To predict the odor quality of an odorant mixture, the interaction between odorants must be taken into account. Previously, an experiment in which mice discriminated between odorant mixtures ...identified a selective adaptation mechanism in the olfactory system. This paper proposes an olfactory model for odorant mixtures that can account for selective adaptation in terms of neural activity. The proposed model uses the spatial activity pattern of the mitral layer obtained from model simulations to predict the perceptual similarity between odors. Measured glomerular activity patterns are used as input to the model. The neural interaction between mitral cells and granular cells is then simulated, and a dissimilarity index between odors is defined using the activity patterns of the mitral layer. An odor set composed of three odorants is used to test the ability of the model. Simulations are performed based on the odor discrimination experiment on mice. As a result, we observe that part of the neural activity in the glomerular layer is enhanced in the mitral layer, whereas another part is suppressed. We find that the dissimilarity index strongly correlates with the odor discrimination rate of mice: r = 0.88 (p = 0.019). We conclude that our model has the ability to predict the perceptual similarity of odorant mixtures. In addition, the model also accounts for selective adaptation via the odor discrimination rate, and the enhancement and inhibition in the mitral layer may be related to this selective adaptation.
Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene ...of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.
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•Homozygous mutant zebrafish with deletion of the kcnq1 gene (kcnq1del/del) was created.•The ventricular APD90 of kcnq1del/del embryos was significantly longer.•It was shortened by co-injecting human KCNQ1 cRNA with human KCNE1 cRNA.•Injecting cRNA of pathogenic KCNQ1 variants did not rescue the prolonged APD90.•Injecting cRNA of KCNQ1 VUS, R451Q identified from a patient with LQTS did not rescue the prolonged APD90 either.
Loss of
, found in several types of lymphoma, induces excessive CXCL13 secretion through RNA dysregulation contributing to body weight loss and early death in lymphoma model mice. Follicular lymphoma ...(FL) is associated with overexpressed BCL-2 and other genetic aberrations, including 6q-. We identified a novel gene on 6q25, "
(
)," from a transformed FL. TFL regulates several cytokines
mRNA degradation, which has been suggested to underlie resolving inflammation. Fluorescence
hybridization revealed a deletion of
occurred in 13.6% of various B-cell lymphoma samples. We developed VavP-
transgenic, TFL deficit mice (
-Tg/
) to seek how TFL affects disease progression in this lymphoma model. While
-Tg mice developed lymphadenopathy and died around 50 weeks,
-Tg/
mice lost body weight around 30 weeks and died about 20 weeks earlier than
-Tg mice. Furthermore, we found a unique B220
IgM
cell population in the bone marrow of
-Tg mice. cDNA array in this population revealed that Cxcl13 mRNA in
-Tg/
mice expressed significantly higher than
-Tg mice. In addition, bone marrow extracellular fluid and serum showed an extremely high Cxcl13 concentration in
-Tg/
mice. Among bone marrow cells, the B220
IgM
fraction was the main producer of Cxcl13 in culture. A reporter assay demonstrated TFL regulates CXCL-13
induction of 3'UTR mRNA degradation in B lineage cells. These data suggest Tfl regulates Cxcl13 in B220
IgM
cells in the bone marrow, and a very high concentration of serum Cxcl13 arising from these cells may contribute to early death in lymphoma-bearing mice. Since several reports have suggested the association of CXCL13 expression with lymphoma, these findings provide new insights into cytokine regulation
TFL in lymphoma.
The direct 4-alkoxylation of 4-iodo-1
-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium
-butoxide (2 ...equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.
This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors.
Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to ...estimate the recommended dose. Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80-160 mg) was administered for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLT). We also conducted biomarker research using paired samples from repeated blood collections and tumor biopsies.
A total of 44 patients with colorectal cancer (
= 29), gastric cancer (
= 8), sarcoma (
= 5), non-small cell lung cancer (
= 1), and melanoma (
= 1) were enrolled. Eleven patients had previously received immune-checkpoint inhibitors. No DLTs were observed at all dose levels, and TAS-116 160 mg was determined as recommended dose. The common grade 3 or worse treatment-related adverse events included liver transaminase increased (7%), creatinine increased (5%), and platelet count decreased (5%). Objective tumor response was observed in 6 patients, including 4 microsatellite stable (MSS) colorectal cancers, 1 microsatellite instability-high colorectal cancer, and 1 leiomyosarcoma, resulting in an objective response rate of 16% in MSS colorectal cancer without prior immune-checkpoint inhibitors. Biomarker analysis showed that TAS-116 inhibited the activity of regulatory T cells in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes.
