Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of the cell cycle.

Loss of long-term hematopoietic stem cell (LT-HSC) function ex vivo hampers the success of clinical protocols that rely on culture. However, the kinetics and mechanisms through which this occurs remain incompletely characterized. In this study, through time-resolved single-cell RNA sequencing, matched in vivo functional analysis, and the use of a reversible in vitro system of early G1 arrest, we defined the sequence of transcriptional and functional events that occur during the first ex vivo division of human LT-HSCs.

Characterization of a novel pesticide transporter and P-glycoprotein orthologues in .

Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach their targets. Specifically, the role of ABC transporters in pesticide absorption and excretion is poorly understood, especially compared to the detailed knowledge about mammalian systems. Here, we present a comprehensive characterization of pesticide transporters in the model insect .

The Landscape of Early Clinical Gene Therapies outside of Oncology.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.

Inhibition of Mitochondrial Complex I Impairs Release of α-Galactosidase by Jurkat Cells.

Fabry disease (FD) is caused by mutations in the gene that encodes lysosomal α-galactosidase-A (α-gal-A). A number of pathogenic mechanisms have been proposed and these include loss of mitochondrial respiratory chain activity. For FD, gene therapy is beginning to be applied as a treatment.

Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice.

Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs.

Surgical regenerative treatment of peri-implantitis.

Data sourcesOvid, Medline, PubMed, Embase and Dentistry and Oral Sciences Source. Databases were searched from January 2006 to March 2016 and restricted to English, manual searches were also carried out in the relevant major journals.Study selectionTwo reviewers independently selected studies.

Targeted genome editing restores T cell differentiation in a humanized X-SCID pluripotent stem cell disease model.

The generation of T cells from pluripotent stem cells (PSCs) is attractive for investigating T cell development and validating genome editing strategies in vitro. X-linked severe combined immunodeficiency (X-SCID) is an immune disorder caused by mutations in the IL2RG gene and characterised by the absence of T and NK cells in patients. IL2RG encodes the common gamma chain, which is part of several interleukin receptors, including IL-2 and IL-7 receptors.

Enhancement of mouse hematopoietic stem/progenitor cell function via transient gene delivery using integration-deficient lentiviral vectors.

Integration-deficient lentiviruses (IdLVs) deliver genes effectively to tissues but are lost rapidly from dividing cells. This property can be harnessed to express transgenes transiently to manipulate cell biology. Here, we demonstrate the utility of short-term gene expression to improve functional potency of hematopoietic stem and progenitor cells (HSPCs) during transplantation by delivering HOXB4 and Angptl3 using IdLVs to enhance the engraftment of HSPCs.

Erratum: Lentiviral vectors can be used for full-length dystrophin gene therapy.

This corrects the article DOI: 10.1038/srep44775.

Lentiviral vectors can be used for full-length dystrophin gene therapy.

Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors.

Lentiviral vectors can be used for full-length dystrophin gene therapy.

Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors.

Vps33b is crucial for structural and functional hepatocyte polarity.

Background & Aims: In the normal liver, hepatocytes form a uniquely polarised cell layer that enables movement of solutes from sinusoidal blood to canalicular bile. Whilst several cholestatic liver diseases with defects of hepatocyte polarity have been identified, the molecular mechanisms of pathogenesis are not well defined. One example is arthrogryposis, renal dysfunction and cholestasis syndrome, which in most patients is caused by VPS33B mutations.

BMI-1 extends proliferative potential of human bronchial epithelial cells while retaining their mucociliary differentiation capacity.

Air-liquid interface (ALI) culture of primary airway epithelial cells enables mucociliary differentiation providing an in vitro model of the human airway, but their proliferative potential is limited. To extend proliferation, these cells were previously transduced with viral oncogenes or mouse + , but the resultant cell lines did not undergo mucociliary differentiation. We hypothesized that use of human alone would increase the proliferative potential of bronchial epithelial cells while retaining their mucociliary differentiation potential.

Minicircle DNA Provides Enhanced and Prolonged Transgene Expression Following Airway Gene Transfer.

