Growth of Remote Therapeutic Monitoring Lands New Opportunities for Case Management.

PURPOSE/OBJECTIVES: An increase in the use of remote therapeutic monitoring (RTM) has been spurred by nationwide factors including the COVID-19 pandemic, authorized reimbursement of RTM by the Centers for Medicare & Medicaid Services, and more frequent use of big data analytics in health care delivery. This article discusses the use of RTM by care teams at the point of care and explores the role of the case manager in RTM to address patients' unmet needs. PRIMARY PRACTICE SETTINGS: Although RTM may be utilized across inpatient and outpatient levels of care, this article focuses on outpatient care such as community clinics, provider groups, and home health care. FINDINGS/CONCLUSIONS: When implemented along with care management interventions, RTM applications have the potential to improve patient adherence, enhance communication between patients and their providers, streamline resource allocation, and address social determinants of health impacting patient care and outcomes. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: RTM reimbursement models are rapidly evolving, utilizing real-world and patient-reported data to identify and initiate timely, individualized solutions that meet the holistic needs of each patient. Use of an RTM system allows the case manager to build rapport with the patient while quickly identifying care gaps and delivering appropriate interventions that can maximize patient outcomes. RTM can drive savings and bring revenue to the system or practice while providing salient documentation of social determinants of health that can be addressed with validation of proven care coordination interventions.

HNRNPU's multi-tasking is essential for proper cortical development.

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) is a nuclear protein that plays a crucial role in various biological functions, such as RNA splicing and chromatin organization. HNRNPU/scaffold attachment factor A (SAF-A) activities are essential for regulating gene expression, DNA replication, genome integrity, and mitotic fidelity. These functions are critical to ensure the robustness of developmental processes, particularly those involved in shaping the human brain. As a result, HNRNPU is associated with various neurodevelopmental disorders (HNRNPU-related neurodevelopmental disorder, HNRNPU-NDD) characterized by developmental delay and intellectual disability. Our research demonstrates that the loss of HNRNPU function results in the death of both neural progenitor cells and post-mitotic neurons, with a higher sensitivity observed in the former. We reported that HNRNPU truncation leads to the dysregulation of gene expression and alternative splicing of genes that converge on several signaling pathways, some of which are likely to be involved in the pathology of HNRNPU-related NDD.

LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways.

Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.

Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice.

Generating effective therapies for neurodevelopmental disorders has remained elusive. An emerging drug discovery approach for neurodevelopmental disorders is to characterize transcriptome-wide dysregulation in an appropriate model system and screen therapeutics based on their capacity to restore functionally relevant expression patterns. We characterized transcriptomic dysregulation in a human model of HNRNPU-related disorder to explore the potential of such a paradigm. We identified widespread dysregulation in functionally relevant pathways and then compared dysregulation in a human model to transcriptomic differences in embryonic and perinatal mice to determine whether dysregulation in an in vitro human model is partially replicated in an in vivo model of HNRNPU-related disorder. Strikingly, we find enrichment of co-dysregulation between 45-day-old human organoids and embryonic, but not perinatal, mice from distinct models of HNRNPU-related disorder. Thus, hnRNPU deficient human organoids may only be suitable to model transcriptional dysregulation in certain cell types within a specific developmental time window.

A Novel Remote Patient and Medication Monitoring Solution to Improve Adherence and Persistence With Inflammatory Bowel Disease Therapy (ASSIST Study): Protocol for a Randomized Controlled Trial.

