Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find that this feature extends to broadly transcribed genes, including Myc and Pim1 cell-cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting, we show that these enhancers recruit lineage-determining factors. Furthermore, we demonstrate that the turning on and off of enhancers during development correlates with promoter activity. We propose that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner.

The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins.

Spt6 coordinates nucleosome dis- and re-assembly, transcriptional elongation, and mRNA processing. Here, we report that depleting Spt6 in embryonic stem cells (ESCs) reduced expression of pluripotency factors, increased expression of cell-lineage-affiliated developmental regulators, and induced cell morphological and biochemical changes indicative of ESC differentiation. Selective downregulation of pluripotency factors upon Spt6 depletion may be mechanistically explained by its enrichment at ESC super-enhancers, where Spt6 controls histone H3K27 acetylation and methylation and super-enhancer RNA transcription. In ESCs, Spt6 interacted with the PRC2 core subunit Suz12 and prevented H3K27me3 accumulation at ESC super-enhancers and associated promoters. Biochemical as well as functional experiments revealed that Spt6 could compete for binding of the PRC2 methyltransferase Ezh2 to Suz12 and reduce PRC2 chromatin engagement. Thus, in addition to serving as a histone chaperone and transcription elongation factor, Spt6 counteracts repression by opposing H3K27me3 deposition at critical genomic regulatory regions.

Increasing Access to Cardiac Rehabilitation Services Among Disadvantaged Populations.

The Prince George's County Health Department encountered several challenges to increasing access to cardiac rehabilitation (CR) services among disadvantaged populations. They include excessive patient out-of-pocket costs; requirements that CR orders must be signed by a physician; provider reluctance to refer patients to CR, with most primary care providers preferring to refer clients to cardiologists for the latter to determine whether the patient needs CR referral; limited availability of CR programs; and difficulty identifying patients eligible for CR services. Discussions with other local health departments and public health practitioners indicate that these challenges are not unique to Maryland but are indicative of policy and system barriers that prevent the optimal delivery of cardiovascular health services. This practice report documents the challenges and the Prince George's County Health Department's efforts to resolve them and provides recommendations for decision-makers seeking to make CR programs more accessible to disadvantaged populations.

Evaluating the Impact of the Prime Time Sister Circles® Intervention on Reducing Depressive Symptoms Among African American Women with Uncontrolled Hypertension.

BACKGROUND: The Prime Time Sister Circles®, a randomized controlled trial (PTSC-RCT), assessed the impact of a community-based peer support program on hypertension management among African American women 40-75 years of age. While the PTSC-RCT was designed to evaluate changes in blood pressure control, subsequent sub-analyses revealed a high proportion of self-reported depressive symptoms in our sample. Accordingly, we conducted an ancillary investigation of the PTSC intervention on depression to ascertain its impact on reduced depressive symptoms in the study population. METHOD: Depressive symptoms were measured using an adapted version of the Center for Epidemiologic Studies Depression Scale Revised (CES-D-10). We used unadjusted and adjusted fixed effect models. Data for this study came from the PTSC-RCT. We collected data between 2017 and 2018 in Washington, DC. We used a balanced analytical sample of 172 African American, English-speaking women between 40 to 75 years old with uncontrolled hypertension. INTERVENTION: The intervention group participated in a 2-h, peer-based support group once a week for 13 weeks. A trained PTSC facilitator facilitated sessions with experts who delivered content on various topics, including psychosocial wellness (e.g., stress, depressive symptoms, anxiety management, and self-esteem), physical health (e.g., hypertension, inflammation, and heart disease), physical activity, and healthy nutrition. RESULTS: Results from the fixed-effects models indicated that participants in the PTSC program exhibited a greater reduction in CES-D-10 score at three months (Coeff: -1.99, 95% CI: -3.49, -0.49) and at 15 months (Coeff: -2.38, 95% CI: -3.94, -0.83), as compared to those in the control group. CONCLUSIONS: Evidence suggests that the Prime Time Sister Circles® intervention reduced depressive symptoms among African American women with low socioeconomic status and hypertension. TRIAL REGISTRATION: NCT04371614.

