Supplementary Data from Cell Cycle Regulator Gene CDC5L, a Potential Target for 6p12-p21 Amplicon in Osteosarcoma

SUMMARY A major impediment to the actualization of the induced pluripotent stem cell (iPSC)-based personalized medicine revolution is the lack of widely accepted standard operating procedures (SOPs) across different groups and institutions. The various methods employed can include choice of starting materials, reprogramming agents, and culture conditions, with each of these factors hypothesized to influence the reprogramming efficiency and transcriptional identity of iPSCs. As such, we systematically compared iPSC reprogramming procedures using cells derived from the somatic cells of three patients with 16p11.2 deletion syndrome (16p11.2del) and found remarkable similarity among the different methods. FACS analysis revealed that regardless of somatic cell type (fibroblast, lymphocyte, erythroblast), route of reprogramming factor introduction (mRNA, Sendai virus, episome), donor sex, or facility (Rutgers, NYSCF), 16p11.2del patient iPSCs were viable as high purity cultures expressing pluripotency marker proteins. This observation was supported at the transcript level by qPCR analysis, which demonstrated the ability for the iPSCs to differentiate into all three embryonic germ cell lineages after 12 days in culture as embryoid bodies. NGN2-mediated differentiation of these iPSCs produced functional neurons that formed active synaptic networks as revealed by multi-electrode array (MEA) recordings. Importantly, no group-wise comparisons among the reprogramming methods yielded consistent statistically significant differences, indicating that these procedures are equally capable of producing pluripotent stem cells that can efficiently differentiate into mature, functional neurons. This work highlights the utility of these reprogramming methods and supports the use of differentially reprogrammed iPSCs for direct comparative studies of human neurodevelopment.

