Essentials The role of C-type lectin-like receptor-2 (CLEC-2) in cancer progression is unclear. CLEC-2-depleted mouse model is generated by using a rat anti-mouse CLEC-2 monoclonal antibody. CLEC-2 ...depletion inhibits hematogenous tumor metastasis of podoplanin-expressing B16F10 cells. CLEC-2 depletion prolongs cancer survival by suppressing thrombosis and inflammation.
Background C-type lectin-like receptor 2 (CLEC-2) is a platelet activation receptor of sialoglycoprotein podoplanin, which is expressed on the surface of certain types of tumor cells. CLEC-2-podoplanin interactions facilitate hematogenous tumor metastasis. However, direct evidence of the role of CLEC-2 in hematogenous metastasis and cancer progression is lacking. Objective and methods We generated immunological CLEC-2-depleted mice by using anti-mouse CLEC-2 monoclonal antibody 2A2B10 and investigated whether CLEC-2 promoted hematogenous tumor metastasis and tumor growth and exacerbated the prognosis of mice bearing podoplanin-expressing B16F10 melanoma cells. Results Our results showed that hematogenous metastasis was significantly inhibited in CLEC-2-depleted mice. B16F10 cells co-cultured with wild-type platelets, but not with CLEC-2-deficient platelets, showed increased proliferation. However, B16F10 cell proliferation was not inhibited in CLEC-2-depleted mice. Histological analysis showed that thrombus formation in tumor vessels was significantly inhibited and functional vessel density was significantly increased in CLEC-2-depleted mice. These data suggest that CLEC-2 deficiency may inhibit thrombus formation in tumor vessels and increase the density of functional vessels, thus improving oxygen and nutrient supply to tumors, indirectly promoting tumor proliferation. Furthermore, the overall survival of CLEC-2-depleted mice was significantly prolonged, which may be due to the suppression of thrombus formation in the lungs and subsequent inhibition of systemic inflammation and cachexia. Conclusions These data provide a rationale for the targeted inhibition of CLEC-2 as a new strategy for preventing hematogenous tumor metastasis and for inhibiting cancer-related thromboembolism.
This paper proposes the use of the minimum entropy deconvolution (MED) technique to enhance the ability of the existing autoregressive (AR) model based filtering technique to detect localised faults ...in gears. The AR filter technique has been proven superior for detecting localised gear tooth faults than the traditionally used residual analysis technique. The AR filter technique is based on subtracting a regular gearmesh signal, as represented by the toothmesh harmonics and immediately adjacent sidebands, from the spectrum of a signal from one gear obtained by the synchronous signal averaging technique (SSAT). The existing AR filter technique performs well but is based on autocorrelation measurements and is thus insensitive to phase relationships which can be used to differentiate noise from impulses. The MED technique can make a use of the phase information by means of the higher-order statistical (HOS) characteristics of the signal, in particular the kurtosis, to enhance the ability to detect emerging gear tooth faults. The experimental results presented in this paper validate the superior performance of the combined AR and MED filtering techniques in detecting spalls and tooth fillet cracks in gears.
The study of the pearl oyster Pinctada fucata is key to increasing our understanding of the molecular mechanisms involved in pearl biosynthesis and biology of bivalve molluscs. We sequenced ∼1150-Mb ...genome at ∼40-fold coverage using the Roche 454 GS-FLX and Illumina GAIIx sequencers. The sequences were assembled into contigs with N50 = 1.6 kb (total contig assembly reached to 1024 Mb) and scaffolds with N50 = 14.5 kb. The pearl oyster genome is AT-rich, with a GC content of 34%. DNA transposons, retrotransposons, and tandem repeat elements occupied 0.4, 1.5, and 7.9% of the genome, respectively (a total of 9.8%). Version 1.0 of the P. fucata draft genome contains 23 257 complete gene models, 70% of which are supported by the corresponding expressed sequence tags. The genes include those reported to have an association with bio-mineralization. Genes encoding transcription factors and signal transduction molecules are present in numbers comparable with genomes of other metazoans. Genome-wide molecular phylogeny suggests that the lophotrochozoan represents a distinct clade from ecdysozoans. Our draft genome of the pearl oyster thus provides a platform for the identification of selection markers and genes for calcification, knowledge of which will be important in the pearl industry.
