and resistance to radiation and chemotherapy. Molecular events driving SC-to-MPNST transformation are incompletely understood. MPNST are heterogeneous tumors with a distinct microenvironment that contributes to the establishment of a tumor niche. Cancer behaviors including initiation, progression, metastasis and relapse cannot be fully defined by genetic mutations alone, but are critically dependent on intercellular communication between tumor cells and the microenvironment. However, currently, a comprehensive understanding of tumor cell lineage evolution, heterogeneity and cell-cell communication network in MPNST is lacking. A better understanding of cellular heterogeneity and tumor-initiating cells during tumorigenesis at a single-cell level will facilitate identifying molecular and cellular determinants underlying malignant transformation in MPNST. We have established a murine model of aggressive peripheral nerve malignancy with HIPPO-TAZ/YAP activation (Lats1/2-def mice), which provides a unique opportunity for dissecting mechanisms of SC malignant transformation. To identify potential PNST-driven progenitor populations, we compare single-cell transcriptome profiles of Lats1/2-def sciatic nerve tumors during pre-neoplastic and advanced stages. Our data reveal that early sciatic nerve tumors contain primarily mature SCs, whereas full-blown tumors harbor neoplastic SCs composed of different subsets: fast-proliferating, mesenchymal-like and neural crest stem cell-like cells, indicative of a developmental trajectory from differentiated SCs to tumor-like SCs with distinct molecular and transcriptional signatures. Interestingly, transformed SCs exhibit inflammation gene signature, which may suggest cell-autonomous inflammation-driven reprogramming that drives tumorigenesis. To characterize cellular heterogeneity in MPNST-like tumors, we further identify cell-cell communication networks between SC-derived tumor cells and cancer-associated stromal cells within the tumor microenvironment. In summary, our studies using single-cell transcriptomics in clinically relevant mouse models of PNST reveal tumor cellular heterogeneity and the microenvironment niche for driving SC tumorigenesis. It will provide principles for identifying potential targets or treatment strategies to cure MPNST.

Glioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. Transcriptional subtypes of glioma are a major source of heterogeneity of expression in gliomas. Gliomas are highly heterogeneous diseases and can be classified into different subtypes including proneural, classical and mesenchymal tumors. We hypothesized that different subtypes of glioma will have different microenvironmental composition and exhibit distinct responses to therapies. To understand whether gliomas induced by different oncogenic drivers affect microenvironment composition, we induced mouse gliomas using a PDGFB and dnp53 driver to model proneural glioma and HRasV12 and dnp53 to model mesenchymal glioma, respectively. We performed single cell transcriptomic profiling to characterize the tumor microenvironment in these glioma models. We found that in the PDGFB/dnp53 glioma model had a large microglia contribution with about 30% tumor-associated microglia. In contrast, the HRasV12/dnp53 glioma model had only sparse microenvironmental cells. In addition, microglia in each model displayed subtype-specific gene expression programs, with microglia in the HRasV12/dnp53 tumor model expressing increased antigen presenting genes while increased levels of osteopontin in the PDGFB/dnp53 tumor model. To determine the tumor-microenvironment interactions, we performed receptor-ligand analysis using CellPhoneDb to identify secretory ligands that support tumor cell growth in microenvironmental cells. We found that tumor-associated pericytes are an important source of growth factor ligands in both PDGFB/dnp53 and HRasV12/dnp53 glioma models. We are investigating the contribution of microglia and pericytes to tumor growth and survival through cell depletion and pharmacological inhibition and determining whether the differences in tumor microglia between the models affects sensitivity to therapies including immunotherapy. Understanding how tumor-intrinsic signaling modulates microenvironment niches and tumor-microenvironment communications aids rational design of combinations targeting the malignant brain tumors.

Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice., Myelin formation is regulated by epigenetic mechanisms and ensures proper neuronal function during development and after demyelination. Here, the authors show that TET1, a DNA hydroxymethylase, regulates myelination during development and remyelination in mice.

