Enhancing Meniscus Repair through Biomaterial Design

The knee meniscus is prone to damage, which leads to pain and inhibits mobility in the joint long term. Due to the minimal vascularity, low cellularity and large mechanical forces imparted on the meniscus with normal use, endogenous repair is limited. Resection of the damaged region of the tissue (meniscectomy) remains the most common treatment for a torn meniscus, but this procedure results in cartilage degradation and other adverse changes in the knee joint. Given the prevalence of meniscus damage, there is thus a pressing need for novel approaches to meniscus repair. To address this issue, this thesis developed in vitro techniques to analyze the time-varying properties of the aging meniscus, and to address how the meniscus repair interface might be modulated through the use of growth factors. Further, electrospun scaffolds were designed to replicate key architectures of the native tissue while providing controlled release of biologic factors. Our findings demonstrated marked biological, biochemical, and structural changes in meniscus with age. These findings pointed to key factors that could play a role in meniscus integration (ie repair) capacity after meniscus injury; these factors were evaluated in the context of meniscus repair using a mechanical in vitro model. To address situations where substantial meniscus tissue would be removed, we tested the integration capacity of electrospun scaffolds with native tissue and maturation of these scaffolds in response to growth factor regimens, as well as how changes in scaffold characteristics (i.e. porosity and organization) and cell seeding techniques influence integration potential. Finally, we developed novel techniques to deliver bioactive growth factors and other molecules from components of electrospun scaffolds, including entrapped microspheres, with distinct release profiles. These novel, bioactive scaffolds were utilized to orchestrate complex regenerative signaling cascades from the scaffolds, with demonstration of efficacy via improved vascular density in an in vivo model. This work provides new approaches for the treatment of meniscus tears using novel electrospun materials, bringing us one step closer to new clinical options for meniscus repair

Transitioning from manual to stirred-tank bioreactor manufacturing of IDCT, An allogeneiccell therapy to treat lumbar degenerative disc disease

DiscGenics is a clinical stage regenerative medicine company focused on developing cell therapies that alleviate pain and restore function in patients with degenerative disc disease (DDD), a major cause of low back pain which is a driver of disability worldwide. The Company’s lead product candidate, IDCT, is a homologous, allogeneic, off-the-shelf, injectable cell therapy under investigational use in the US (ClinicalTrials.gov Identifier: NCT03347708). The manufacturing process for IDCT involves isolating cells from donated intervertebral disc tissue and expanding them into proprietary progenitor cells known as discogenic cells. For preclinical and early clinical testing, cell production was a manual process which relied on pooling individual flasks to achieve the desired lot size. For successful scale-up and commercial production, DiscGenics seeks to modify the IDCT manufacturing process to utilize one large, single vessel per lot, while also applying bioprocess controls and more robust analytical methods to ensure consistent and optimal production of drug product. Once these changes are implemented, the product critical quality attributes (CQAs) must be maintained. DiscGenics has engaged GE Healthcare (GEHC) and the Centre for Commercialization of Regenerative Medicine (CCRM) for assay, media, and process development at the Centre for Advanced Therapeutic Cell Technologies (CATCT) in Toronto, ON., Canada. In partnership with the Federal Economic Development Agency for Southern Ontario (FedDev Ontario), CATCT accelerates the development, industrialization, and adoption of cell manufacturing technologies to improve patient access to cell and gene therapies. In this collaborative project, discogenic cells were generated in traditional static culture using CellStacks (Corning), in PBS-MINI bioreactor systems (PBS Biotech), and in stirred-tank reactors (STRs) (Eppendorf), which was led by the GEHC/CCRM team. Parameters such as cell viability, fold growth, and identity via flow cytometry were compared across modalities. For the STRs, multiple control parameters were evaluated to improve cell growth and assess successful maintenance of a consistent environment for cell quality. In this study, we found that we are able to maintain CQAs between the production modalities, with cell growth being significantly improved in the STR platform. In the STRs, in-process measurements of metabolites aligned with cell growth found using a custom sampling method. Increased cell expansion was facilitated by modified agitation, inoculation, and perfusion feeding strategies. Additionally, the process-controlled STRs provide non-invasive, continuous process data monitoring which allow for development of specified control ranges of manufacturing parameters. The quality by design (QbD) approach taken for the STR process development and improvement has allowed an increase in the lot size, process knowledge, and data-driven process definition. This presentation describes the approach and benefits of transitioning from a manual process to a suspension-based, process-controlled, stirred-tank reactor to produce allogeneic cell therapies

AGN-Host Galaxy Connection: Morphology and Colours of X-ray Selected AGN at z < 2

The connection between AGN and their host galaxies has been widely studied over recent years, showing it to be of great importance for providing answers to some fundamental questions related with AGN fueling mechanisms, their formation and evolution. Using X-ray and one of the deepest broad-band optical data sets, we studied morphology and colours in relationship with X-ray properties for sources at redshifts z < 2.0, using a sample of 262 AGN in the Subaru/XMM-Newton Deep Survey (SXDS). Morphological classification was obtained using the galSVM code, one of the new methods useful especially when dealing with high-redshift sources and low-resolution data. Colour-magnitude diagrams were studied in relationship with redshift, morphology, X-ray obscuration, and X-ray-to-optical flux ratio. Finally, the significance of different regions was analysed on colour-magnitude diagrams, relating the observed properties of AGN populations with some models of their formation and evolution.Comment: 24 pages, 19 figures, accepted for publication in Astronomy&Astrophysic

Performance of the test Mini-Mental State Examination y elderly without cognitive impairment

Objetivo: Establecer datos normativos de la prueba MMSE estratificada por edad y escolaridad en personas adultas mayores costarricenses sin deterioro cognitivo, identificar los ítems que presentan mayor dificultad en relación con esas dos variables y brindar recomendaciones desde la gerontología de evaluación e interpretación. Metodología: Se estudió las puntuaciones del MMSE de 649 sujetos entre 60 y 108 años con una calificación global de 0 en la escala de clasificación de demencia. Resultados: se creó una tabla por edad y escolaridad con datos normativos. Los ítems que presentan mayor dificultad en relación con la edad son: escritura, construcción visoespacial, orientación; en cuanto a la escolaridad son construcción visoespacial, escritura y atención. Conclusiones: se considera el primer reporte sobre datos normativos de MMSE, se propone alternativas sobre los ajustes durante la aplicación, se brinda recomendaciones para guiar un mejor tamizaje de la función cognitiva y se proponen elementos de comparaciónObjective: to establish the normative data of the test stratified by age and scholarship in Costa Ricans elderly adults without cognitive impairment, in the MMSE test, identify the items associated in relation to these two variables and provide recommendations from gerontology of evaluation and interpretation. Methodology: It is studied the MMSE results of 649 subjects between 60 and 108 years with a global score of 0 on the Dementia Classification Scale. Results: we created a table with normative data, by age and schooling. The items that are presented with greater frequency present in relation to age: writing, visual-spatial construction, orientation, while with schooling they are: visual-spatial construction, writing and attention. Conclusions: the first report on the normative data of the MMSE is considered, the alternatives on the adjustments for the effects of the application are proposed, a recommendation is offered for a better screening of the cognitive function and the elements of comparison has given.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)UCR::Vicerrectoría de Investigación::Sistema de Estudios de Posgrado::Ciencias Sociales::Maestría Profesional en Psicología Clínica y de la Salu

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

OTELO Survey: Deep BVRI broadband photometry of the Groth strip. II Properties of X-ray Emitters

The Groth field is one of the sky regions that will be targeted by the OTELO (OSIRIS Tunable Filter Emission Line Object) survey in the optical 820 nm and 920 nm atmospheric windows. This field has been observed by AEGIS (All-wavelength Extended Groth strip International Survey) covering the full spectral range, from X-rays to radio waves. Chandra X-ray data with total exposure time of 200ksec are analyzed and combined with optical broadband data of the Groth field in order to study a set of structural parameters of the X-ray emitters and its relation with X-ray properties. We processed the raw, public X-ray data using the Chandra Interactive Analysis of Observations and determined and analyzed different structural parameters in order to produce a morphological classification of X-ray sources. Finally, we analyzed the angular clustering of these sources using 2-point correlation functions. We present a catalog of 340 X-ray emitters with optical counterpart. We obtained the number counts and compared them with AEGIS data. Objects have been classified by nuclear type using a diagnostic diagram relating X-ray-to-optical ratio (X/O) to hardness ratio (HR). Also, we combined structural parameters with other X-ray and optical properties, and found for the first time an anticorrelation between the X/O ratio and the Abraham concentration index which might suggest that early type galaxies have lower Eddington rates than those of late type galaxies. A significant positive angular clustering was obtained from a preliminary analysis of 4 subsamples of the X-ray sources catalog. The clustering signal of the opticaly extended counterparts is similar to that of strongly clustered populations like red and very red galaxies, suggesting that the environment plays an important role in AGN phenomena.Comment: 23 pages, 19 Postscript figure

HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma

<div><p>Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.</p></div

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

status: publishe