Spectral kurtosis (SK) represents a valuable tool for extracting transients buried in noise, which makes it very powerful for the diagnostics of rolling element bearings. However, a high value of SK ...requires that the individual transients are separated, which in turn means that if their repetition rate is high their damping must be sufficiently high that each dies away before the appearance of the next. This paper presents an algorithm for enhancing the surveillance capability of SK by using the minimum entropy deconvolution (MED) technique. The MED technique effectively deconvolves the effect of the transmission path and clarifies the impulses, even where they are not separated in the original signal. The paper illustrates these issues by analysing signals taken from a high-speed test rig, which contained a bearing with a spalled inner race. The results show that the use of the MED technique dramatically sharpens the pulses originating from the impacts of the balls with the spall and increases the kurtosis values to a level that reflects the severity of the fault. Moreover, when the algorithm was tested on signals taken from a gearbox for a bearing with a spalled outer race, it shows that each of the impulses originating from the impacts is made up of two parts (corresponding to entry into and exit from the spall). This agrees well with the literature but is often difficult to observe without the use of the MED technique. The use of the MED along with SK analysis also greatly improves the results of envelope analysis for making a complete diagnosis of the fault and trending its progression.
The incidence of wall enhancement of cerebral aneurysms on vessel wall MR imaging has been described as higher in ruptured intracranial aneurysms than in unruptured intracranial aneurysms, but the ...difference in the degree of enhancement between ruptured and unruptured aneurysms is unknown. We compared the degree of enhancement between ruptured and unruptured intracranial aneurysms by using quantitative MR imaging measures.
We performed quantitative analyses of circumferential enhancement along the wall of cerebral aneurysms in 28 ruptured and 76 unruptured consecutive cases by using vessel wall MR imaging. A 3D-T1-weighted fast spin-echo sequence was obtained before and after contrast media injection, and the wall enhancement index was calculated. We then compared characteristics between ruptured and unruptured aneurysms.
The wall enhancement index was significantly higher in ruptured than in unruptured aneurysms (1.70 ± 1.06 versus 0.89 ± 0.88, respectively; P = .0001). The receiver operating characteristic curve analysis found that the most reliable cutoff value of the wall enhancement index to differentiate ruptured from unruptured aneurysms was 0.53 (sensitivity, 0.96; specificity, 0.47). The wall enhancement index remained significant in the multivariate logistic regression analysis (P < .0001).
Greater circumferential enhancement along the wall of cerebral aneurysms correlates with the ruptured state. A quantitative evaluation of circumferential enhancement by using vessel wall MR imaging could be useful in differentiating ruptured from unruptured intracranial aneurysms.
Hsp70 is often overexpressed in cancer cells, and the selective cellular survival advantage that it confers may contribute to the process of tumour formation. Thus, the pharmacological manipulation ...of Hsp70 levels in cancer cells may be an effective means of preventing the progression of tumours. We found that the downregulation of Hsp70 by ibuprofen in vitro enhances the antitumoural activity of cisplatin in lung cancer. Ibuprofen prominently suppressed the expression of Hsp70 in A549 cells derived from lung adenocarcinoma and sensitized them to cisplatin in association with an increase in the mitochondrial apoptotic cascade, whereas ibuprofen alone did not induce cell death. The cisplatin-dependent events occurring up- and downstream of mitochondrial disruption were accelerated by treatment with ibuprofen. The increase in cisplatin-induced apoptosis caused by the depletion of Hsp70 by RNA interference is evidence that the increased apoptosis by ibuprofen is mediated by its effect on Hsp70. Our observations indicate that the suppression of Hsp70 by ibuprofen mediates the sensitivity to cisplatin by enhancing apoptosis at several stages of the mitochondrial cascade. Ibuprofen, therefore, is a potential therapeutic agent that might allow lowering the doses of cisplatin and limiting the many challenge associated with its toxicity and development of drug resistance.