BACKGROUND: Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract. Although adherence to IBD therapies is associated with improved clinical outcomes, overall adherence is poor. Consequently, there is a critical need to develop interventions that monitor adherence in real time and identify reasons for nonadherence to support clinical teams in initiating effective interventions. Recently, electronic- and web-based platforms have been developed to monitor adherence and guide interventions. A novel remote therapy monitoring (RTM) technology, the Tappt digital health system, has been developed to monitor real-time medication adherence patterns through smart label technologies, capture patient-reported outcomes and barriers to care, and process patient data through algorithms that trigger personalized digital and human touch points between clinical visits. Such a digital health solution enables care teams to proactively identify and mitigate nonadherence and worsening clinical outcomes. OBJECTIVE: We propose a 12-month multicenter randomized controlled trial to assess the effectiveness of the Tappt digital health system on adherence, clinical outcomes, and health care use among patients diagnosed with IBD starting a new oral or subcutaneous therapy. METHODS: The digital health system intervention will provide automatic measurement of medication adherence via smart labels for pill bottles or injectors as well as a monitoring platform for providers. The system will prompt patients to complete a two-item assessment of symptoms monthly using the PRO-2 scales for UC and Crohn disease, from which increased symptoms will be alerted to providers. Participants will be randomized 2:1 to the intervention group or the control group, which will receive standard of care. All participants are required to complete questionnaires at baseline as well as at 12, 26, and 52 weeks. Assuming an adherence rate of 0.65 and 0.9 among control and intervention participants, respectively, we will need to enroll 123 participants: 82 (66.7%) in the intervention group and 41 (33.3%) controls. We will compare adherence as measured by the medication possession ratio, defined as the number of days of supply of medication obtained during the observation period out of the total number of days in the observation period, in participants using the RTM versus those receiving standard of care. We will also compare clinical outcomes and health care use in participants using the RTM versus those receiving standard of care. RESULTS: We anticipate starting recruitment in December 2022. CONCLUSIONS: Effective medication adherence monitoring and intervention programs need to be cost-efficient, pose little or no burden to the patient, record reliable data in real time, and provide actionable insights to the health care team. We anticipate the Tappt digital health system to improve the medication possession ratio, clinical outcomes, and health care use compared with standard of care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05316584; https://clinicaltrials.gov/ct2/show/NCT05316584. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/40382.

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex.

HNRNPU encodes the heterogeneous nuclear ribonucleoprotein U, which participates in RNA splicing and chromatin organization. Microdeletions in the 1q44 locus encompassing HNRNPU and other genes and point mutations in HNRNPU cause brain disorders, including early-onset seizures and severe intellectual disability. We aimed to understand HNRNPU's roles in the developing brain. Our work revealed that HNRNPU loss of function leads to rapid cell death of both postmitotic neurons and neural progenitors, with an apparent higher sensitivity of the latter. Further, expression and alternative splicing of multiple genes involved in cell survival, cell motility, and synapse formation are affected following Hnrnpu's conditional truncation. Finally, we identified pharmaceutical and genetic agents that can partially reverse the loss of cortical structures in Hnrnpu mutated embryonic brains, ameliorate radial neuronal migration defects and rescue cultured neural progenitors' cell death.

Brain Organization and Human Diseases.

The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common cortical malformations and their manifestation in the human brain.

A Quality Improvement Initiative Is Associated With Reduced Time to Administer Biologics and Small Molecules and Emergency Room Visits in Inflammatory Bowel Disease.

BACKGROUND: Delays in biologic or small molecule medication administration are associated with increased adverse events, hospitalization, and surgery in inflammatory bowel disease (IBD). We evaluated the impact of a quality improvement (QI) intervention on the time to administration of biologics or small molecules (TABS) in IBD. METHODS: Data were retrospectively extracted for IBD patients prescribed biologics or small molecules from a convenience sample of providers participating in an accredited QI educational intervention (baseline cohort). Subsequent to the intervention, data were prospectively collected from patients prescribed these medications (postintervention cohort). Dates related to steps between a treatment decision to medication administration were collected. The primary outcome compared TABS in baseline and postintervention cohorts. RESULTS: Eighteen physicians provided survey and patient data for 200 patients in each cohort (n=400). The median time to medication administration (TABS) decreased from baseline to postintervention cohorts (30 vs. 26 d, P=0.04). Emergency room visits before medication administration also decreased (25.5% vs. 12.5%, P=0.001). Similar numerical TABS reductions were observed in subgroups limited to physicians providing patients to both cohorts and for individual medications prescribed. Primary contributors to delays included filling prescriptions subsequent to insurance approval and dispensation subsequent to this. CONCLUSIONS: A QI intervention successfully reduced medication administration times (TABS) by accelerating provider-dependent steps. This intervention was associated with reduced emergency room visits. We propose TABS as a quality metric to assess the effective delivery of therapies in IBD. Further evaluation of QI interventions, patient education on prescription drug insurance, and quality metrics are warranted.

Does Evaluation and Management of COPD Follow Therapeutic Strategy Recommendations?