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2+ progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2+ progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.

Oligodendrocyte precursor cells (OPCs), also known as NG2 glia, arise from neural progenitor cells in the embryonic ganglionic eminences that also generate inhibitory neurons. They are ubiquitously distributed in the central nervous system, remain proliferative through life, and generate oligodendrocytes in both gray and white matter. OPCs exhibit some lineage plasticity, and attempts have been made to reprogram them into neurons, with varying degrees of success. However, little is known about how epigenetic mechanisms affect the ability of OPCs to undergo fate switch and whether OPCs have a unique chromatin environment around neuronal genes that might contribute to their lineage plasticity. Our bioinformatic analysis of histone posttranslational modifications at interneuron genes in OPCs revealed that OPCs had significantly fewer bivalent and repressive histone marks at interneuron genes compared to astrocytes or fibroblasts. Conversely, OPCs had a greater degree of deposition of active histone modifications at bivalently marked interneuron genes than other cell types, and this was correlated with higher expression levels of these genes in OPCs. Furthermore, a significantly higher proportion of interneuron genes in OPCs than in other cell types lacked the histone posttranslational modifications examined. These genes had a moderately high level of expression, suggesting that the "no mark" interneuron genes could be in a transcriptionally "poised" or "transitional" state. Thus, our findings suggest that OPCs have a unique histone code at their interneuron genes that may obviate the need for erasure of repressive marks during their fate switch to inhibitory neurons.

Collis gastroplasty (CG) remains an important procedure to lengthen the esophagus when indicated in patients undergoing fundoplication for longstanding refractory gastroesophageal reflux disease (GERD) or large hiatal hernias. Concerns over potential sequelae of CG such as dysphagia and worsening heartburn as well as questions regarding the durability of the procedure remain a subject of debate. In this study, 3 and 4-year postoperative data is presented assessing patient quality of life (QOL) measures for those undergoing laparoscopic antireflux surgery (LARS) with and without CG. Comparative review of a prospectively maintained GERD patient database was conducted between patients undergoing LARS with CG versus non-CG (NC) at two institutions between October 2004 and February 2019. Patient demographic, perioperative, and QOL data was analyzed at 3 and 4 years postoperatively using four validated instruments: the Reflux Symptom Index (RSI), Laryngopharyngeal Reflux QOL (LPR-QOL), Swallowing QOL (SWAL), and Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQOL) surveys. A total of 214 CG and 798 NC patients were included in this study. The CG group was older (66.1 ± 12.9 vs. 59.0 ± 14.1, p < 0.001), had a higher frequency of ASA class 3 patients (39.7% vs. 29.7%), and had greater proportion of comorbid disease compared to NG. The groups were parallel in BMI (Collis 28.4 ± 5.2 kg/m2 vs. non-Collis 28.6 ± 5.3 kg/m2, p = 0.673). Subset analysis revealed persistent benefits through 4 years reflected by survey results in both groups. There were no statistically significant differences in QOL outcomes between CG and NC. A majority of patients in both groups reported discontinuation of antireflux medications and satisfaction with surgical outcomes and symptom control. Long-term QOL outcomes after laparoscopic CG are comparable to patients treated with fundoplication alone in cases of long-standing GERD and hiatal hernias. Furthermore, CG patients enjoyed equivalent durability of the procedure without risk of subsequent dysphagia. Collis gastroplasty remains an important tool in the armamentarium of foregut surgeons.