A near‐future, 2‐K warming climate simulation comprising over 3,000 years of ensemble simulations was performed using 60‐km global and 20‐km regional atmospheric models. Even in the +2‐K climate, ...indices of extreme precipitation and dryness increased significantly in the extratropics compared with the historical climate. Mean precipitation increases in the rainy season and decreases in the dry season, indicating that the seasonal precipitation range becomes amplified with global warming. The intensification of precipitation and dryness from +2 to +4 K was also robust in the mean for climatological wet and arid regions. Around Japan, which was classified as a wet region, the regional atmospheric model predicts that the extreme hourly precipitation in the future climate becomes more extreme on hot days, but slightly weaker on cold days. This extreme precipitation has a high sensitivity to air temperature exceeding 7%/K.
Plain Language Summary
Our study shows the precipitation changes in the near‐future around the 2040s, +2‐K climate. Even in the +2‐K climate, both extreme precipitation and dryness in the extratropics increase significantly. These results urge to plan for adaptation to extreme weather in the near future. The 2‐K warming climate simulation was performed with over 3,000 years of ensemble member using 60‐km global and 20‐km regional atmospheric models. A large number of ensemble data elucidated statistically significant increment of the precipitation extremes, moreover the amplifying of the seasonal precipitation range. The data are helpful to investigate the climate in the near‐future containing mixed uncertainty both internal variation and effects of future scenario. It would provide valuable information for policy‐making, planning of mitigation, and adaptation for extreme weather events, such as flooding or droughts in the near‐future climate.
Key Points
High‐resolution large‐ensemble simulations are performed to assess precipitation change under the +2‐K climate
Even in the +2‐K climate, both extreme precipitation and dryness in the extratropics increase significantly compared with the historical climate
The tendency for the seasonal precipitation range to amplify becomes robust with global warming from the +2‐K to +4‐K climate
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular ...heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained. Dormant lung cancer cells were found to be resistant to EGFR tyrosine kinase inhibitor (TKI) treatment. In terms of mechanism, we found that a negative regulator of ERBB signaling, MIG6/ERRFI1/RALT/Gene33, was induced by hypoxia both in vitro and in vivo. MIG6 expression prevented heterodimer formation of ERBB family RTKs, and suppressed their downstream signaling. Knockdown of MIG6 enhanced tumor cell growth under hypoxic conditions, and promoted the phosphorylation of ERK and AKT via increased EGFR-HER3 binding. Critically, sensitivity to an EGFR-TKI, as well as to irradiation under hypoxic conditions, was increased in MIG6 knockdown cells. The expression of MIG6 was partly correlated with a pS6 negative zone in patient tumors. Analyses of tumor sections from 68 patients with activating EGFR mutations showed that patients with high MIG6 expression showed significantly shorter survival after EGFR-TKI treatment than other groups. Collectively, our data suggest that dormant cancer cells with a high MIG6 expression level might be one of the causes of EGFR-TKI resistance in EGFR mutant lung cancer cells.
J-PARC, Japan Proton Accelerator Research Complex provides short pulse proton beam at a repetition rate 25Hz and the maximum power is expected to be 1MW. Materials and Life Science Experimental ...Facility (MLF) has 23 neutron beam ports and 21 instruments have already been operated or under construction/commissioning. There are 6 inelastic/quasi-elastic neutron scattering spectrometers and the complementary use of these spectrometers will open new insight for life science.
This article is part of a Special Issue entitled “Science for Life” Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo.
•Status of inelastic- and quasi-elastic neutron scattering spectrometers in J-PARC is shown.•Six spectrometers cover wide E–Q space and give opportunities for biology and biophysics.•Two experimental results on bio-related materials are shown as examples.
Secrecy issues of free-space optical links realizing information theoretically secure communications and high transmission rates are discussed. We numerically study secrecy communication rates of ...optical wiretap channel based on on-off keying (OOK) modulation under typical conditions met in satellite-ground links. It is shown that, under reasonable degraded conditions on a wiretapper, information theoretically secure communications should be possible in a much wider distance range than a range limit of quantum key distribution, enabling secure optical links between geostationary Earth orbit satellites and ground stations with currently available technologies. We also provide the upper bounds on the decoding error probability and the leaked information to estimate a necessary code length for given required levels of performances. This result ensures that a reasonable length of wiretap channel code for our proposed scheme must exist.
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