Financial burden of prostate cancer in the Iranian population: a cost of illness and financial risk protection analysis.

BACKGROUND: Prostate cancer is the second most common cancer in males worldwide and the third most common among Iran's male population. However, there is a lack of evidence regarding its direct and indirect costs in low and middle-income countries. This study intends to bridge the gap using a cost of illness approach, assessing the costs of prostate cancer from the perspectives of patients, society, and the insurance system. METHODS: Two hundred ninety seven patients were included in the study. Data for a 2-month period were obtained from patients registered at two hospitals (Tabriz, Tehran) in Iran in 2017. We applied a prevalence-based, bottom-up approach to assess the costs of the illness. We used the World Health Organization methods to measure the prevalence and investigate the determinants of catastrophic and impoverishing health expenditures. RESULTS: We determined the total costs of the disease for the patients to be IRR 68 million (PPP $ 5,244.44). Total costs of the disease from the perspective of the society amounted to IRR 700,000 million (PPP $ 54 million). Insurance companies expended IRR 20 million (PPP $ 1,558.80) per patient. Our findings show that 31% of the patients incurred catastrophic health expenditure due to the disease. Five point forty-four percent (5.44%) of the patients were impoverished due to the costs of this cancer. CONCLUSION: We found an alarmingly high prevalence of catastrophic health expenditures among prostate cancer patients. In addition, prostate cancer puts a substantial burden on both the patients and society.

Influence of Not-for-Profit Hospital Ownership Type on Community Benefit and Charity Care.

Non-profit hospitals are expected to provide charity care and other community benefits to adjust their tax exemption status. Using the Medicare Hospital Cost Report, American Hospital Association Annual Survey, and the American Community Survey datasets, we examined if church-affiliated hospitals spent more on charity care and community benefit. For this analysis, we defined five main categories of community benefits were measured: total community benefit; charity care; Medicaid shortfall; unreimbursed other means-tested services; and the total of unreimbursed education and unfunded research. Multiple regression was used to examine the effect of church ownership, controlling for other factors, on the level of community benefit in 2644 general acute care non-profit hospitals. Descriptive analyses and multiple regression were used to show the relationship between the provision of community benefits and church affiliation including Catholic (CH), other church-affiliated hospitals (OCAH), and non-church affiliated hospitals (NCAH). The non-profit hospital on average spent 6.5% of its total expenses on community benefits. NCAH spent 6.09%, CH spent 7.5%, and OCAH spent 9.4%. Non-profits spent 2.8% of their total expenses on charity care, with the highest charity care spending for OCAH (5.2%), followed by CH (3.9%), and NCAH (2.4%). Regression results showed that CH and OCAH, on average, spent 1.08% and 2.16% more on community benefits than NCAHs. In addition, CH and OCAH spent more on other categories of community benefits except for education and research. Church-affiliated hospitals spend more on community benefits and charity care than non-church affiliated nonprofit hospitals.

When States Mandate Hospital Community Benefit Reports, Provision Increases.

GOAL: We examined the variation in community benefit and charity care reporting standards mandated by states to determine whether state-mandated community benefit and charity care reporting is associated with greater provision of these services. METHODS: We used 2011-2019 data from IRS Form 990 Schedule H for 1,423 nonprofit hospitals to create a sample of 12,807 total observations. Random effects regression models were used to examine the association between state reporting requirements and community benefit spending by nonprofit hospitals. Specific reporting requirements were analyzed to determine whether certain requirements were associated with increased spending on these services. PRINCIPAL FINDINGS: Nonprofit hospitals in states that required reports spent a higher percentage of total hospital expenditures on community benefits (9.1%, SD = 6.2%) compared to states without these requirements (7.2%, SD = 5.7%). A similar association between the percentage of charity care and total hospital expenditures (2.3% and 1.5%) was found. The greater number of reporting requirements was associated with lower levels of charity care provision, as hospitals allocated more resources to other community benefits. PRACTICAL APPLICATIONS: Mandating the reporting of specific services is associated with greater provision of certain specific services, but not all. A concern is that when many services must be reported, the provision of charity care might be reduced as hospitals choose to allocate their community benefit dollars to other categories. As a result, policymakers may want to focus their attention on the services they most want to prioritize.