Biopreservation and BiobankingVol. 20, No. 5 Brief ReportFree AccessLetter to the Editor: Biobanks and International Initiatives Are Playing a Critical Role in Redressing Historic Inadequacies in Biosample and Data Access from Underrepresented Minority PopulationsMichael Sheldon, Robin Grimwood, and Shareef A. NahasMichael Sheldonhttps://orcid.org/0000-0002-8986-140XSampled, Piscataway, New Jersey, USA.Search for more papers by this author, Robin GrimwoodSampled, Piscataway, New Jersey, USA.Search for more papers by this author, and Shareef A. NahasAddress correspondence to: Shareef A. Nahas PhD, FACMGG, Sampled, 30 Knightsbridge Road, Piscataway, NJ 08854, USA E-mail Address: shareef.nahas@sampled.comSampled, Piscataway, New Jersey, USA.Search for more papers by this authorPublished Online:17 Oct 2022https://doi.org/10.1089/bio.2022.0059AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail History and the Problem at HandBiobanking and biorepository operations are among the oldest organized efforts in the modern era of scientific research, dating back >100 years.1 In the early days, biobanks consisted of small facilities in academic institutions that were seldom interconnected or in communication with one another, hampering the ability of the global community to coordinate projects that rely on access to large numbers of well-curated biospecimens and associated data.The advent of genomics technologies based on molecular techniques, including genotyping and next-generation sequencing, has led to a shift in the biobanking paradigm from storage to utilization of large numbers of high-quality samples (tissues, blood, and saliva) for translational research and diagnostic purposes.2,3 The goal of these genomics approaches, when combined with improvements in our understanding of disease phenotyping, is the development of targeted molecular-based assays and companion treatments that provide early detection and inform effective therapeutic approaches for a number of serious conditions.2 This objective requires studies with high statistical power based on access to large numbers of biospecimens and associated clinical data of uniformly high quality.In recognition of this need, the National Institutes of Health (NIH) was one of the first major funding agencies to establish a centralized facility that would expand the scope and capabilities of the conventional biobank to meet the demands of large-scale science.4 The first major effort was the establishment of the NIMH Repository and Genomics Resource (NRGR; https://www.nimhgenetics.org/), operated since 1996 by Sampled (formerly RUCDR Infinite Biologics). The NRGR plays a key role in facilitating research in psychiatric disorders, providing well-phenotyped participant samples from a wide range of illnesses4 such as schizophrenia. To date, studies utilizing NRGR samples and data have resulted in >800 publications with >70,000 citations.Genome-wide association studies are large-scale genomics studies designed to identify SNP alleles at loci with a high degree of association with a disease phenotype. Candidate loci with the highest degree of risk for developing a disease then become the focus of development of polygenic risk score (PRS) assays. It is well documented that ethnic groups have differing risks associated with disease, as well as drug and pharmacological metabolic diversity.5,6 The development of effective precision medicine tests cannot, therefore, be fully realized without representative inclusion of samples from subjects in underrepresented minority (URM) populations in sample collection, processing, and analysis. Several factors such as inadequate recruitment programs and mistrust of the medical community by URM subjects has led to racial and ethnic disparities in large-scale genomics studies,7 with as much as 86% of participants characterized as being of European descent.SolutionsWe highlight two avenues to improving the representation of URM in major sample collections, genetic tests, and the databases upon which they are based. The first relies on the global biobanking community and its funding institutions to prioritize programs that focus on increased recruitment of participants in URM communities for collection and sharing of biomaterials. Because most large biobanks are located in the United States and Europe and, therefore, skewed to biomaterials and data from subjects of European ancestry, international collaborations are critical.There are an increasing number of such initiatives, including the Nigerian 100K Genome Project,8 the NIMH-funded GENetics of SchizophRenia in Pakistan study and the International HundredK+ Cohorts Consortium (IHCC). In addition, integration with agencies such as NIH and its biobanking facilities will enable easier access to these technologies and allow providers, clinical trial partners, and patients who are hesitant to donate biospecimens a path forward.The second centers on the development and implementation of advanced analytical approaches such as PRS assessment based on alleles with broad population coverage. As an illustration of how biobanking solutions can facilitate this process, consider the example of the development and validation of a next-generation sequencing assay for breast cancer risk. The Sampled Breast Cancer Test uses PRS assessment (lifetime risk of development breast cancer) for detection of early- and late-stage disease to meet critical public health needs and ensure translational medicine. Metadata (e.g., race, age, family history, and clinical information) collected from each individual is required to generate a patients absolute and relative risk over a 5 years and lifetime period.These data are combined in a meta-analysis with molecular data on a set of genes consisting of 34 genes associated with breast cancer, 77 single nucleotide variants (SNV) representative of the Caucasian population risk,9 and 8 SNVs representative of increased risk in African American and Hispanic populations.10 This combinatorial approach allows for enhanced representation of URM in an important cancer susceptibility test and is a model for providing testing options that have traditionally been available only to those of particular ethnic groups or who can afford testing outside biobank facilities.ConclusionIn redressing historical inequities in ethnic representation, modern biobanks, utilizing processes compliant with regulatory requirements such as those of the College of American Pathologists, Clinical Laboratory Improvement Amendments (CLIA) and careful specimen chain of custody documentation, are uniquely positioned to support this and many aspects of clinical research, including clinical trial management, discovery, and development of assays and therapies. In addition, strict governance over protected health information, adherence to validated standard operating procedures for processing genomic data, and a storage infrastructure designed to safeguard specimen integrity are of paramount importance.The equal importance of increased outreach programs, often coordinated globally by major biobanks, cannot be overstated. As an example of one such program, the Sampled Clinical Laboratory located in Oakdale Minnesota collaborated with state public health officials to offer free SARS-CoV-2 testing for URM. Combining storage, management, and analytical approaches in one facility, particularly one that places emphasis on public outreach and communication of the importance of testing, will be crucial for success.AcknowledgmentsThe authors also wish to thank the scientists at Genetic Technologies for the development of the breast cancer risk algorithm, and support during validation and implementation.Authors' ContributionsConceptualization, methodology, visualization, and writing (original draft, review, and editing) by M.S. Conceptualization, resources, and supervision by R.G. Conceptualization, methodology, visualization, resources, supervision, and writing (original draft, review, and editing) by S.A.N.References1. De Souza YG, Greenspan JS. Biobanking past, present and future: Responsibilities and benefits. AIDS 2013;27(3):303–312; doi: 10.1097/QAD.0b013e32835c1244 Crossref, Medline, Google Scholar2. Coppola L, Cianflone A, Grimaldi AM, et al. Biobanking in health care: Evolution and future directions. J Transl Med 2019;17(1):172; doi: 10.1186/s12967-019-1922-3 Crossref, Medline, Google Scholar3. Kim P, Milliken EL. Minority participation in biobanks: An essential key to progress. Methods Mol Biol 2019;1897:43–50; doi: 10.1007/978-1-4939-8935-5_5 Crossref, Medline, Google Scholar4. Lehner T, Senthil G, Addington AM. Convergence of advances in genomics, team science, and repositories as drivers of progress in psychiatric genomics. Biol Psychiatry 2015;77(1):6–14; doi: 10.1016/j.biopsych.2014.01.003 Crossref, Medline, Google Scholar5. Kamiza AB, Toure SM, Vujkovic M, et al. Transferability of genetic risk scores in African populations. Nat Med 2022;28(6):1163–1166; doi: 10.1038/s41591-022-01835-x Crossref, Medline, Google Scholar6. Ju D, Hui D, Hammond DA, et al. Importance of including non-European populations in large human genetic studies to enhance precision medicine. Annu Rev Biomed Data Sci 2022 [published online ahead of print, 2022 May 16]; doi: 10.1146/annurev-biodatasci-122220-112550 Crossref, Google Scholar7. Fatumo S, Chikowore T, Choudhury A, et al. A roadmap to increase diversity in genomic studies. Nat Med 2022;28(2):243–250; doi: 10.1038/s41591-021-01672-4 Crossref, Medline, Google Scholar8. Fatumo S, Yakubu A, Oyedele O, et al. Promoting the genomic revolution in Africa through the Nigerian 100K Genome Project. Nat Genet 2022;54(5):531–536; doi: 10.1038/s41588-022-01071-6 Crossref, Medline, Google Scholar9. Dite GS, MacInnis RJ, Bickerstaffe A, et al. Breast cancer risk prediction using clinical models and 77 independent risk-associated SNPs for women aged under 50 years: Australian breast cancer family registry. Cancer Epidemiol Biomarkers Prev 2016;25(2):359–365; doi: 10.1158/1055-9965 Crossref, Medline, Google Scholar10. Allman R, Dite GS, Hopper JL, et al. SNPs and breast cancer risk prediction for African American and Hispanic women. Breast Cancer Res Treat 2015;154(3):583–589; doi: 10.1007/s10549-015-3641-7 Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 20Issue 5Oct 2022 InformationCopyright 2022, Mary Ann Liebert, Inc., publishersTo cite this article:Michael Sheldon, Robin Grimwood, and Shareef A. Nahas.Letter to the Editor: Biobanks and International Initiatives Are Playing a Critical Role in Redressing Historic Inadequacies in Biosample and Data Access from Underrepresented Minority Populations.Biopreservation and Biobanking.Oct 2022.465-466.http://doi.org/10.1089/bio.2022.0059Published in Volume: 20 Issue 5: October 17, 2022PDF download

