PTPσ inhibitors promote hematopoietic stem cell regeneration.

Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration

TSCOT + Thymic Epithelial Cell-Mediated Sensitive CD4 Tolerance by Direct Presentation

Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII). When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR) transgenic reactive against LacZ (BgII), there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45- and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells

Source Contributions to Carbon Monoxide Concentrations During KORUS‐AQ Based on CAM‐chem Model Applications

We investigate regional sources contributing to CO during the Korea United States Air Quality (KORUS-AQ) campaign conducted over Korea (1 May to 10 June 2016) using 17 tagged CO simulations from the Community Atmosphere Model with chemistry (CAM-chem). The simulations use three spatial resolutions, three anthropogenic emission inventories, two meteorological fields, and nine emission scenarios. These simulations are evaluated against measurements from the DC-8 aircraft and Measurements Of Pollution In The Troposphere (MOPITT). Results show that simulations using bottom-up emissions are consistently lower (bias: -34 to -39%) and poorer performing (Taylor skill: 0.38-0.61) than simulations using alternative anthropogenic emissions (bias: -6 to -33%; Taylor skill: 0.48-0.86), particularly for enhanced Asian CO and volatile organic compound (VOC) emission scenarios, suggesting underestimation in modeled CO background and emissions in the region. The ranges of source contributions to modeled CO along DC-8 aircraft from Korea and southern (90 degrees E to 123 degrees E, 20 degrees N to 29 degrees N), middle (90 degrees E to 123 degrees E, 29 degrees N to 38.5 degrees N), and northern (90 degrees E to 131.5 degrees E, 38.5 degrees N to 45 degrees N) East Asia (EA) are 6-13%, similar to 5%, 16-28%, and 9-18%, respectively. CO emissions from middle and northern EA can reach Korea via transport within the boundary layer, whereas those from southern EA are transported to Korea mainly through the free troposphere. Emission contributions from middle EA dominate during continental outflow events (29-51%), while Korean emissions play an overall more important role for ground sites (up to 25-49%) and plumes within the boundary layer (up to 25-44%) in Korea. Finally, comparisons with four other source contribution approaches (FLEXPART 9.1 back trajectory calculations driven by Weather Research and Forecasting (WRF) WRF inert tracer, China signature VOCs, and CO to CO2 enhancement ratios) show general consistency with CAM-chem.National Science Foundation (NSF); U.S. Department of Energy (DOE); National Aeronautics and Space Administration (NASA) Earth Observing System (EOS) Program; NCAR Advanced Study Program Postdoctoral Fellowship; Environment Research and Technology Development Fund of the Ministry of the Environment, Japan [2-1505, 2-1803]; National Science Foundation; NASA [NNX16AD96G, NNX16AE16G, NNX17AG39G]6 month embargo; published online: 1 February 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Small anisotropy of the lower critical field and s±s_\pm-wave two-gap feature in single crystal LiFeAs

The in- and out-of-plane lower critical fields and magnetic penetration depths for LiFeAs were examined. The anisotropy ratio $\gamma_{H_{c1}}(0)$ is smaller than the expected theoretical value, and increased slightly with increasing temperature from 0.6$T_c$ to $T_c$. This small degree of anisotropy was numerically confirmed by considering electron correlation effect. The temperature dependence of the penetration depths followed a power law($\sim$$T^n$) below 0.3$T_c$, with $n$$>$3.5 for both $\lambda_{ab}$ and $\lambda_c$. Based on theoretical studies of iron-based superconductors, these results suggest that the superconductivity of LiFeAs can be represented by an extended $s_\pm$-wave due to weak impurity scattering effect. And the magnitudes of the two gaps were also evaluted by fitting the superfluid density for both the in- and out-of-plane to the two-gap model. The estimated values for the two gaps are consistent with the results of angle resolved photoemission spectroscopy and specific heat experiments.Comment: 10 pages, 5 figure

Bojungikgitang and banhabaekchulchonmatang in adult patients with tinnitus, a randomized, double-blind, three-arm, placebo-controlled trial - study protocol

