Ex Vivo Gene Therapy Using Patient iPSC-Derived NSCs Reverses Pathology in the Brain of a Homologous Mouse Model

SummaryNeural stem cell (NSC) transplantation is a promising strategy for delivering therapeutic proteins in the brain. We evaluated a complete process of ex vivo gene therapy using human induced pluripotent stem cell (iPSC)-derived NSC transplants in a well-characterized mouse model of a human lysosomal storage disease, Sly disease. Human Sly disease fibroblasts were reprogrammed into iPSCs, differentiated into a stable and expandable population of NSCs, genetically corrected with a transposon vector, and assessed for engraftment in NOD/SCID mice. Following neonatal intraventricular transplantation, the NSCs engraft along the rostrocaudal axis of the CNS primarily within white matter tracts and survive for at least 4 months. Genetically corrected iPSC-NSCs transplanted post-symptomatically into the striatum of adult Sly disease mice reversed neuropathology in a zone surrounding the grafts, while control mock-corrected grafts did not. The results demonstrate the potential for ex vivo gene therapy in the brain using human NSCs from autologous, non-neural tissues

Coal Miners and Third-Party Politics in Illinois, 1880-1924: A Statistical Analysis of Voting Behavior

http://deepblue.lib.umich.edu/bitstream/2027.42/50857/1/76.pd

Contextuality without incompatibility

The existence of incompatible measurements is often believed to be a feature of quantum theory which signals its inconsistency with any classical worldview. To prove the failure of classicality in the sense of Kochen-Specker noncontextuality, one does indeed require sets of incompatible measurements. However, a more broadly applicable and more permissive notion of classicality is the existence of a generalized-noncontextual ontological model. In particular, this notion can imply constraints on the representation of outcomes even within a single nonprojective measurement. We leverage this fact to demonstrate that measurement incompatibility is neither necessary nor sufficient for proofs of the failure of generalized noncontextuality. Furthermore, we show that every proof of the failure of generalized noncontextuality in a prepare-measure scenario can be converted into a proof of the failure of generalized noncontextuality in a corresponding scenario with no incompatible measurements

Vocal tract resonances in singing: variation with laryngeal mechanism for male operatic singers in chest and falsetto registers

International audienceSeven male operatic singers sang the same notes and vowels in their chest and their falsetto registers, covering the overlap frequency range where two main laryngeal mechanisms can be identified by means of electroglottography: M1 in chest register and M2 in falsetto register. Glottal contact quotients determined using electroglottography were typically lower by 0.27 in M2 than in M1. Vocal tract resonance frequencies were measured by using broadband excitation at the lips and found to be typically lower in M2 than in M1 sung at the same pitch and vowel; R1 typically by 65 Hz and R2 by 90 Hz. These shifts in tract resonances were only weakly correlated with the changes in the contact quotient or laryngeal height that were measured simultaneously. There was considerable variability in the resonance tuning strategies used by the singers, and no evidence of a uniform systematic tuning strategy used by all singers. A simple model estimates that the shifts in resonance frequencies are consistent with the effective glottal area in falsetto register (M2) being 60%-70% of its value in chest register (M1)

Economic evaluation of a clinical protocol for diagnosing emergency patients with suspected pulmonary embolism

BACKGROUND: The objective of this paper is to estimate the amount of cost-savings to the Australian health care system from implementing an evidence-based clinical protocol for diagnosing emergency patients with suspected pulmonary embolism (PE) at the Emergency department of a Victorian public hospital with 50,000 presentations in 2001–2002. METHODS: A cost-minimisation study used the data collected in a controlled clinical trial of a clinical protocol for diagnosing patients with suspected PE. Thenumber and type of diagnostic tests in a historic cohort of 185 randomly selected patients, who presented to the emergency department with suspectedPE during an eight month period prior to the clinical trial (January 2002 -August 2002) were compared with the number and type of diagnostic tests in745 patients, who presented to the emergency department with suspected PE from November 2002 to August 2003. Current Medicare fees per test were usedas unit costs to calculate the mean aggregated cost of diagnostic investigation per patient in both study groups. A t-test was used to estimate the statistical significance of the difference in the cost of resources used for diagnosing PE in the control and in the intervention group. RESULTS: The trial demonstrated that diagnosing PE using an evidence-based clinical protocol was as effective as the existing clinical practice. The clinical protocol offers the advantage of reducing the use of diagnostic imaging, resulting in an average cost savings of at least $59.30 per patient. CONCLUSION: Extrapolating the observed cost-savings of$59.30 per patient to the wholeof Australia could potentially result in annual savings between $3.1 million to$3.7 million

Transcriptional response to lactic acid stress in the hybrid yeast Zygosaccharomyces parabailii

Lactic acid has a wide range of applications starting from its undissociated form, and its production using cell factories requires stress-tolerant microbial hosts. The interspecies hybrid yeast Zygosaccharomyces parabailii has great potential to be exploited as a novel host for lactic acid production, due to high organic acid tolerance at low pH, and a fermentative metabolism with a fast growth rate. Here we used RNA-seq to analyze Z. parabailii's transcriptional response to lactic acid added exogenously, and we explore the biological mechanisms involved in tolerance. Z. parabailii contains two homeologous copies of most genes. Under lactic acid stress, the two genes in each homeolog pair tend to diverge in expression to a significantly greater extent than in control conditions, indicating that stress tolerance is facilitated by interactions between the two gene sets in the hybrid. Lactic acid induces downregulation of genes related to cell wall and plasma membrane functions, possibly altering the rate of diffusion of lactic acid into cells. Genes related to iron transport and redox processes were upregulated, suggesting an important role for respiratory functions and oxidative stress defense. We found differences in the expression profiles of genes putatively regulated by Haa1 and Aft1/2, previously described as lactic acid-responsive in Saccharomyces cerevisiae. Furthermore, formate dehydrogenase (FDH) genes form a lactic acid-responsive gene family that has been specifically amplified in Z. parabailii as compared to other closely related species. Our study provides a useful starting point for the engineering of Z. parabailii as a host for lactic acid production.Importance Hybrid yeasts are important in biotechnology because of their tolerance to harsh industrial conditions. The molecular mechanisms of tolerance can be studied by analyzing differential gene expression in conditions of interest, and relating gene expression patterns to protein functions. However, hybrid organisms present a challenge to the standard use of mRNA sequencing (RNA-seq) to study transcriptional responses to stress, because their genomes contain two similar copies of almost every gene. Here we used stringent mapping methods and a high-quality genome sequence to study the transcriptional response to lactic acid stress in Zygosaccharomyces parabailii ATCC60483, a natural interspecies hybrid yeast that contains two complete subgenomes that are approximately 7% divergent in sequence. Beyond the insights we gained into lactic acid tolerance in this study, the methods we developed will be broadly applicable to other yeast hybrid strains

Recovery and Utilization of Deceased Donor Kidneys from Small Pediatric Donors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72146/1/j.1600-6143.2006.01353.x.pd

Masked Bobwhite Recovery: The Need for a Multifaceted Approach

Masked bobwhite (Colinus virginianus ridgwayi) is a critically endangered quail historically found in the Sonoran grasslands of southern Arizona, USA and Sonora, Mexico. Native populations of masked bobwhite may already be extinct in the wild, but captive populations exist in the United States at G. M. Sutton Avian Research Center (Oklahoma, USA), Buenos Aires National Wildlife Refuge (Arizona, USA), and various zoos. The 47,000-hectare Buenos Aires National Wildlife Refuge, located in south-central Arizona, was established primarily for reintroduction of this bird. Recovery efforts within the refuge boundary in the 1980s and 1990s were initially successful but suffered debilitating setbacks that ultimately resulted in failure. Substantial releases were suspended in 2005. Improved habitat restoration efforts and promising conditioning and release techniques led to the belief that reintroductions could again be attempted and successful. In 2016–2017 plans were developed to increase captive propagation and reinitiate release efforts. Releases began in 2018. Over-winter survival of birds released in 2018–2019 was encouraging, and reproduction of wild birds was documented in 2019. An existing base of wild birds established from these releases could help masked bobwhite populations recover in the state. Habitat restoration, better methods of rearing, release, and conditioning, and improved production from captive facilities also inspire hope that a full recovery of the species in Arizona is possible

The Clp1/Cdc14 phosphatase contributes to the robustness of cytokinesis by association with anillin-related Mid1

Cdc14 phosphatases antagonize cyclin-dependent kinase–directed phosphorylation events and are involved in several facets of cell cycle control. We investigate the role of the fission yeast Cdc14 homologue Clp1/Flp1 in cytokinesis. We find that Clp1/Flp1 is tethered at the contractile ring (CR) through its association with anillin-related Mid1. Fluorescent recovery after photobleaching analyses indicate that Mid1, unlike other tested CR components, is anchored at the cell midzone, and this physical property is likely to account for its scaffolding role. By generating a mutation in mid1 that selectively disrupts Clp1/Flp1 tethering, we reveal the specific functional consequences of Clp1/Flp1 activity at the CR, including dephosphorylation of the essential CR component Cdc15, reductions in CR protein mobility, and CR resistance to mild perturbation. Our evidence indicates that Clp1/Flp1 must interact with the Mid1 scaffold to ensure the fidelity of Schizosaccharomyces pombe cytokinesis