Gene therapy for cystic fibrosis using non-viral, plasmid-based formulations has been the subject of intensive research for over two decades but a clinically viable product has yet to materialise in large part due to inefficient transgene expression. Minicircle DNA give enhanced and more persistent transgene expression compared to plasmid DNA in a number of organ systems but has not been assessed in the lung. In this study we compared minicircle DNA with plasmid DNA in transfections of airway epithelial cells.

In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters.

The application of transcription factor activated luciferase reporter cassettes in vitro is widespread but potential for in vivo application has not yet been realized. Bioluminescence imaging enables non-invasive tracking of gene expression in transfected tissues of living rodents. However the mature immune response limits luciferase expression when delivered in adulthood.

Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates.

Several acute monogenic diseases affect multiple body systems, causing death in childhood. The development of novel therapies for such conditions is challenging. However, improvements in gene delivery technology mean that gene therapy has the potential to treat such disorders.

Evidence for contribution of CD4+ CD25+ regulatory T cells in maintaining immune tolerance to human factor IX following perinatal adenovirus vector delivery.

Following fetal or neonatal gene transfer in mice and other species immune tolerance of the transgenic protein is frequently observed; however the underlying mechanisms remain largely undefined. In this study fetal and neonatal BALB/c mice received adenovirus vector to deliver human factor IX (hFIX) cDNA. The long-term tolerance of hFIX was robust in the face of immune challenge with hFIX protein and adjuvant but was eliminated by simultaneous administration of anti-CD25+ antibody.

Site- and allele-specific polycomb dysregulation in T-cell leukaemia.

T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1(+) cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms.

A comparison of WISC-IV and SB-5 intelligence scores in adolescents with autism spectrum disorder.

In autism spectrum disorders, results of cognitive testing inform clinical care, theories of neurodevelopment, and research design. The Wechsler Intelligence Scale for Children and the Stanford-Binet are commonly used in autism spectrum disorder evaluations and scores from these tests have been shown to be highly correlated in typically developing populations. However, they have not been compared in individuals with autism spectrum disorder, whose core symptoms can make testing challenging, potentially compromising test reliability.

Impulsivity predicts time to reach euthymia in adults with bipolar disorder.

Objectives: Specific demographic and illness characteristics have been identified as predictors of overall morbidity and treatment course among individuals with bipolar disorder. However, the role of specific cognitive limitations on disease severity and treatment response is unclear. The present study evaluated whether impulsiveness during acute mania was a significant predictor of achieving euthymia within one year following psychiatric hospitalization.

Superior longitudinal fasciculus and language functioning in healthy aging.

Structural deterioration of brain tissue in older adults is thought to be responsible for the majority of age-related cognitive decline. Disruption of widespread cortical networks due to a loss of axonal integrity may also play an important role. Research examining correlations between structural change and functional decline has focused heavily on working memory, processing speed, and executive processes while other aspects of cognition, such as language functioning, have received less attention.

Assimilation approach to measuring organizational change from pre- to post-intervention.

Aim: To present a conceptual and measurement strategy that allows to objectively, sensitively evaluate intervention progress based on data of participants' perceptions of presenting problems.

Methods: We used as an example an organization development intervention at a United States Veterans Affairs medical center. Within a year, the intervention addressed the hospital's initially serious problems and multiple stakeholders (employees, management, union representatives) reported satisfaction with progress made.

Behavior and adaptive functioning in adolescents with Down syndrome: specifying targets for intervention.

Background: Research suggests that adolescents with Down syndrome experience increased behavior problems as compared to age matched peers; however, few studies have examined how these problems relate to adaptive functioning. The primary aim of this study was to characterize behavior in a sample of adolescents with Down syndrome using two widely-used caregiver reports: the Behavioral Assessment System for Children, 2 Edition (BASC-2) and Child Behavioral Checklist (CBCL). The clinical utility of the BASC-2 as a measure of behavior and adaptive functioning in adolescents with Down syndrome was also examined.