Factors Associated with Compliance to the Hospital Price Transparency Final Rule: a National Landscape Study.

BACKGROUND: The Hospital Price Transparency Final Rule, effective January 1, 2021, requires hospitals to post online a machine-readable file that includes payer-specific negotiated commercial prices for all services. The regulation aims to improve the affordability of hospital care by promoting price competition. However, a low compliance level among hospitals would compromise the operational effectiveness of this regulation. Understanding hospitals' compliance status to the regulation has important implications for its enforcement effort and effectiveness assessment. OBJECTIVE: To analyze nationwide hospitals' compliance status to the Hospital Price Transparency Rule. DESIGN: Cross-sectional observational study. PARTICIPANTS: A total of 3558 Medicare-certified general acute-care hospitals were examined. MAIN MEASURES: A binary compliance rating was generated by using data collected by Turquoise Health. "Noncompliance" means that no machine-readable file was posted or the posted file contains no commercial negotiated prices. "Compliance" means that a machine-readable file was posted with commercial negotiated prices for at least one insurance plan. KEY RESULTS: As of June 1, 2021, 55% of the 3558 Medicare-certified general acute-care hospitals we examined had not posted a machine-readable file containing commercial negotiated prices. Wide variations of compliance existed across states and hospital referral regions. A hospital's compliance status is strongly associated with the average compliance status of peer hospitals in the same market. Hospitals with greater IT preparedness, for-profit hospitals, system-affiliated hospitals, large hospitals, and non-urban hospitals had greater compliance. More concentrated hospital markets had greater average compliance. CONCLUSIONS: Hospitals take into consideration the behavior of their peers in the same market when making price disclosure decisions. Compliant hospitals are likely to have better IT preparedness, more financial resources and personnel expertise to mitigate the cost required for the implementation of the Price Transparency Rule. The compliance cost, therefore, might be a barrier for some hospitals.

How place and race drive the numbers of fatal police shootings in the US: 2015-2020.

Place and race are two important predictors of fatal police shootings. We used Mapping Police Violence Data and the Washington Post Fatal Force Data to determine whether a county's deprivation status within communities influences the association between the number of fatal police shootings, and how the number of fatal police shootings differs by race and ethnicity. We categorized counties based on the Social Vulnerability Index (SVI) to three categories: low-, medium-, and high-SVI. The analytical sample included 3136 US counties between 2015 and 2020; during this time, 5525 individuals were fatally shot by police. Our findings show that place strongly impacts the number of fatal police shootings. Among all fatal shootings, 713 occurred in low-SVI counties, 1660 in middle-SVI, and 3152 in high-SVI counties. Race played a significant role; fatal shooting deaths increased by 2.3 times among White individuals, 9.6 times among Black individuals, and 15 times among Hispanic individuals between low- and high-SVI counties. The results of negative binomial regressions show a strong association between fatal police shootings and the counties' characteristics. In comparison with low-SVI counties, residents in counties with moderate and high-SVI are more likely to be fatally shot by police by 4.9 and 5.8 percentage points. In addressing violence and fatal police shootings, the vulnerability of counties and the population's racial composition play significant roles and need specific attention in addressing systemic racial disparities in the criminal justice system.

A Meta-Analysis of the Effectiveness of Cognitive Rehabilitation in Improving Memory Function in Patients With Posttraumatic Stress Disorder.

ABSTRACT: Posttraumatic stress disorder (PTSD) may have a detrimental effect on a patient's memory function. Memory problems are common after PTSD and can cause problems with a patient's day-to-day life. Cognitive rehabilitation is considered an effective treatment for patients with PTSD who want to improve cognitive memory. We searched keywords in electronic databases to find studies that looked into the effect of cognitive rehabilitation on memory function in patients with PTSD. This report is based on data from four studies with double-blind and placebo-controlled experiments totaling 198 participants. Effect size estimates were calculated using a mixed-effects meta-analysis for memory function. During cognitive rehabilitation, patients with PTSD demonstrated gains in memory in a variety of ways. Our results pointed to the need for further research into the most promising interventions for improving memory function in patients with PTSD. Furthermore, well-designed studies with large sample sizes are needed to confirm our results and determine the magnitude of the problem.