The repair and functional recovery of the nervous system is a highly regulated process that requires the coordination of many different components including the proper myelination of regenerated axons. Dysmyelination and remyelination failures after injury result in defective nerve conduction, impairing normal nervous system functions. There are many convergent regulatory networks and signaling mechanisms between development and regeneration. For instance, the regulatory mechanisms required for oligodendrocyte lineage progression could potentially play fundamental roles in myelin repair. In recent years, epigenetic chromatin modifications have been implicated in CNS myelination and functional nerve restoration. The pro-regenerative transcriptional program is likely silenced or repressed in adult neural cells including neurons and myelinating cells in the central and peripheral nervous systems limiting the capacity for repair after injury. In this review, we will discuss the roles of epigenetic mechanisms, including histone modifications, chromatin remodeling, and DNA methylation, in the maintenance and establishment of the myelination program during normal oligodendrocyte development and regeneration. We also discuss how these epigenetic processes impact myelination and axonal regeneration, and facilitate the improvement of current preclinical therapeutics for functional nerve regeneration in neurodegenerative disorders or after injury.

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.

Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Signaling Pathways > Cell Fate Signaling.

RUNX 1 and RUNX3 drive Nf1 neurofibromagenesis by mediating the promoter usage and inducing levels of protein expression of PMP22., Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.

This chapter describes the repair of diastasis recti using the extended-view totally extraperitoneal hernia repair technique. The chapter focuses on patient positioning, access into the extraperitoneal space, port placement in relation to the defect and the principle of crossover.

This chapter describes the repair of parastomal hernia using the combination of a transversus abdominis release with principles of a Sugarbaker repair using a robotic platform that has been modified. This modification limits mesh exposure to intraabdominal viscera and provides a wide retromuscular space for implantation of the mesh. The typical Sugarbaker repair is also presented.

This paper aims to compare Bitcoin with gold in the diversification of Chinese portfolios using daily data over the 2010–2020 period. We propose a new development of copula-based joint distribution function of returns to simulate the Value-at-Risk and expected shortfall of portfolios including Bitcoin (or gold) and those without it. The stochastic dominance method is also used to compare the return distributions of the three types of portfolios. Empirical results show that gold is a better portfolio diversifier than Bitcoin as it helps better reduce the risk of portfolios. On the other hand, Bitcoin better increases the return but also increases the risk. The stochastic dominance results further show that portfolios diversified by gold dominate those diversified by Bitcoin. Based on these findings, we conclude that in China, gold is a better portfolio diversifier than Bitcoin for risk-averse investors. However, for risk-seeking investors, Bitcoin can be a better choice. This result is found to be robust to the time, frequency and currency effects.

Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found thatOlig2and its downstream targetGpr17are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted theGpr17locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic geneXaf1. The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevatedEpac1expression and promoted oligodendrocyte differentiation. The loss ofGpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate thatGpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination.SIGNIFICANCE STATEMENTGenome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation ofXaf1and cell differentiation by reducingEpac1expression. The loss ofGpr17in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.

Cloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care.Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.Cloud-based BP system does not require any technical skills and is therefore suitable for every age group. BackgroundLess than 50% of patients with hypertensive disease manage to maintain their blood pressure (BP) within normal levels. ObjectiveThe aim of this study is to evaluate whether cloud BP system integrated with computerized physician order entry (CPOE) can improve BP management as compared with traditional care. MethodsA randomized controlled trial done on a random sample of 382 adults recruited from 786 patients who had been diagnosed with hypertension and receiving treatment for hypertension in two district hospitals in the north of Taiwan. Physicians had access to cloud BP data from CPOE. Neither patients nor physicians were blinded to group assignment. The study was conducted over a period of seven months. ResultsAt baseline, the enrollees were 50% male with a mean (SD) age of 58.18 (10.83) years. The mean sitting BP of both arms was no different. The proportion of patients with BP control at two, four and six months was significantly greater in the intervention group than in the control group. The average capture rates of blood pressure in the intervention group were also significantly higher than the control group in all three check-points. ConclusionsCloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care. This system does not require any technical skills and is therefore suitable for every age group. The praise and assurance to the patients from the physicians after reviewing the Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.