TAS-116 160 mg plus nivolumab had manageable safety profiles and antitumor activity, especially for MSS colorectal cancer patients.
Store operated calcium (Ca2+) entry (SOCE) is the process whereby endoplasmic reticulum (ER) Ca2+ store depletion causes Orai1-composed Ca2+ channels on the plasma membrane (PM) to open, mediating a ...rise in cytosolic Ca2+ levels. Stromal interaction molecules (STIMs) are the proteins that directly sense ER Ca2+ content and gate Orai1 channels due to store depletion. The trigger for STIM activation is Ca2+ unbinding from the ER lumen-oriented domains, which consist of a nonconserved amino (N) terminal region and EF-hand and sterile α motif (SAM) domains (EF–SAM), highly conserved from humans to Caenorhabditis elegans. Solution NMR structures of the human EF–SAM domains have been determined at high Ca2+ concentrations; however, no direct structural view of the Ca2+ binding mode has been elucidated. Further, no atomic resolution data currently exists on EF–SAM at low Ca2+ levels. Here, we determined the X-ray crystal structure of the C. elegans STIM luminal domain, revealing that EF–SAM binds a single Ca2+ ion with pentagonal bipyramidal geometry and an ancillary α-helix formed by the N-terminal region acts as a brace to stabilize EF–SAM. Using solution NMR, we observed EF-hand domain unfolding and a conformational exchange between folded and unfolded states involving the ancillary α-helix and the canonical EF-hand in low Ca2+. Remarkably, we also detected an α-helix (+Ca2+) to β-strand (−Ca2+) transition at the terminal SAM domain α-helix. Collectively, our analyses indicate that one canonically bound Ca2+ ion is sufficient to stabilize the quiescent luminal domain structure, precluding unfolding, conformational exchange, and secondary structure transformation.
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•Caenorhabditiselegans and human STIMs activate SOCE after sensing decreases in ER Ca2+.•A crystal structure revealed pentagonal bipyramidal coordination of a single Ca2+.•An ancillary α-helix formed in the variable N-terminal region stabilizes EF–SAM.•Ca2+ depletion causes unfolding and conformational exchange of the EF-hand.•The terminal α-helix transitions to β-strand after Ca2+ depletion of EF–SAM.
Background: In recent years, various biomarkers of ulcerative colitis (UC) have emerged; however, few studies have simultaneously examined the utility of multiple biomarkers for monitoring disease ...activity. Additionally, serum leucine-rich alpha-2 glycoprotein (LRG), a new biomarker, may show a blunt response to anti-TNF antibody therapy. This prospective study explored effective biomarkers that could monitor disease activity changes in patients with UC. In addition, we examined the effect of anti-TNF antibody therapy on changes in LRG. Methods: Blood and stool samples were collected twice from patients with UC: at baseline and at least 8 weeks later. Changes in serum LRG, interleukin (IL)-6, prealbumin (pre-Alb), high-sensitivity C-reactive protein (hs-CRP), CRP, and fecal calprotectin (FC) were measured and correlated with changes in disease activity. The relationship between anti-TNF antibody therapy and LRG levels was also examined in patients with the same disease activity. Results: Forty-eight patients with UC (96 samples) were analyzed. ΔLRG and ΔIL-6 correlated strongly with the change in the partial Mayo (pMayo) score between the two time points (ΔpMayo) (r = 0.686, 0.635, respectively). In contrast, FC and IL-6 were particularly accurate predictors of clinical remission, and their area under the curves (AUCs) were significantly higher than that of CRP (AUC: 0.81, 0.76 vs. 0.50; p = 0.001, 0.005). No association was found between the administration of anti-TNF antibody preparations and the LRG values. Conclusions: Correlations were found between changes in UC disease activity and LRG, IL-6, pre-Alb, hs-CRP, CRP, and FC. LRG reflects disease activity during anti-TNF antibody therapy.
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