The Centers for Disease Control and Prevention contracted with laboratories to sequence the SARS-CoV-2 genome from positive samples across the United States to enable public health officials to investigate the impact of variants on disease severity as well as the effectiveness of vaccines and treatment. Herein we present the initial results correlating RT-PCR quality control metrics with sample collection and sequencing methods from full SARS-CoV-2 viral genomic sequencing of 24,441 positive patient samples between April and June 2021. RT-PCR confirmed (N Gene Ct value < 30) positive patient samples, with nucleic acid extracted from saliva, nasopharyngeal and oropharyngeal swabs were selected for viral whole genome SARS-CoV-2 sequencing. Sequencing was performed using Illumina COVIDSeq™ protocol on either the NextSeq550 or NovaSeq6000 systems. Informatic variant calling, and lineage analysis were performed using DRAGEN COVID Lineage applications on Illumina’s Basespace cloud analytical system. All sequence data and variant calls were uploaded to NCBI and GISAID. An association was observed between higher sequencing coverage, quality, and samples with a lower Ct value, with < 27 being optimal, across both sequencing platforms and sample collection methods. Both nasopharyngeal swabs and saliva samples were found to be optimal samples of choice for SARS-CoV-2 surveillance sequencing studies, both in terms of strain identification and sequencing depth of coverage, with NovaSeq 6000 providing higher coverage than the NextSeq 550. The most frequent variants identified were the B.1.617.2 Delta (India) and P.1 Gamma (Brazil) variants in the samples sequenced between April 2021 and June 2021. At the time of submission, the most common variant > 99% of positives sequenced was Omicron. These initial analyses highlight the importance of sequencing platform, sample collection methods, and RT-PCR Ct values in guiding surveillance efforts. These surveillance studies evaluating genetic changes of SARS-CoV-2 have been identified as critical by the CDC that can affect many aspects of public health including transmission, disease severity, diagnostics, therapeutics, and vaccines.