<p>Abstract</p> <p>Background</p> <p>Tinnitus is the perception of hearing a sound for which there is no external acoustic source. It is often associated with sudden, temporary hearing loss and has a clear impact on a patient's quality of life. Despite numerous trials, there are no treatments that can be considered well established in terms of providing replicable long-term tinnitus reduction. Complementary and alternative medical approaches have been employed to relieve symptoms of tinnitus. Bojungikgitang and banhabaekchulchonmatang are among the most strongly preferred and widely used herbal medicines for tinnitus in Korea, as they cause very few serious adverse effects.</p> <p>We aim to establish basic clinical efficacy and safety data for bojungikgitang and banhabaekchulchonmatang, which are approved as herbal medications by the Korea Food and Drug Administration in adult patients with tinnitus.</p> <p>Methods/Design</p> <p>This study was a randomised, double-blind, placebo-controlled trial with three parallel arms (bojungikgitang, banhabaekchulchonmatang, and a placebo). Participants included in the study met the following criteria: typical conditions of intermittent or continuous tinnitus, for more than three months, with involuntary perceptions of the concept of a sound in the absence of an external source. Participants received bojungikgitang, banhabaekchulchonmatang, or a placebo-drug for eight weeks. The total duration of each arm was eleven weeks. Each participant was examined for signs and symptoms of tinnitus before and after taking medication. Post-treatment follow-up was performed two weeks after the final administration of medication.</p> <p>Discussion</p> <p>This trial provided evidence for the efficacy and safety of bojungikgitang and banhabaekchulchonmatang in adult patients with tinnitus. The primary outcome measure was the Tinnitus Handicap Inventory, an assessment used to identify difficulties that may be experienced due to tinnitus. The secondary measures were included an Acoustic Examination and the Visual Analogue Scale. We employed the Euro-Qol 5-Dimension and the Health Utilities Index Mark 3, a health-related quality of life questionnaire. Safety was assessed by complete blood cell count, erythrocyte sedimentation rate, blood chemistry, urine analysis, PA chest film, brain computed tomography, otologic examination, and vital signs.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN23691284</p

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders

Background: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. Methods: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. Results: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10−16, Wilcoxon test) with a module of genes significantly associated with ASD. Conclusions: Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism

Natural Products in the Prevention of Metabolic Diseases: Lessons Learned from the 20th KAST Frontier Scientists Workshop

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases

Dietary intakes in people with irritable bowel syndrome

<p>Abstract</p> <p>Background</p> <p>Irritable Bowel Syndrome (IBS) is a functional bowel disorder characterised by episodes of abdominal pain associated with altered bowel habits. Many IBS sufferers believe that diet may play a role in triggering these episodes and may avoid certain foods. However relatively few studies have undertaken a dietary assessment in IBS sufferers to examine the wider impact of the condition upon diet.</p> <p>Methods</p> <p>104 individuals with IBS were recruited and asked to complete a validated food frequency questionnaire (FFQ). The data were analysed against Dietary Reference Values for food energy and nutrients for the United Kingdom and observed intakes for the general population and for differences between IBS subtypes and the UK population.</p> <p>Results</p> <p>The data show that the dietary intakes of this population of IBS sufferers met the UK Dietary Reference Values. The average energy intake of the population exceeded the Estimated Average Requirements of the UK population and the balance of macronutrients was favourable. Intakes of selected micronutrients significantly exceeded the reference nutrient intakes. There were no differences between IBS subtypes.</p> <p>Conclusions</p> <p>The IBS subpopulation appear to have an adequate and balanced macronutrient intake with no evidence of inadequate micronutrient intake.</p

Multicenter retrospective analysis of 581 patients with primary intestinal non-hodgkin lymphoma from the Consortium for Improving Survival of Lymphoma (CISL)

<p>Abstract</p> <p>Background</p> <p>Primary intestinal non-Hodgkin lymphoma (NHL) is a heterogeneous disease with regard to anatomic and histologic distribution. Thus, analyses focusing on primary intestinal NHL with large number of patients are warranted.</p> <p>Methods</p> <p>We retrospectively analyzed 581 patients from 16 hospitals in Korea for primary intestinal NHL in this retrospective analysis. We compared clinical features and treatment outcomes according to the anatomic site of involvement and histologic subtypes.</p> <p>Results</p> <p>B-cell lymphoma (n = 504, 86.7%) was more frequent than T-cell lymphoma (n = 77, 13.3%). Diffuse large B-cell lymphoma (DLBCL) was the most common subtype (n = 386, 66.4%), and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) was the second most common subtype (n = 61, 10.5%). B-cell lymphoma mainly presented as localized disease (Lugano stage I/II) while T-cell lymphomas involved multiple intestinal sites. Thus, T-cell lymphoma had more unfavourable characteristics such as advanced stage at diagnosis, and the 5-year overall survival (OS) rate was significantly lower than B-cell lymphoma (28% versus 71%, P < 0.001). B symptoms were relatively uncommon (20.7%), and bone marrow invasion was a rare event (7.4%). The ileocecal region was the most commonly involved site (39.8%), followed by the small (27.9%) and large intestines (21.5%). Patients underwent surgery showed better OS than patients did not (5-year OS rate 77% versus 57%, P < 0.001). However, this beneficial effect of surgery was only statistically significant in patients with B-cell lymphomas (P < 0.001) not in T-cell lymphomas (P = 0.460). The comparison of survival based on the anatomic site of involvement showed that ileocecal regions had a better 5-year overall survival rate (72%) than other sites in consistent with that ileocecal region had higher proportion of patients with DLBCL who underwent surgery. Age > 60 years, performance status ≥ 2, elevated serum lactate dehydrogenase, Lugano stage IV, presence of B symptoms, and T-cell phenotype were independent prognostic factors for survival.</p> <p>Conclusions</p> <p>The survival of patients with ileocecal region involvement was better than that of patients with involvement at other sites, which might be related to histologic distribution, the proportion of tumor stage, and need for surgical resection.</p