Demyelinating diseases such as multiple sclerosis (MS) are among the most disabling and cost-intensive neurological disorders. The loss of myelin in the central nervous system, produced by oligodendrocytes (OLs), impairs saltatory nerve conduction, leading to motor and cognitive deficits. Immunosuppression therapy has a limited efficacy in MS patients, arguing for a paradigm shift to strategies that target OL lineage cells to achieve myelin repair. The inhibitory microenvironment in MS lesions abrogates the expansion and differentiation of resident OL precursor cells (OPCs) into mature myelin-forming OLs. Recent studies indicate that OPCs display a highly plastic ability to differentiate into alternative cell lineages under certain circumstances. Thus, understanding the mechanisms that maintain and control OPC fate and differentiation into mature OLs in a hostile, non-permissive lesion environment may open new opportunities for regenerative therapies. In this review, we will focus on 1) the plasticity of OPCs in terms of their developmental origins, distribution, and differentiation potentials in the normal and injured brain; 2) recent discoveries of extrinsic and intrinsic factors and small molecule compounds that control OPC specification and differentiation; and 3) therapeutic potential for motivation of neural progenitor cells and reprogramming of differentiated cells into OPCs and their likely impacts on remyelination. OL-based therapies through activating regenerative potentials of OPCs or cell replacement offer exciting opportunities for innovative strategies to promote remyelination and neuroprotection in devastating demyelinating diseases like MS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only).

International audience; Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown Chd7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome.

Most commonly interacting Chinese herbs were Ephedrae Herba and Angelicae Sinensis Radix/Angelicae Dahuricae Radix.Unique cultural factors that have resulted in widespread acceptance of both western and traditional Chinese medicine.Taiwan stands well positioned to report on the prevalence of interactions between western drugs and traditional Chinese medicine. BackgroundDrug-drug interactions have long been an active research area in clinical medicine. In Taiwan, however, the widespread use of traditional Chinese medicines (TCM) presents additional complexity to the topic. Therefore, it is important to see the interaction between traditional Chinese and western medicine. Objective(1) To create a comprehensive database of multi-herb/western drug interactions indexed according to the ways in which physicians actually practice and (2) to measure this database's impact on the detection of adverse effects between traditional Chinese medicine compounds and western medicines. MethodsFirst, a multi-herb/western medicine drug interactions database was created by separating each TCM compound into its constituent herbs. Each individual herb was then checked against an existing single-herb/western drug interactions database. The data source comes from the National Health Insurance research database, which spans the years 1998-2011. This study estimated the interaction prevalence rate and further separated the rates according to patient characteristics, distribution by county, and hospital accreditation levels. Finally, this new database was integrated into a computer order entry module of the electronic medical records system of a regional teaching hospital. The effects it had were measured for two months. ResultsThe most commonly interacting Chinese herbs were Ephedrae Herba and Angelicae Sinensis Radix/Angelicae Dahuricae Radix. Ephedrae Herba contains active ingredients similar to in ephedrine. 15 kinds of traditional Chinese medicine compounds contain Ephedrae Herba. Angelicae Sinensis Radix and Angelicae Dahuricae Radix contain ingredients similar to coumarin, a blood thinner. 9 kinds of traditional Chinese medicine compounds contained Angelicae Sinensis Radix/Angelicae Dahuricae Radix. In the period from 1998 to 2011, the prevalence of herb-drug interactions related to Ephedrae Herba was 0.18%. The most commonly prescribed traditional Chinese compounds were MA SHING GAN SHYR TANG (23.1%), followed by SHEAU CHING LONG TANG (15.5%) and DINQ CHUAN TANG (13.2%). The prevalence of herb-drug interactions related to Angelicae Sinensis Radix, Angelicae Dahuricae Radix was 4.59%. The most common traditional Chinese compound formula were TSANG EEL SAAN (32%), followed by HUOH SHIANG JENQ CHIH SAAN (31.4%) and SHY WUH TANG (10.7%).Once the multi-herb drug interaction database was deployed in a hospital system, there were 480 prescriptions that indicated a TCM-western drug interaction. Physicians were alerted 24 times during two months. These alerts resulted in a prescription change four times (16.7%). ConclusionDue to the unique cultural factors that have resulted in widespread acceptance of both western and traditional Chinese medicine, Taiwan stands well positioned to report on the prevalence of interactions between western drugs and traditional Chinese medicine and devise ways to reduce their incidence. This study built a multi-herb/western drug interactions database, embedded inside a hospital clinical information system, and then examined the effects that drug interaction alerts had on clinician prescribing behaviour. The results demonstrated that western drug/traditional Chinese medicine interactions are prevalent and that western-trained physicians tend to change their prescribing behaviour more than traditional Chinese medicine physicians in their response to medication interaction alerts.