Analysis of trends in nurse practitioner billing for emergency medical services: 2015-2018.

STUDY OBJECTIVE: Despite projections of an oversupply of residency-trained emergency medicine physicians by 2030 and amidst intensifying national debate over Nurse Practitioner (NP) qualifications to practice independently and unsupervised, NPs are increasingly staffing Emergency Departments (EDs) as hospitals seek to contain costs while simultaneously expanding services. We sought to characterize NP practice in the ED by examining NP independent billing by level of severity of illness, and relationship to practice authority, State Medicaid expansion status, and rurality. METHODS: Medicare provider utilization and payment data between 2015-2018 was used to explore NP billing as compared to five other clinician provider types for common emergency services acuity codes (CPT codes 99281-99285) to determine services billed for levels of severity of illness and trends over time. Number of services billed by clinician provider type related to state policies on NP practice authority, location, and population characteristics was explored. RESULTS: NPs who independently billed for ED CPT codes (99282-99285), increased during this time and decreased for acuity code 99281 (minor and self-limiting). Overall, NPs saw a greater increase than all other providers in both the highest severity CPT codes of 99284 and 99285. The analysis revealed that type of clinician, state practice authority policy, number of NPs, and percent of population 65 years and older (by zipcode) and population size are positive predictors for services billed. The negative predictors were rurality, states which accepted the Medicaid expansion, having a higher number of non-English speaking residents, and non-emergency medicine clinicians. CONCLUSION: As a proportion of the providers independently billing in the ED, NPs are increasingly managing higher acuity patients as evidenced by billing percentage of the highest acuity CPT codes (99284 and 99285). During the same time period, ED MDs decreased their billing in the same categories. Current employment of NPs in the ED may not be fulfilling its original vision to care for the lower acuity patients in order to allow MDs to care for the more acutely and critically ill patients, and to increase the services for underserved populations in rural areas, those over age 65, and those with limited English language proficiency. Future research should investigate ED policies resulting in NPs as opposed to MDs seeing patients with greater severity codes.

The regulation of CD47-SIRPα signaling axis by microRNAs in combination with conventional cytotoxic drugs together with the help of nano-delivery: a choice for therapy?

CD47, a member of the immunoglobulin superfamily, is an important "Don't Eat-Me" signal in phagocytosis process [clearance of apoptotic cells] as well as a regulator of the adaptive immune response. The lower level of CD47 on the cell surface leads to the clearance of apoptotic cells. Dysregulation of CD47 plays a critical role in the development of disorders, particularly cancers. In cancers, recognition of CD47 overexpression on the surface of cancer cells by its receptor, SIRPα on the phagocytic cells, inhibits phagocytosis of cancer cells. Thus, blocking of CD47-SIRPα signaling axis might be as a promising therapeutic target, which promotes phagocytosis of cancer cells, antigen-presenting cell function as well as adaptive T cell-mediated anti-cancer immunity. In this respect, it has been reported that CD47 expression can be regulated by microRNAs (miRNAs). MiRNAs can regulate phagocytosis of macrophages apoptotic process, drug resistance, relapse of disease, radio-sensitivity, and suppress cell proliferation, migration, and invasion through post-transcriptional regulation of CD47-SIRPα signaling axis. Moreover, the regulation of CD47 expression by miRNAs and combination with conventional cytotoxic drugs together with the help of nano-delivery represent a valuable opportunity for effective cancer treatment. In this review, we review studies that evaluate the role of miRNAs in the regulation of CD47-SIRPα in disorders to achieve a novel preventive, diagnostic, and therapeutic strategy.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct. Confirmed.Journal standard instruction requires a structured abstract; however, none was provided. Please supply an Abstract with subsections..Not confirmed. This is a review article. According to submission guidelines: "The abstract should be presented divided into subheadings (unless it is a mini or full review article)". Kindly check and confirm whether the corresponding authors and mail ID are correctly identified. Confirmed.

eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.