INTRODUCTION: Recommendations for chronic obstructive pulmonary disease (COPD) diagnosis and management requires symptom and exacerbation risk assessment. Adherence to these recommendations appears to be limited. We examined the impact of a COPD quality improvement (QI) program in the Southeastern United States. METHODS: From 2017 to 2018, nine pulmonary and 15 primary care physicians were included in our study and asked to identify 6 to 7 of their COPD patients using maintenance COPD medications with at least 2 office visits in the past year. A separate group of COPD patients (n=135 pulmonary and 165 primary care) from the same practices were evaluated. Physicians underwent focused, educational, peer-to-peer small group webinars. Data were collected from physicians and their patients using a systematic survey. Chart audits occurred at baseline and 6 months after the webinars. RESULTS: The majority of physicians (67%) saw ≥ 20 COPD patients/week. There were important discrepancies between the care clinicians thought they provided, and the care recalled by their patients. Clinicians felt that 33% of their patients experienced at least 2 exacerbations in the past year; 56% of their patients reported this frequency. There was discrepancy in the clinicians' interpretations and the patients' reasons for discontinuing their medications and in the use of referrals. Self-reported changes were noted by clinicians after educational webinars and improvements in patient care were noted in the year following intervention. CONCLUSION: We identified notable discrepancies between the clinicians' impression of care provided and the components actually recalled by their patients. We also identified improvements in processes of care and outcomes following an educational intervention based on the principles of audit and feedback.

Modeling human neuronal migration deficits in 3D.

During the past few decades, we have witnessed an impressive gain in the knowledge regarding the basic mechanisms underlying human neuronal migration disorders by the usage of mouse models. Nevertheless, despite the remarkable conservation both in the genetic encoded information and the developmental processes, there are still numerous important differences between human and mouse. This may explain the vast excitement following the realization that technological breakthroughs enabled generating tissue-like human-based organoids for modeling human neuronal migration diseases. This review will provide a short introduction on human and mouse neuronal migration processes, and highlight human brain organoid models of neuronal migration diseases.

Using multi-organ culture systems to study Parkinson's disease.

In recent years, it has been revealed that Parkinson's disease pathology may begin to manifest in the gastrointestinal track at a much earlier time point than in the brain. This paradigm shift has been suggested following evidence in humans that has been reproduced in animal models. Since rodent models cannot recapitulate many of the human disease features, human induced pluripotent stem cells derived from Parkinson's patients have been used to generate brain organoids, greatly contributing to our understanding of the disease pathophysiology. To understand the multifaced aspects of Parkinson's disease, it may be desirable to expand the complexity of these models, to include different brain regions, vasculature, immune cells as well as additional diverse organ-specific organoids such as gut and intestine. Furthermore, the contribution of gut microbiota to disease progression cannot be underestimated. Recent biotechnological advances propose that such combinations may be feasible. Here we discuss how this need can be met and propose that additional brain diseases can benefit from this approach.

A regional analysis of payer and provider views on cholesterol management: PCSK9 inhibitors as an illustrative alignment model.