The past decade has witnessed an extremely rapid increase in the number of newly established stem cell lines. However, due to the lack of a standardized format, data exchange among stem cell line resources has been challenging, and no system can search all stem cell lines across resources worldwide. To solve this problem, we have developed the Integrated Collection of Stem Cell Bank data (ICSCB) (http://icscb.stemcellinformatics.org/), the largest database search portal for stem cell line information, based on the standardized data items and terms of the MIACARM framework. Currently, ICSCB can retrieve >16,000 cell lines from four major data resources in Europe, Japan, and the United States. ICSCB is automatically updated to provide the latest cell line information, and its integrative search helps users collect cell line information for over 1,000 diseases, including many rare diseases worldwide, which has been a formidable task, thereby distinguishing itself from other database search portals.

As the coronavirus disease 2019 (COVID-19) pandemic sweeps across the world, the availability of viral transport medium (VTM) has become severely limited, contributing to delays in diagnosis and rationing of diagnostic testing. Given that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA has demonstrated stability, we posited that phosphate-buffered saline (PBS) may be a viable transport medium, as an alternative to VTM, for clinical real-time quantitative PCR (qPCR) testing. The intra-individual reliability and interindividual reliability of SARS-CoV-2 qPCR were assessed in clinical endotracheal secretion samples transported in VTM or PBS to evaluate the stability of the qPCR signal for three viral targets (N gene, ORF1ab, and S gene) when samples were stored in these media at room temperature for up to 18 hours. We report that the use of PBS as a transport medium allows high intra-individual and interindividual reliability, maintains viral stability, and compares with VTM in the detection of the three SARS-CoV-2 genes through 18 hours of storage. This study establishes PBS as a clinically useful medium that can be readily deployed for transporting and short-term preservation of specimens containing SARS-CoV-2. Use of PBS as a transport medium has the potential to increase testing capacity for SARS-CoV-2, aiding more widespread screening and early diagnosis of COVID-19.

This report summarizes the recent activity of the International Stem Cell Banking Initiative held at Harvard Stem Cell Institute, Boston, MA, USA, on June 18, 2017. In this meeting, we aimed to find consensus on ongoing issues of quality control (QC), safety, and efficacy of human pluripotent stem cell banks and their derivative cell therapy products for the global harmonization. In particular, assays for the QC testing such as pluripotency assays test and general QC testing criteria were intensively discussed. Moreover, the recent activities of global stem cell banking centers and the regulatory bodies were briefly summarized to provide an overview on global developments and issues. Stem Cells 2019;37:1130–1135

Unambiguous cell line authentication is essential to avoid loss of association between data and cells. The risk for loss of references increases with the rapidity that new human pluripotent stem cell (hPSC) lines are generated, exchanged, and implemented. Ideally, a single name should be used as a generally applied reference for each cell line to access and unify cell-related information across publications, cell banks, cell registries, and databases and to ensure scientific reproducibility. We discuss the needs and requirements for such a unique identifier and implement a standard nomenclature for hPSCs, which can be automatically generated and registered by the human pluripotent stem cell registry (hPSCreg). To avoid ambiguities in PSC-line referencing, we strongly urge publishers to demand registration and use of the standard name when publishing research based on hPSC lines.

