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Human brain organoids generated with current technologies recapitulate histological features of the human brain, but they lack a reproducible topographic organization. During development, spatial topography is determined by gradients of signaling molecules released from discrete signaling centers. We hypothesized that introduction of a signaling center into forebrain organoids would specify the positional identity of neural tissue in a distance-dependent manner. Here, we present a system to trigger a Sonic Hedgehog (SHH) protein gradient in developing forebrain organoids that enables ordered self-organization along dorso-ventral and antero-posterior positional axes. SHH-patterned forebrain organoids establish major forebrain subdivisions that are positioned with in vivo -like topography. Consistent with its behavior in vivo , SHH exhibits long-range signaling activity in organoids. Finally, we use SHH-patterned cerebral organoids as a tool to study the role of cholesterol metabolism in SHH signaling. Together, this work identifies inductive signaling as an effective organizing strategy to recapitulate in vivo -like topography in human brain organoids. Supplying forebrain organoids with a developmental signaling gradient induces topographical patterning along dorso-ventral and antero-posterior axes.

Despite the numerous pathogenic variants linked to neurodevelopmental disorders (NDDs) including autism (ASD) and intellectual disability, our understanding of the underlying mechanisms caused by risk genes remain unclear. Here, we show that mutations in ZMYND11 , a newly implicated risk gene, impair human cortical progenitor and neuron production. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor. ZMYND11-deficient cortical neural stem cells upregulate inappropriate developmental pathways, leading to disrupted neurogenesis. In addition to its role on chromatin, ZMYND11 regulates a brain-specific RNA isoform switch involving the splicing regulator RBFOX2. Similar defects are observed in other chromatin-related ASD risk genes, some of which are partially rescued by enhancing ZMYND11 function. These findings uncover convergent pathways linking chromatin regulation and splicing to human brain development and advance our understanding of how genetic risk contributes to NDD. Here authors report that mutations in the neurodevelopmental risk gene ZMYND11 disrupt human cortical neuron development by altering chromatin regulation and RNA splicing.

Abstract BACKGROUND Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (WHO) grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. OBJECTIVE To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan–Meier method. RESULTS Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {CI} 0.000-0.074] and HR = 0.001 [95% CI 0.00-0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17-4.13] and HR = 2.99 [95% CI 0.15-61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wtLGGs, but the impact on IDH1 mtLGGs requires further study.

Despite the litany of pathogenic variants linked to neurodevelopmental disorders (NDD) including autism (ASD) and intellectual disability , our understanding of the underlying mechanisms caused by risk genes remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in , a newly implicated risk gene . ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor . Our findings reveal that ZMYND11-deficient cortical neural stem cells showed upregulation of latent developmental pathways, impairing progenitor and neuron production. In addition to its role on histones, ZMYND11 controls a brain-specific isoform switch involving the splicing regulator RBFOX2. Extending our findings to other chromatin-related ASD risk factors revealed similar developmental pathway activation and splicing dysregulation, partially rescuable through ZMYND11's regulatory functions.

Abstract BACKGROUND: Survival duration and prognostic factors in adult high-grade glioma have been comprehensively analyzed, but less is known about factors contributing to overall survival (OS) and progression-free survival (PFS) in pediatric patients. OBJECTIVE: To identify these factors in the pediatric population. METHODS: We retrospectively reviewed institutional databases evaluating all patients ⩽21 years with high-grade glioma treated between 1988 and 2010. Kaplan-Meier curves and log-rank statistics were used to compare groups univariately. Multivariate analyses were completed using Cox proportional hazards regression models. RESULTS: Ninety-seven patients were identified with a median age of 11 years. Median OS was 1.7 years, and median PFS was 272 days. Location was significant for OS (P > .001). Patients with gross total resection (GTR) had a median OS of 3.4 years vs 1.6 years for subtotal resection and 1.3 years for biopsy patients (P > .001). Female patients had improved OS (P = .01). Female patients with GTR had a mean OS of 8.1 years vs 2.4 years for male patients with GTR and 1.4 years for all other female patients and male patients (P = .001). PFS favored patients ⩽3 and ≥13 years and females (P = .003 and .001). CONCLUSION: OS was significantly correlated with the location of the tumor and the extent of resection. GTR significantly improved overall survival for both glioblastoma multiforme and anaplastic astrocytoma patients, and female patients showed a much larger survival benefit from GTR than male patients.

Abstract BACKGROUND Spine and nonspine skeletal metastases occur in more than 80% of patients with prostate cancer. OBJECTIVE To examine the characteristics of the patient population undergoing surgery for the treatment of prostate cancer metastatic to the spine. METHODS A retrospective chart review was performed on all patients treated at our institution from June 1993 to August 2014 for surgical management of metastatic spine disease from prostate cancer. RESULTS During the study period, 139 patients with 157 surgical lesions underwent surgery for metastatic spine disease. Decompression for high-grade epidural spinal cord compression was required for 126 patients with 143 lesions. Preoperatively, 69% had a motor deficit and 21% were nonambulatory, with 32% due to motor weakness. At surgery, 87% of patients had hormone-refractory prostate cancer (HRPC) and 61% failed prior radiation. Median overall survival for HRPC patients was 6.6 mo (95% confidence interval [CI]: 5.6-8.6) while the median overall survival for hormone-sensitive patients was 16.3 mo (95% CI: 4.0-26.6). CONCLUSION The majority of patients undergoing surgery for prostate cancer metastases to the spine were refractory to hormone therapy, indicating that patients with hormone-sensitive prostate cancer are unlikely to develop symptomatic spinal cord compression or spinal instability. A significant number of HRPC patients presented with neurological deficits attributable to spinal cord compression. Vigilant monitoring for the development of signs and symptoms of epidural spinal cord compression and spinal instability in hormone-refractory patients is recommended. Surgical decision making may be affected by the much shorter postoperative survival for HRPC patients as compared to patients with hormone-sensitive cancer.