Morbidity and recurrence rates are higher in obese patients undergoing open abdominal wall reconstruction (AWR). Historically, body mass index (BMI) ≥ 40 has served as a relative contraindication to open AWR. The purpose of this study is to evaluate the impact of minimally invasive surgery (MIS) on outcomes after AWR for higher versus lower BMI patients. A retrospective review of a prospectively maintained database was conducted of all patients who underwent MIS AWR between September 2015 and April 2019 at our institution. Patients were subdivided into two groups based on their BMI: BMI ≤ 35 kg/m2 and BMI > 35 kg/m2. Patient demographics and perioperative data were evaluated using univariate and multivariate analysis. 461 patients were identified and divided into two groups: BMI ≤ 35 (n = 310) and BMI > 35 (n = 151). The two groups were similar in age (BMI ≤ 35: 56.3 ± 14.1 years vs. BMI > 35: 54.4 ± 11.9, p = .154). BMI > 35 group had more patients with ASA score of 3 (81% vs. 32%, p 35 group underwent a robotic approach at higher rates (74% vs. 45%, p 35: 11.1 ± 4.6 cm, p = .069). Both groups benefited similarly from a short length of stay, similar hospital charges, and lower postoperative complications. Initial findings of our data support the benefits of elective MIS approach to AWR for patients with higher BMI. These patients derive similar benefits, such as faster recovery with low recurrence rates, when compared to lower BMI patients, while avoiding preoperative hernia incarceration, postoperative wound complications, and hernia recurrences. Future follow-up is required to establish long-term perioperative and quality of life outcomes in this patient cohort.

This study examines the effects of a prominent principles-based standard (SFAS-142, Goodwill and Other Intangible Assets) on financial statement comparability. Using non-goodwill-intensive firms as our control group, we implement a difference-in-differences research design to examine how SFAS-142 affects comparability among goodwill-intensive firms (i.e. a treatment group), and comparability between goodwill-intensive firms and non-goodwill-intensive firms (i.e. another treatment group). We find that SFAS-142 decreases comparability among goodwill-intensive firms, as well as comparability between goodwill-intensive and non-goodwill-intensive firms. We also find that these reductions in comparability are less severe when the verifiability of net assets is higher. Overall, the results suggest that principles-based standards may reduce comparability, particularly when the accounting items entail high uncertainty and verifiability is low.

Oligodendrocytes are the critical cell types giving rise to the myelin nerve sheath enabling efficient nerve transmission in the central nervous system (CNS). Oligodendrocyte precursor cells differentiate into mature oligodendrocytes and are maintained throughout life. Deficits in the generation, proliferation, or differentiation of these cells or their maintenance have been linked to neurological disorders ranging from developmental disorders to neurodegenerative diseases and limit repair after CNS injury. Understanding the regulation of these processes is critical for achieving proper myelination during development, preventing disease, or recovering from injury. Many of the key factors underlying these processes are epigenetic regulators that enable the fine tuning or reprogramming of gene expression during development and regeneration in response to changes in the local microenvironment. These include chromatin remodelers, histone-modifying enzymes, covalent modifiers of DNA methylation, and RNA modification–mediated mechanisms. In this review, we will discuss the key components in each of these classes which are responsible for generating and maintaining oligodendrocyte myelination as well as potential targeted approaches to stimulate the regenerative program in developmental disorders and neurodegenerative diseases.

