Contact-dependent cell communication has the potential to generate elaborate cell patterns, and this occurs in vivo. We used the Delta-Notch signaling system, consisting of the ligand Delta and the ...receptor Notch, to construct a positive feedback loop between adjacent cells to generate a propagating signal in cultured cells. To amplify the responses of Notch to Delta, we created a cell-cell positive feedback loop using an engineered transcriptional cascade and a Notch positive regulator, Lunatic fringe. We used mathematical modeling to determine the appropriate amount of amplification to enable the induction of Delta to propagate from one cell to its neighboring cells, which generated bistability within the local cell populations and resulted in discrete groups of cells that were either positive or negative for Delta. These results demonstrate the sufficiency of the cell-cell positive feedback loop to generate signal propagation and cell population-level bistability. This study represents a step in engineering more elaborate cell patterns in mammalian cells.
•Variability in fiber dispersions causes different flexural responses of SFRC beams.•Flexural prediction of SFRC beams via an FE method and X-ray imaging is proposed.•Post-cracking tensile strengths ...are deduced by a calibration method via FE analysis.•Variability in fiber dispersions are considered in the FE model using X-ray images.•Proposed method provides good agreement with experimental results.
Several studies have revealed that the fiber distribution is usually not uniform since many parameters during the fabrication process cause different fiber distributions and orientations within individual steel fiber-reinforced concrete (SFRC) members. This phenomenon results in large scattering in the post-cracking flexural responses among the material characterization specimens. Consequently, when estimating the flexural behavior of SFRC beams, conflicting results are often obtained using only a single constitutive stress-crack opening laws to characterize the material behavior in tension without considering the different fiber distributions and orientations. In this paper, a novel integrated approach is established to estimate the flexural behavior of SFRC beams using both a finite element (FE) method and X-ray imaging. In the prediction approach, a parameter that can be determined using the measured fiber distribution properties from an X-ray image is proposed to consider the variability of the fiber dispersion in each SFRC member. A method is presented for deducing the constitutive stress-crack opening laws using an FE analysis and the proposed parameter from X-ray images. In the numerical FE method, the variability of the fiber dispersion of the individual SFRC beams is determined by identifying the stress-strain relation in each mesh based on the proposed parameter from the X-ray images. The FE method provides better prediction results of the loading capacity for the SFRC beams.
We previously examined the utility of rituximab‐bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to 2 cycles of the R‐CHOP chemotherapy regimen. The ...aim of this study was to identify molecular biomarkers that can predict prognosis in RB‐treated patients in the context of the prospective cohort. We first analyzed the mutational status of 410 genes in diagnostic tumor specimens by target capture and Sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however none was predictive for progression‐free survival (PFS) in the RB‐treated patients (n = 34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or the immune response showed that expression levels of CD8+ T‐cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within the 24‐mo (POD24) group (n = 8) than in the no POD24 group (n = 31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS using principal component analysis, which dichotomized the RB‐treated patients into immune IIShigh (n = 19) and IISlow (n = 20) groups. The 3‐y PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% 95% CI: 27.1‐69.2% vs. 84.2% 95% CI: 58.7‐94.6%, P = .0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r = 0.460, P = .00355). These results suggest that the T‐cell‐associated immune markers could be useful to predict prognosis in RB‐treated FL patients. (UMIN:000 013 795, jRCT:051 180 181)
The expression levels of T‐cell‐associated immune markers were significantly lower in RB‐treated patients with POD24 than those without POD24. Furthermore, FL patients were classified into infiltration low and high scores based on the expression of T‐cell‐associated genes, which was useful to predict the prognosis of RB‐treated FL patients.
Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, ...the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting. KGB-1 and AP-1 are involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhances protein ubiquitination and reduces protein carbonylation. Our results thus identify a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity, partly through regulating proteostasis.
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► JNK/AP-1 signaling and DAF-16 play a central role in fasting-stimulus responses ► AP-1 and DAF-16 mediate induction of fasting genes that play key roles in life-span extension ► The SCF E3 ubiquitin ligase complex is a target of fasting-responsive signaling ► Fasting enhances protein ubiquitination, causing a reduction in protein carbonylation
Dietary restriction is the most effective environmental manipulation for extending life span in many species. However, the precise mechanisms by which dietary restriction extends life span are still unclear. Honjoh, Nishida, and colleagues have now identified a fasting-responsive signaling network that senses and transduces the fasting stimulus to induce the transcriptional changes that cause life-span extension. Fasting-induced upregulation of the components of SCF E3 ubiquitin ligase complex via this signaling network enhances protein degradation and plays an important role in fasting-induced longevity.
Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response ...to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β
microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system.
We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti‐desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and ...seborrheic and interstitial blistering. A high level of anti‐Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti‐Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey‐Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio‐exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti‐Dsg1 antibody‐positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti‐Dsg1 antibody‐positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.
We investigated the texture and the shape change in the equiatomic TiPd alloy, and discussed the relationship between the shape change and the atomic movements associated with martensitic ...transformation. Thermomechanical analyzer tests indicate that the direction of the shape change was different between the 0° and 90° samples, cutting out parallel and perpendicular to the hearth side of button ingot, respectively. In the 0° sample, shrinking and expansion were observed during the reverse and forward martensitic transformations, respectively, whereas the opposite tendency was confirmed in the 90° sample compared to the 0° sample. During the isobaric test, the martensitic variants were oriented to a (010) plane with compressive loading, and the B2 parent phase crystals also became coarse. There is a close relationship between the shape change due to the crystal orientation by the isobaric test and the shear-shuffling direction due to martensitic transformation.
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