Transcription factors and DNA regulatory binding motifs are fundamental components of the gene regulatory network. Here, by using genome-wide binding profiling, we show extensive occupancy of transcription factors of myogenesis (MyoD and Myogenin) at extragenic enhancer regions coinciding with RNA synthesis (i.e., eRNA). In particular, multiple regions were transcribed to eRNA within the regulatory region of MYOD1, including previously characterized distal regulatory regions (DRR) and core enhancer (CE). While (CE)RNA enhanced RNA polymerase II (Pol II) occupancy and transcription at MYOD1, (DRR)RNA acted to activate the downstream myogenic genes. The deployment of transcriptional machinery to appropriate loci is contingent on chromatin accessibility, a rate-limiting step preceding Pol II assembly. By nuclease sensitivity assay, we found that eRNAs regulate genomic access of the transcriptional complex to defined regulatory regions. In conclusion, our data suggest that eRNAs contribute to establishing a cell-type-specific transcriptional circuitry by directing chromatin-remodeling events.

Study protocol of a randomized controlled trial evaluating the Prime Time Sister Circles (PTSC) program's impact on hypertension among midlife African American women.

BACKGROUND: The Prime-Time Sister Circles® (PTSC) program is a multifaceted, community-based peer support intervention targeting African American women who are 40 to 75 years of age. It aims to reduce hypertension disparities observed among African American women by promoting adherence to antihypertensive therapies, including lifestyle modification and therapeutic regimens. METHODS: The PTSC randomized controlled trial will evaluate the effectiveness of the PTSC Program on improved blood pressure control, healthcare utilization attributed to cardiovascular events, and healthcare costs. The study began in 2016 and will end in 2022. African American women who are 40-75 years old, have been diagnosed with hypertension, reside in Washington, D.C. or Baltimore, Maryland, and receive their care from Unity Health Care, a federally qualified health center in Washington, D.C., or Baltimore Medical System, a federally qualified health center in Baltimore, Maryland, are eligible to participate. Those randomized to the intervention group participate in the PTSC Program, which spans 13 weeks and comprises facilitator-led discussions, didactic training about hypertension management, and peer-based problem-solving concerning CVD risk factors and their amelioration. Blood pressure, weight, body mass index, waist circumference, self-reported adherence, physical activity, dietary practices, stress, and healthcare utilization data are collected at baseline, 13 weeks (end of the intervention), 9 months (months post-intervention), and 15 months (one year after the intervention). Healthcare costs will be computed at the end of the study. The study's design is reported in the present manuscript, wherein we employed the SPIRIT checklist to guide its construction. DISCUSSION: Disparities in hypertension prevalence and management observed among mid-life African American women exist as a result of a confluence of structural determinants of health. Consequently, there is a need to develop, implement, and evaluate culturally appropriate and relevant interventions that are tailored to their lived experiences. The PTSC Trial aims to assess the impact of the program on participants' cardiovascular, psychosocial, and cost outcomes. Its results have implications for advancing the science of designing and implementing culturally relevant interventions for African American women. TRIAL REGISTRATION: Unique identifier: NCT04371614 . Retrospectively registered on April 30, 2020.

Geographic disparities in COVID-19 infections and deaths: The role of transportation.

The US government imposed two travel restriction policies to prevent the spread of the COVID-19 but may have funneled asymptomatic air travelers to selected major airports and transportation hubs. Using the most recent JHU COVID-19 database, American Community Survey, Airport and Amtrak data form Bureau of Transportation Statistics from 3132 US counties we ran negative binomial regressions and Cox regression models to explore the associations between COVID-19 cases and death rates and proximity to airports, train stations, and public transportation. Counties within 25 miles of an airport had 1.392 times the rate of COVID-19 cases and 1.545 times the rate of COVID-19 deaths in comparison to counties that are more than 50 miles from an airport. More effective policies to detect and isolate infected travelers are needed. Policymakers and officials in transportation and public health should collaborate to promulgate policies and procedures to protect travelers and transportation workers from COVID-19.