Abstract INTRODUCTION Accumulating evidence suggests that maximizing extent of resection (EOR) improves outcomes for patients with WHO grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. To answer this question, we evaluated a cohort of patients with surgically-resection WHO grade II gliomas and known IDH1 mutation status, to assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS). METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing surgical resection at a single institution. EOR was assessed with quantitative three-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan-Meier method. RESULTS >52 (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median pre-operative tumor volume was 37.4 cm3 (range: 0.9-190.2 cm3). Median EOR was 57.6% (range: 0.08% 99.3%). Median follow-up was 44.4 months. Malignant progression was identified in 31 patients and 17 patients died. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, Cox regression analysis stratified by IDH status demonstrated that a greater EOR independently prolonged MPFS and OS for wtIDH patients (HR = 0.002 [95% CI 0.000 - 0.074] and HR = 0.001 [95% CI 0.00 - 0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17 - 4.13] and HR = 2.99 [95% CI 0.15 - 61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wild-type LGGs. However, the impact of EOR on IDH1 mutant LGGs is less significant and requires further study.

Neurodevelopmental disorders (NDDs), which affect 1 in 6 children in the United States, are a group of disabilities caused by abnormal growth and function of the brain. Despite this prevalence, elucidating causative disease mechanisms has remained challenging. This is in large part due to current limitations in experimental modeling of NDDs. Two factors in particular that present challenges for disease modeling are 1) the cellular diversity of brain development and 2) the genetic diversity of disease risk. Human pluripotent stem cells (hPSCs) have great potential for modeling NDDs, and may be well suited to address the challenges of cellular and genetic diversity for the following reasons. First, hPSCs can generate diverse cell types of the human body, thus providing unprecedented access to disease tissue. Second, hPSCs can organize cellular diversity into functional tissue structures through the use of three-dimensional culture systems called organoids. Third, hPSCs can be engineered to harbor any type of gene mutation, including both monogenic and polygenic genetic risk variants. In this dissertation, I explore how the unique properties of hPSCs can be harnessed to dissect the complex cellular and genetic landscapes of NDD risk. First, I collaborate to develop a forebrain organoid culture model of ZIKA virus induced microcephaly and find that ZIKA virus infection inhibits growth and degrades the local architecture of forebrain progenitor zones. We further identify small molecules that inhibit ZIKA virus infection of SOX2+ forebrain progenitors. While organoids recapitulate the cellular diversity and microarchitecture of progenitor zones, and have thus been successful at modeling disorders of tissue growth, they do not recapitulate the overall regional organization of the brain, in which each discrete brain area arise in a stereotyped anatomical location. I therefore next developed a method to trigger spatial patterning in organoids, thus generating topographically organized brain tissue that contains at least five major forebrain subdivisions. Using this system as a tool to study drug toxicity during fetal brain development, I find that cholesterol synthesis-inhibiting drugs, including statins, perturb sonic hedgehog-dependent spatial patterning and growth. Finally, I develop an hPSC-based multiplex analysis platform for the simultaneous functional characterization of many disease-associated mutations. This approach is applied to model autism, a disorder of social isolation in which hundreds of distinct mutations contribute to diverse clinical outcomes. Multiplex analysis of 27 high-confidence, early developmental, de novo autism mutations in hPSC-derived prefrontal cortex tissue identifies that autism mutations commonly perturb cortical neurogenesis and WNT signaling. These phenotypes were used to segregate mutations into distinct subgroups. Autism patients that fall into distinct subgroups exhibit average differences in clinical parameters of communication skills and language development. Taken together, these findings demonstrate that hPSCs are a powerful and general platform to disentangle primary disease pathways from the complex cellular and genetic environments that give rise NDDs.

Negative ions are important in many areas of science and technology, e.g., in interstellar chemistry, for accelerator-based radionuclide dating, and in anti-matter research. They are unique quantum systems where electron-correlation effects govern their properties. Atomic anions are loosely bound systems, which with very few exceptions lack optically allowed transitions. This limits prospects for high-resolution spectroscopy, and related negative-ion detection methods. Here, we present a method to measure negative ion binding energies with an order of magnitude higher precision than what has been possible before. By laser-manipulation of quantum-state populations, we are able to strongly reduce the background from photodetachment of excited states using a cryogenic electrostatic ion-beam storage ring where keV ion beams can circulate for up to hours. The method is applicable to negative ions in general and here we report an electron affinity of 1.461 112 972(87) eV for 16 O. High-precision measurements are useful to find isotopic shifts and electron correlation. Here the authors measure electron affinity and hyperfine splitting of atomic oxygen with higher precision than previous studies.

We store a 10 keV OH− ion-beam at 13.5 ± 0.5 K in one of the DESIREE storage rings. Using photodetachment thermometry we measure the effective relative photodetachment cross section at different storage times and determine the rotational temperature of the ions to be 13.4 ± 0.2 K in agreement with the macroscopic temperature. A model cross section in the threshold range taking into account the formation of excited neutral OH molecules is calculated as a function of rotational temperature in order to justify the use of the rotational thermometry method developed earlier by the group of Roland Wester at Innsbruck University in the present case. In addition, we apply a selective photodetachment technique to produce an ion beam with more than 99% of the ions in the rotational ground state. The intrinsic lifetime of the J = 1 rotational level is measured to be 145 ± 28 s.