BACKGROUND: Multiple barriers exist for appropriate use of the proprotein convertase subtilisin/kexin type 9 enzyme inhibitors (PCSK9i) in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) with inadequately controlled hypercholesterolemia despite standard therapies. Among these barriers, high payer rejection rates and inadequate prior authorization (PA) documentation by providers hinder optimal use of PCSK9i. OBJECTIVES: To (a) identify and discuss provider and payer discordances on barriers to authorization and use of PCSK9i based on clinical and real-world evidence and (b) align understanding and application of clinical, cost, safety, and efficacy data of PCSK9i. METHODS: Local groups of 3 payers and 3 providers met in 6 separate locations across the United States through a collaborative project of AMCP and PRIME Education. Responses to selected pre- and postmeeting survey questions measured changes in attitudes and beliefs regarding treatment barriers, lipid thresholds for considering PCSK9i therapy, and tactics for improving PA processes. Statistical analysis of inter- and intragroup changes in attitudes were performed by Cox proportional hazards test and Fisher's exact test for < 5 variables. RESULTS: The majority of providers and payers (67%-78%) agreed that high patient copayments and inadequate PA documentation were significant barriers to PCSK9i usage. However, payers and providers differed on beliefs that current evidence does not support PCSK9i cost-effectiveness (6% providers, 56% payers; P = 0.003) and that PA presents excessive administrative burden (72% providers, 44% payers; P = 0.09) Average increases pre- to postmeeting were noted in provider beliefs that properly documented PA forms expedite access to PCSK9i (22%-50% increase) and current authorization criteria accurately distinguish patients who benefit most from PCSK9i (6%-22%). Payers decreased in their belief that current authorization criteria accurately distinguish benefiting patients (72%-50%). Providers and payers increased in their belief that PCSK9i are cost-effective (44%-61% and 28%-50%, respectively) and were more willing to consider PCSK9i at the low-density lipoprotein cholesterol threshold of > 70 mg/dL for patients with ASCVD (78%-83% and 44%-67%, respectively) or FH (22%-39% and 22%-33%). Payers were more agreeable to less stringent PA requirements for patients with FH (33%-72%, P = 0.019) and need for standardized PA requirements (50%-83%, P = 0.034); these considerations remained high (89%) among providers after the meeting. Most participants supported educational programs for patient treatment adherence (83%) and physician/staff PA processes (83%-94%). CONCLUSIONS: Provider and payer representatives in 6 distinct geographic locations provided recommendations to improve quality of care in patients eligible for PCSK9i. Participants also provided tactical recommendations for streamlining PA documentation processes and improving awareness of PCSK9i cost-effectiveness and clinical efficacy. The majority of participants supported development of universal, standardized patient eligibility criteria and PA forms. DISCLOSURES: The study reported in this article was part of a continuing education program funded by an independent educational grant awarded by Sanofi US and Regeneron Pharmaceuticals to PRIME Education. The grantor had no role in the study design, execution, analysis, or reporting. AMCP received grant funding from PRIME to assist in the study, as well as in writing the manuscript. McCormick, Bhatt, Bays, Taub, Caldwell, Guerin, Steinhoff, and Ahmad received an honorarium from PRIME for serving as faculty for the continuing education program. McCormick, Bhatt, Bays, Taub, Caldwell, Guerin, Steinhoff, and Ahmad were involved as participants in the study. Bhatt discloses the following relationships: Advisory board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site co-investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded research: FlowCo, Merck, Novo Nordisk, Takeda. Bays' research site has received research grants from 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Amgen, AstraZeneca, Axsome, Boehringer Ingelheim, Civi, Eli Lilly, Esperion, Evidera, Gan and Lee, Home Access, Janssen, Johnson and Johnson, Lexicon, Matinas, Merck, Metavant, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Selecta, TIMI, and Urovant. Bays has served as a consultant/advisor for 89Bio, Amarin, Esperion, Matinas, and Gelesis, and speaker for Esperion. McCormick, Caldwell, Guerin, Ahmad, Singh, Moreo, Carter, Heggen, and Sapir have nothing to disclose.

Building Bridges Between the Clinic and the Laboratory: A Meeting Review - Brain Malformations: A Roadmap for Future Research.

In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting.

The Interactome of Palmitoyl-Protein Thioesterase 1 (PPT1) Affects Neuronal Morphology and Function.

Palmitoyl-protein thioesterase 1 (PPT1) is a depalmitoylation enzyme that is mutated in cases of neuronal ceroid lipofuscinosis (NCL). The hallmarks of the disease include progressive neurodegeneration and blindness, as well as seizures. In the current study, we identified 62 high-confident PPT1-binding proteins. These proteins included a self-interaction of PPT1, two V-type ATPases, calcium voltage-gated channels, cytoskeletal proteins and others. Pathway analysis suggested their involvement in seizures and neuronal morphology. We then proceeded to demonstrate that hippocampal neurons from Ppt1-/- mice exhibit structural deficits, and further investigated electrophysiology parameters in the hippocampi of mutant mice, both in brain slices and dissociated postnatal primary cultures. Our studies reveal new mechanistic features involved in the pathophysiology of this devastating neurodegenerative disease.

The HERV-K accessory protein Np9 controls viability and migration of teratocarcinoma cells.

Human endogenous retroviruses are remnants of ancient germline infections that make up approximately 8% of the modern human genome. The HERV-K (HML-2) family is one of the most recent entrants into the human germline, these viruses appear to be transcriptionally active, and HERV-K viral like particles (VLPs) are found in cell lines from a number of human malignancies. HERV-K VLPs were first found to be produced in teratocarcinoma cell lines, and since then teratocarcinoma has been thought of as the classical model for HERV-Ks, with the NCCIT teratocarcinoma cell line particularly known to produce VLPs. Treatment for teratocarcinoma has progressed since its discovery, with improved prognosis for patients. Since the introduction of platinum based therapy, first year survival has greatly improved even with disseminated disease; however, it is estimated that 20% to 30% of patients present with metastatic germ cell tumor relapse following initial treatments. Also, the toxicity associated with the use of chemotherapeutic agents used to treat germ cell tumors is still a major concern. In this study, we show that the depletion of the HERV-K accessory protein Np9 increases the sensitivity of NCCIT teratocarcinoma cells to bleomycin and cisplatin. While decreasing the expression of Np9 had only a modest effect on the baseline viability of the cells, the reduced expression of Np9 increased the sensitivity of the teratocarcinoma cells to environmental (serum starvation) and chemical (chemotherapeutic) stresses. Np9 is also essential to the migration of NCCIT teratocarcinoma cells: in a wound closure assay, reduced expression of Np9 resulted in cells migrating into the wound at a slower rate, whereas reintroduction of Np9 resulted in NCCIT cells migrating back into the wound in a manner similar to the control. These findings support the implication that the HERV-K accessory protein Np9 has oncogenic potential.