Polycomb protein Ezh1 promotes RNA polymerase II elongation.

Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, enhancer of zeste homolog 2 (Ezh2), triggers transcriptional repression by catalyzing the addition of methyl groups onto lysine 27 of histone H3 (H3K27me2/3). This action facilitates the binding of other PcG proteins to chromatin for purposes of transcriptional silencing. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 complex with active epigenetic mark (H3K4me3), RNA polymerase II (Pol II), and mRNA production. Ezh1 depletion reduced global Pol II occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, overexpression of wild-type Ezh1 led to premature gene activation and rescued Pol II occupancy defects in Ezh1-depleted cells. Collectively, these findings reveal a role for a PcG complex in promoting mRNA transcription.

Evaluating the effectiveness of cognitive rehabilitation on everyday memory in multiple sclerosis patients.

The aim was to determine the effectiveness of cognitive rehabilitation for everyday memory function in patients with multiple sclerosis. A total of 60 multiple sclerosis patients with cognitive impairment were randomly assigned to three groups, experimental, placebo and control. The groups were well matched in baseline characteristics. Everyday memory was assessed at baseline immediately post-intervention (8 weeks) and five weeks post-intervention. The experimental group received cognitive rehabilitation programme in 1-hour sessions on a weekly basis for 8 weeks. The placebo group received relaxation techniques on a weekly basis for eight weeks and the control group received no intervention. The results indicated that a cognitive rehabilitation programme had a positive effect on the everyday memory of patients in the experimental group post-intervention. However, there was no significant effect of intervention 5 weeks post-intervention. The present study demonstrated that cognitive rehabilitation had a positive effect on the everyday function of the multiple sclerosis patients. However, the effect did not last and that everyday memory function returned to its pre-intervention level.

Point-of-Use Rapid Detection of SARS-CoV-2: Nanotechnology-Enabled Solutions for the COVID-19 Pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the COVID-19 pandemic that has been spreading around the world since December 2019. More than 10 million affected cases and more than half a million deaths have been reported so far, while no vaccine is yet available as a treatment. Considering the global healthcare urgency, several techniques, including whole genome sequencing and computed tomography imaging have been employed for diagnosing infected people. Considerable efforts are also directed at detecting and preventing different modes of community transmission. Among them is the rapid detection of virus presence on different surfaces with which people may come in contact. Detection based on non-contact optical techniques is very helpful in managing the spread of the virus, and to aid in the disinfection of surfaces. Nanomaterial-based methods are proven suitable for rapid detection. Given the immense need for science led innovative solutions, this manuscript critically reviews recent literature to specifically illustrate nano-engineered effective and rapid solutions. In addition, all the different techniques are critically analyzed, compared, and contrasted to identify the most promising methods. Moreover, promising research ideas for high accuracy of detection in trace concentrations, via color change and light-sensitive nanostructures, to assist fingerprint techniques (to identify the virus at the contact surface of the gas and solid phase) are also presented.

Polycomb Ezh2 controls the fate of GABAergic neurons in the embryonic cerebellum.

Although the genetic interactions between signaling pathways and transcription factors have been largely decoded, much remains to be learned about the epigenetic regulation of cerebellar development. Here, we report that cerebellar deletion of Ezh2, the methyltransferase subunit of the PRC2 complex, results in reduced H3K27me3 and profound transcriptional dysregulation, including that of a set of transcription factors directly involved in cerebellar neuronal cell-type specification and differentiation. Such transcriptional changes lead to increased GABAergic interneurons and decreased Purkinje cells. Transcriptional changes also inhibit the proliferation of granule precursor cells derived from the rhombic lip. The loss of both cell types ultimately results in cerebellar hypoplasia. These findings indicate Ezh2/PRC2 plays crucial roles in regulating neurogenesis from both cerebellar germinal zones.