The return and risk of dollar-cost averaging (DCA) and self-annuitization (SA) investing are compared with the underlying return in this paper. The underlying return, which is assumed to be normally distributed, is generated by Monte Carlo simulations under six market scenarios including upward and mean reverting markets across several investment horizons. Owing to the multiple cash flows of DCA and SA, the annual internal rate of return is used to measure the DCA and SA returns. The results show that the mean return of DCA is slightly higher than the underlying return, while the SA is lower, particularly under short investment horizons. Both DCA and SA produce higher return volatility and riskiness than the underlying return. They also create negative skewness and excess kurtosis for the return distributions. For comparing their performances, we use the economic performance measure which can consider those high moments of distribution. Except for the mean reverting market, the underlying return is the best performer, while SA is the worst. This evidence becomes even clearer and convincing as the investment horizon increases. DCA can have lower riskiness and perform better only under the mean reverting market.

Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury re-myelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.

Analysis of microRNA (miR) expression in the central nervous system white matter of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) revealed a significant reduction of miR-219, a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic before disease onset ameliorates clinical disease, reduces neurogliosis, and partially recovers motor and sensorimotor function by negatively regulating proinflammatory cytokines and virus RNA replication. Moreover, RNA sequencing of host lesions showed that miR-219 significantly downregulated two genes essential for the biosynthetic cholesterol pathway, Cyp51 (lanosterol 14-α-demethylase) and Srebf1 (sterol regulatory element-binding protein-1), and reduced cholesterol biosynthesis in infected mice and rat CG-4 glial precursor cells in culture. The change in cholesterol biosynthesis had both anti-inflammatory and anti-viral effects. Because RNA viruses hijack endoplasmic reticulum double-layered membranes to provide a platform for RNA virus replication and are dependent on endogenous pools of cholesterol, miR-219 interference with cholesterol biosynthesis interfered virus RNA replication. These findings demonstrate that miR-219 inhibits TMEV-induced demyelinating disease through its anti-inflammatory and anti-viral properties. MicroRNAs (miRs) are small noncoding RNAs that regulate a myriad of biological processes by controlling gene expression. In the latest issue of Molecular Therapy, Moyano et al. show that intranasal delivery of miR-219 in a mouse model of viral demyelination reduces neurological burden and improves life quality through anti-inflammatory and anti-viral mechanisms. Fil: Moyano, Ana Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina. University of Illinois; Estados Unidos Fil: Steplowski, Jeffrey. University of Illinois; Estados Unidos Fil: Wang, Haibo. Cincinnati Children's Hospital Medical Center; Estados Unidos Fil: Son, Kyung No. University of Illinois; Estados Unidos Fil: Rapolti, Diana I.. University of Illinois; Estados Unidos Fil: Marshall, Jeffrey. University of Illinois; Estados Unidos Fil: Elackattu, Vince. University of Illinois; Estados Unidos Fil: Marshall, Michael S.. University of Illinois; Estados Unidos Fil: Hebert, Amy K.. University of Illinois; Estados Unidos Fil: Reiter, Cory R.. University of Illinois; Estados Unidos Fil: Ulloa, Viviana. University of Illinois; Estados Unidos Fil: Pituch, Katarzyna C.. University of Illinois; Estados Unidos Fil: Givogri, Maria I.. University of Illinois; Estados Unidos Fil: Lu, Q. Richard. Cincinnati Children's Hospital Medical Center; Estados Unidos Fil: Lipton, Howard L.. University of Illinois; Estados Unidos Fil: Bongarzone, Ernesto R.. University of Illinois; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina

NG2 cells are a resident glial progenitor cell population that is uniformly distributed throughout the developing and mature mammalian CNS. Those in the postnatal CNS generate exclusively myelinating and non-myelinating oligodendrocytes and are thus equated with oligodendrocyte precursor cells. Prenatally, NG2 cells in the ventral gray matter of the forebrain generate protoplasmic astrocytes as well as oligodendrocytes. The fate conversion from NG2 cells into protoplasmic astrocytes is dependent on downregulation of the key oligodendrocyte transcription factor Olig2. We showed previously that constitutive deletion of Olig2 in NG2 cells converts NG2 cells in the neocortex into protoplasmic astrocytes at the expense of oligodendrocytes. In this study, we show that postnatal deletion of Olig2 caused NG2 cells in the neocortex but not in other gray matter regions to become protoplasmic astrocytes. However, NG2 cells in the neocortex became more resistant to astrocyte fate switch over the first 3 postnatal weeks. Fewer NG2 cells differentiated into astrocytes and did so with longer latency after Olig2 deletion at postnatal day 18 (P18) compared with deletion at P2. The high-mobility group transcription factor Sox10 was not downregulated for at least 1 month after Olig2 deletion at P18 despite an early transient upregulation of the astrocyte transcription factor NFIA. Furthermore, inhibiting cell proliferation in slice culture reduced astrocyte differentiation from Olig2-deleted perinatal NG2 cells, suggesting that cell division might facilitate nuclear reorganization needed for astrocyte transformation.SIGNIFICANCE STATEMENTNG2 cells are glial progenitor cells that retain a certain degree of lineage plasticity. In the normal postnatal neocortex, they generate mostly oligodendrocyte lineage cells. When the oligodendrocyte transcription factor Olig2 is deleted in NG2 cells in the neocortex, they switch their fate to protoplasmic astrocytes. However, the efficiency of the fate switch decreases with age over the first 3 postnatal weeks and is reduced when cell proliferation is inhibited. As the neocortex matures, sustained expression of the oligodendrocyte lineage-specific key transcription factor Sox10 becomes less dependent on Olig2. Together, our findings suggest a gradual stabilization of the oligodendrocyte lineage genes and loss of lineage plasticity during the first 3 weeks after birth, possibly due to nuclear reorganization.

Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat–Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lackingZeb2in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developingZeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast,Zeb2ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused byZeb2mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat–Wilson syndrome.SIGNIFICANCE STATEMENTBergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lackingZeb2in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established inZeb2mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat–Wilson syndrome.

Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide-treated IL10−/− BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS.

Myelination by oligodendrocytes in the central nervous system permits high-fidelity saltatory conduction from neuronal cell bodies to axon terminals. Dysmyelinating and demyelinating disorders impair normal nervous system functions. Consequently, an understanding of oligodendrocyte differentiation that moves beyond the genetic code into the field of epigenetics is essential. Chromatin reprogramming is critical for steering stage-specific differentiation processes during oligodendrocyte development. Fine temporal control of chromatin remodeling through ATP-dependent chromatin remodelers and sequential histone modifiers shapes a chromatin regulatory landscape conducive to oligodendrocyte fate specification, lineage differentiation, and maintenance of cell identity. In this Review, we will focus on the biological functions of ATP-dependent chromatin remodelers and histone deacetylases in myelinating oligodendrocyte development and implications for myelin regeneration in neurodegenerative diseases.

Significance Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective (re)myelination. Mutations in chromatin remodelers CHD7 and CHD8 are the cause of CHARGE syndrome and some autism spectrum disorders (ASD). Here we show that Chd7 protects OPCs from apoptosis by chromatin closing and gene repression of p53, while Chd7 induces chromatin opening and gene activation of OPC-differentiation regulators. Chd7 is, however, dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles, including ASD-risk–associated genes. Our results thus involve oligodendroglia in ASD and CHARGE and offer new avenues to understand and modulate CHD7/CHD8 functions in normal and pathological brain development., Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk–associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53. Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17. However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

In this paper, we will investigate whether there is any Sharpe ratio rule or Omega ratio rule that can be used to show that one asset outperforms another asset if it has a higher Sharpe ratio and/or Omega ratio. We find that Sharpe ratio rule could not detect preference of both risk averters and risk seekers in some strong dominance cases. We set up the Omega ratio rule and find that the Omega ratio rule is better than the mean-variance rule because the former could the former can detect the first order stochastic dominated asset but the latter cannot. We also show the superiority of the Omega ratio rule over any Sharpe ratio rule by using hedging funds data and discuss the advantage of using the Omega ratio rule to stochastic dominance rule.