A Double Fail-Safe Approach to Prevent Tumorigenesis and Select Pancreatic ß Cells from Human Embryonic Stem Cells.

The transplantation of human embryonic stem cell (hESC)-derived insulin-producing ß cells for the treatment of diabetes is finally approaching the clinical stage. However, even with state-of-the-art differentiation protocols, a significant percentage of undefined non-endocrine cell types are still generated. Most importantly, there is the potential for carry-over of non-differentiated cell types that may produce teratomas. We sought to modify hESCs so that their differentiated progeny could be selectively devoid of tumorigenic cells and enriched for cells of the desired phenotype (in this case, ß cells). Here we report the generation of a modified hESC line harboring two suicide gene cassettes, whose expression results in cell death in the presence of specific pro-drugs. We show the efficacy of this system at enriching for ß cells and eliminating tumorigenic ones both in vitro and in vivo. Our approach is innovative inasmuch as it allows for the preservation of the desired cells while eliminating those with the potential to develop teratomas.

Complement C3 Affects Rac1 Activity in the Developing Brain.

The complement system, which is part of the innate immune response system, has been recently shown to participate in multiple key processes in the developing brain. Here we aimed to elucidate downstream signaling responses linking complement C3, a key molecule of the pathway, to small GTPases, known to affect the cytoskeleton. The expression pattern of the activated small GTPase Rac1 resembled that of complement C3. C3-deficient mice exhibited reduced Rac1 and elevated RhoA activity in comparison with control mice. The most pronounced reduction of Rac1 activity occurred at embryonic day 14. Rac1 has been implicated in neuronal migration as well as neuronal stem cell proliferation and differentiation. Consistent with the reduction in Rac1 activity, the expression of phospho-cofilin, decreased in migrating neurons. Reduced Rac1-GTP was also correlated with a decrease in the expression of progenitor markers (Nestin, Pax6 and Tbr2) and conversely the expression of neuronal markers (Dcx and NeuN) increased in C3 knockout (KO) cortices in comparison with wild-type (WT) cortices. More specifically, C3 deficiency resulted in a reduction in the number of the cells in S-phase and an elevation in the number of cells that precociously exited the cell cycle. Collectively, our findings suggest that C3 impacts the activity of small GTPases resulting in cell cycle defects and premature neuronal differentiation.

A Coated Sponge: Toward Neonatal Brain Repair.

In this issue of Cell Stem Cell, Jinnou et al. (2018) identify a limited time window wherein neonatal brain injuries may be treated through neuroblast migration toward the injury site on radial glial fibers. Implanting a sponge coated with an adhesive factor in the injured neonatal brain supports the migration of neuroblasts and improves functional recovery.

Notch Activation by Shootin1 Opposing Activities on 2 Ubiquitin Ligases.

The evolutionarily conserved Notch pathway plays an important role in regulation of stem cell renewal and cell fate determination in numerous organs, and as such is a key pathway in normal health and disease processes. Canonical Notch signaling is usually activated by cell contact where transmembrane ligands such as Delta-like and Jagged bind to Notch receptors. Notch activation results in the translocation of the cleaved Notch intracellular domain (NICD) into the nucleus and subsequent activation of transcription. Poly-ubiquitination leading to proteosome degradation of pathway components is one mean of regulating the Notch pathway. Here, we identified that Shootin1 exhibits the surprising propensity of activating the pathway either by interacting with LNX1/2 and promoting poly-ubiquitination of Numb or by complexing with Itch and impairing poly-ubiquitination of NICD. Within the developing brain Shootin1 modulates neuroblasts cell fate by executing 2 opposing activities on ubiquitin ligases, which control Notch signaling on 2 different levels.