Use of clinical-grade human induced pluripotent stem cell (iPSC) lines as a starting material for the generation of cellular therapeutics requires demonstration of comparability of lines derived from different individuals and in different facilities. This requires agreement on the critical quality attributes of such lines and the assays that should be used. Working from established recommendations and guidance from the International Stem Cell Banking Initiative for human embryonic stem cell banking, and concentrating on those issues more relevant to iPSCs, a series of consensus workshops has made initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade, which are outlined in this report. Continued evolution of this field will likely lead to revision of these guidelines on a regular basis.

The discovery that human primary cells such as nucleated blood cells or cultured skin fibroblasts can be reprogrammed into induced pluripotent stem cells (hiPSC) has ushered in a new era for research on the genetic etiology of neuropsychiatric disorders. Such hiPSC can be differentiated into several types of neurons, which may provide a primitive model for studying cellular variation in neuronal function due to underlying genetic variants causing the disorder. It is critical that source cells for possible reprogramming and their derived hiPSC be banked in an accredited facility capable of proper quality assurance that includes a genetic profile for future authentication of secondary biomaterials (e.g., differentiated cellular derivatives). Nucleated blood cells are more easily obtained compared to skin fibroblasts and can be cryopreserved for many years before they are reprogrammed to hiPSC. However, to enable all possible future uses of biosamples, some of which may not yet even be contemplated, researchers and biobanks must obtain clear informed consent from subjects for broad use of their biosamples in research.

Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment of patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite for such applications but have only recently been established. Whether such cGMP lines are capable of hepatic differentiation is not known. To address this knowledge gap, we examined the proficiency of three recently derived cGMP lines (two hiPSC and one hESC) to differentiate into hepatocytes and their suitability for therapy. hPSC-Heps generated using a chemically defined four-step hepatic differentiation protocol uniformly demonstrated highly reproducible phenotypes and functionality. Seeding into a 3D PEG-DA fabricated inverted colloid crystal (ICC) scaffold converted these immature progenitors into more advanced hepatic tissue structures. Hepatic constructs could also be successfully encapsulated into the immune-privileged material alginate. This is the first report we are aware of demonstrating cGMP-compliant hPSCs can generate cells with advanced hepatic function potentially suitable for future therapeutic applications.

Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment of patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite for such applications but have only recently been established. Whether such cGMP lines are capable of hepatic differentiation is not known. To address this knowledge gap, we examined the proficiency of three recently derived cGMP lines (two hiPSC and one hESC) to differentiate into hepatocytes and their suitability for therapy. hPSC-Heps generated using a chemically defined four-step hepatic differentiation protocol uniformly demonstrated highly reproducible phenotypes and functionality. Seeding into a 3D poly(ethylene glycol)-diacrylate fabricated inverted colloid crystal scaffold converted these immature progenitors into more advanced hepatic tissue structures. Hepatic constructs could also be successfully encapsulated into the immune-privileged material alginate and remained viable as well as functional upon transplantation into immune competent mice. This is the first report we are aware of demonstrating cGMP-compliant hPSCs can generate cells with advanced hepatic function potentially suitable for future therapeutic applications. Stem Cells Translational Medicine 2019;8:124&14

This article summarizes the recent activity of the International Stem Cell Banking Initiative (ISCBI) held at the California Institute for Regenerative Medicine (CIRM) in California (June 26, 2016) and the Korean National Institutes for Health in Korea (October 19–20, 2016). Through the workshops, ISCBI is endeavoring to support a new paradigm for human medicine using pluripotent stem cells (hPSC) for cell therapies. Priority considerations for ISCBI include ensuring the safety and efficacy of a final cell therapy product and quality assured source materials, such as stem cells and primary donor cells. To these ends, ISCBI aims to promote global harmonization on quality and safety control of stem cells for research and the development of starting materials for cell therapies, with regular workshops involving hPSC banking centers, biologists, and regulatory bodies. Here, we provide a brief overview of two such recent activities, with summaries of key issues raised. Stem Cells Translational Medicine 2017;6:1956–1962