The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.

We present three cases of genetically confirmed Gorlin syndrome with desmoplastic medulloblastoma (DMB) in whom tumor recurred despite standard therapy. One patient was found to have a novel germline missense PTCH1 mutation. Molecular analysis of recurrent tumor using fluorescent in situ hybridization (FISH) revealed PTEN and/ or PTCH1 loss in 2 patients. Whole exome sequencing (WES) of tumor in one patient revealed loss of heterozygosity of PTCH1 and a mutation of GNAS gene in its non-coding 3' -untranslated region (UTR) with corresponding decreased protein expression. While one patient died despite high-dose chemotherapy (HDC) plus stem cell rescue (ASCR) and palliative radiotherapy, two patients are currently alive for 18+ and 120+ months respectively following retrieval therapy that did not include irradiation. Infants with DMB and GS should be treated aggressively with chemotherapy at diagnosis to prevent relapse but radiotherapy should be avoided. The use of molecular prognostic markers for DMB should be routinely used to identify the subset of tumors that might have an aggressive course.

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.

Mural endocarditis is a rare clinical entity with an extremely high mortality rate. It is usually predisposed by an underlying structural intracardiac abnormality. We present two cases of mural endocarditis occurring in the right atrium which were complicated by septic pulmonary embolism, one of which was predisposed by a jet lesion secondary to a coronary artery fistula. Both cases were successfully managed conservatively with excellent long-term outcomes.

Medulloblastoma represents the most common childhood malignant brain tumor. Despite aggressive multimodal therapy, a significant proportion of surviving patients suffer from severe treatment-related side effects, including tumor relapse. Thus, there is an urgent need for novel therapeutic modalities that can improve medulloblastoma patient survival while minimizing tumor recurrence. Our recent study identified GNAS as a novel tumor suppressor gene in Sonic hedgehog-driven medulloblastomas (He et al., Nature Medicine 2014). We show that low expression or mutation of GNAS was tightly correlated with poor prognosis of Sonic hedgehog-group tumors and their resistance to the treatment of Sonic hedgehog signaling inhibitors alone. Ablation of the single GNAS gene in anatomically-distinct progenitors in the ventricular zone of the cerebellum and dorsal brainstem is sufficient to induce the formation of medulloblastomas, which recapitulate their human counterparts. Gsα activation suppresses Sonic hedgehog signaling by regulating both the cAMP-dependent PKA pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor growth in GNAS mutants. Strikingly, we find that in the drug-resistant tumor lesion and recurrent tumors after radiation therapy, there is an increase of Olig2 expression and Olig2+ progenitor cells. High levels of Olig2 are correlated with poor prognosis of medulloblastomas in human patients. We show that elimination of the mitotic Olig2-expressing cells blocks tumor progression in Olig2-thymidine kinase (TK) transgenic mice. In addition, cell type-specific deletion of Olig2 halts tumor progression. Moreover, we find that Olig2 activates gene regulatory networks inferred for tumor cell stemness and regulates chromatin accessibility of oncogenic factors by altering epigenome landscapes. Furthermore, our single cell analyses reveal that Olig2-expressing progenitors are the distinct tumor-initiating cells during the onset of primary and recurrent medulloblastoma, highlighting potential therapeutic avenues for treating recurrent medulloblastomas by targeting Olig2-expressing progenitors.

Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT(2) receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients.