: Endogenous dermal stem cells (DSCs) reside in the adult hair follicle mesenchyme and can be isolated and grown in vitro as self-renewing colonies called skin-derived precursors (SKPs). Following ...transplantation into skin, SKPs can generate new dermis and reconstitute the dermal papilla and connective tissue sheath, suggesting they could have important therapeutic value for the treatment of skin disease (alopecia) or injury. Controlled cell culture processes must be developed to efficiently and safely generate sufficient stem cell numbers for clinical use. Compared with static culture, stirred-suspension bioreactors generated fivefold greater expansion of viable SKPs. SKPs from each condition were able to repopulate the dermal stem cell niche within established hair follicles. Both conditions were also capable of inducing de novo hair follicle formation and exhibited bipotency, reconstituting the dermal papilla and connective tissue sheath, although the efficiency was significantly reduced in bioreactor-expanded SKPs compared with static conditions. We conclude that automated bioreactor processing could be used to efficiently generate large numbers of autologous DSCs while maintaining their inherent regenerative function.
Recent work has demonstrated the existence of dermal stem cells (DSCs) that reside within adult hair follicles and might serve as a renewable source of inductive dermal cells to regenerate dermis or rejuvenate dermal papilla to restore follicle growth. In order to realize this clinical potential, it is essential that in vitro bioprocesses are developed to rapidly and safely expand DSCs. The present study showed that computer-controlled stirred suspension bioreactors can be used to efficiently and safely generate large numbers of DSCs while maintaining their phenotype and at least some of their inherent inductive function. This builds on a foundation of research supporting automated bioprocessing as an effective approach for culturing stem cells. The bioprocess described has important implications for ex vivo expansion of inductive dermal stem/progenitor cells that could be used for composite skin engineering strategies, drug screens related to hair growth, and the regeneration of dermis within severe skin wounds.
Thesis (M.C.P.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 2010.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 57-63).
This research ...is designed to examine the potential mismatch between neighborhood stabilization plans and resources with the unique needs of smaller post-industrial cities in the United States. Given the distinct demographic, economic and physical characteristics of smaller, postindustrial cities, I rely on Lawrence, MA as a case study to examine housing tenure and homeownership strategies-particularly within the current economic climate and foreclosure crisis. The primary goal of this thesis is to combine first-hand observations with quantitative analysis in order to address the question: is increasing homeownership an appropriate and feasible goal for cities with high concentrations of poverty and a prevalence of multi-family housing stock? If not, what alternative housing strategies and policy approaches are needed in order to stabilize distressed neighborhoods and improve quality of living? Consistent with Lawrence's growing challenge with foreclosures and research on low-income homeownership, the findings of this thesis demonstrate that focusing on homeownership strategies in Lawrence and other smaller, post-industrial cities may not lead to more stable neighborhoods. To the contrary, due to localized concentrations of poverty and multi-family housing stock, homeownership strategies serve to put low-income households at greater risk while neglecting the needs of the most distressed neighborhoods altogether.
(cont.) Further, this thesis examines alternative forms of housing tenure, arguing that neighborhood stability does not accompany increased homeownership, per se, but rather, is facilitated by healthy residential environments where residents choose to stay. Thus, this thesis recommends that Lawrence pursue housing strategies that seek to improve residential stability in distressed neighborhoods, while simultaneously developing a diversity of tenure options for individual households.
by Holly Jo Sparks.
M.C.P.
Insecticide resistance has been and continues to be a significant problem for invertebrate pest control. As such, effective insecticide resistance management (IRM) is critical to maintain the ...efficacy of current and future insecticides. A technical group within CropLife International, the Insecticide Resistance Action Committee (IRAC) was established 35 years ago (1984) as an international association of crop protection companies that today spans the globe. IRAC's focus is on preserving the long-term utility of insect, mite, and most recently nematode control products through effective resistance management to promote sustainable agriculture and improved public health. A central task of IRAC has been the continual development and documentation of the Mode of Action (MoA) Classification scheme, which serves as an important tool for implementing IRM strategies focused on compound rotation / alternations. Updates to the IRAC MoA Classification scheme provide the latest information on the MoA of current and new insecticides and acaricides, and now includes information on biologics and nematicides. Details for these new changes and additions are reviewed herein.
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•Insecticide resistance continues to expand - >600 species resistant to ≥1 insecticide.•Since 1984 IRAC has been industry's response to long term resistance management.•IRAC - information on insecticide modes of action (MoA) – continually updated.•MoA classification provides the basis for effective resistance management.•Biologics, biopesticides and nematicides now included in the MoA classification.
The impact of the 2019 coronavirus pandemic (COVID-19) in the United States is unprecedented, with unknown implications for the autism community. We surveyed 3502 parents/caregivers of individuals ...with an autism spectrum disorder (ASD) enrolled in Simons Powering Autism Research for Knowledge (SPARK) and found that most individuals with ASD experienced significant, ongoing disruptions to therapies. While some services were adapted to telehealth format, most participants were not receiving such services at follow-up, and those who were reported minimal benefit. Children under age five had the most severely disrupted services and lowest reported benefit of telehealth adaptation. Caregivers also reported worsening ASD symptoms and moderate family distress. Strategies to support the ASD community should be immediately developed and implemented.
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic ...potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC50 values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)–cell growth, increases IFN-γ production, and reduces conversion to regulatory T (Treg)–like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86high DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.
A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously ...unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of “drug-like” space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. ...However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. In addition, we identified variants that are possibly associated with ASD in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.1 provides statistical support for 26 ASD risk genes. While most of these genes are already known ASD risk genes,
has the strongest statistical support and reaches genome-wide significance as a risk gene for ASD (
-value = 2.3e-06). Future studies leveraging the thousands of individuals with ASD who have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate ASD research that incorporates genetic etiology.
Historical industrial activities have resulted in soil contamination at sites globally. Many of these sites are located along coastlines, making them vulnerable to hydrologic and biogeochemical ...alterations due to climate change and sea-level rise. However, the impact of hydrologic dynamics on contaminant mobility in tidal environments has not been well studied. Here, we collected data from pressure transducers in wells, multi-level redox sensors, and porewater samplers at an As-contaminated site adjacent to a freshwater tidal channel. Results indicate that sharp redox gradients exist and that redox conditions vary on tidal to seasonal timescales due to sub-daily water level fluctuations in the channel and seasonal groundwater–surface water interactions. The As and Fe2+ concentrations decreased during seasonal periods of net discharge to the channel. The seasonal changes were greater than tidal variations in both Eh and As concentrations, indicating that impacts of the seasonal mechanism are stronger than those of sub-daily water table fluctuations. A conceptual model describing tidal and seasonal hydro-biogeochemical coupling is presented. These findings have broad implications for understanding the impacts of sea-level rise on the mobility of natural and anthropogenic coastal solutes.
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