Advances in stem cell research have triggered scores of studies in regenerative medicine in a large number of institutions and companies around the world. However, reproducibility and data exchange among laboratories or cell banks are constrained by the lack of a standardized format for experiments. To enhance information flow in stem cell and derivative cell research, here we propose a minimum information standard to describe cellular assay data to facilitate practical regenerative medicine. Based on the existing Minimum Information About a Cellular Assay, we developed Minimum Information About a Cellular Assay for Regenerative Medicine (MIACARM), which allows for the description of advanced cellular experiments with defined taxonomy of human cell types. By using controlled terms, such as ontologies, MIACARM will provide a platform for cellular assay data exchange among cell banks or registries that have been established at more than 20 sites in the world.

Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 x 10(-) (4); 2-back, P = 1.39 x 10(-) (5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.

Background: Copy number variation on chromosome 15q11.2 (BP1-BP2) causes a deletion of CYFIP1, NIPA1, NIPA2 and TUBGCP5. Furthermore, it also affects brain structure and elevates the risk for several neurodevelopmental disorders that are associated with dendritic spine abnormalities. In rodents, altered cyfip1 expression changes dendritic spine morphology, motivating analyses of human neuronal cells derived from induced pluripotent stem cells (iPSCs; iPSC-neurons). Methods: iPSCs were generated from a mother and her offspring, both carrying the 15q11.2 (BP1-BP2) deletion, and a non-deletion control. Gene expression in the deletion region was estimated using quantitative real-time PCR assays. Neural progenitor cells (NPCs) and iPSC-neurons were characterized using immunocytochemistry. Results:CYFIP1, NIPA1, NIPA2 and TUBGCP5 gene expression was lower in iPSCs, NPCs and iPSC-neurons from the mother and her offspring in relation to control cells. CYFIP1 and PSD-95 protein levels were lower in iPSC-neurons derived from the copy number variant-bearing individuals using Western blot analysis. Ten weeks after differentiation, iPSC-neurons appeared to show dendritic spines, and qualitative analysis suggested that dendritic morphology was altered in 15q11.2-deletion subjects compared with control cells. Conclusions: The 15q11.2 (BP1-BP2) deletion is associated with a reduced expression of four genes in iPSC-derived neuronal cells; it may also be associated with altered iPSC-neuron dendritic morphology.

A major challenge in robotics is the ability to learn, from novel experiences, new behavior that is useful for achieving new goals and skills. Autonomous systems must be able to learn solely through the environment, thus ruling out a priori task knowledge, tuning, extensive training, or other forms of pre-programming. Learning must also be cumulative and incremental, as complex skills are built on top of primitive skills. Additionally, it must be driven by intrinsic motivation because formative experience is gained through autonomous activity, even in the absence of extrinsic goals or tasks. This paper presents an approach to these issues through robotic implementations inspired by the learning behavior of human infants. We describe an approach to developmental learning and present results from a demonstration of longitudinal development on an iCub humanoid robot. The results cover the rapid emergence of staged behavior, the role of constraints in development, the effect of bootstrapping between stages, and the use of a schema memory of experiential fragments in learning new skills. The context is a longitudinal experiment in which the robot advanced from uncontrolled motor babbling to skilled hand/eye integrated reaching and basic manipulation of objects. This approach offers promise for further fast and effective sensory-motor learning techniques for robotic learning.

There is growing recognition of the potential value of human induced pluripotent stem cells (hiPSC) for understanding disease and identifying drugs targets. This has been reflected in the establishment of multiple large-scale hiPSC initiatives worldwide. Representatives of these met recently at a workshop supported by the Welcome Trust in the UK and in a focus session at the 2014 ISSCR annual meeting in Vancouver. The purpose was to discuss strategies for making thousands of hiPSC lines widely available with as few restrictions as possible while retaining financial viability and donor privacy. The outcome of these discussions is described here.

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 3 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.