North Atlantic climate far more predictable than models imply.

Quantifying signals and uncertainties in climate models is essential for the detection, attribution, prediction and projection of climate change1-3. Although inter-model agreement is high for large-scale temperature signals, dynamical changes in atmospheric circulation are very uncertain4. This leads to low confidence in regional projections, especially for precipitation, over the coming decades5,6. The chaotic nature of the climate system7-9 may also mean that signal uncertainties are largely irreducible. However, climate projections are difficult to verify until further observations become available. Here we assess retrospective climate model predictions of the past six decades and show that decadal variations in North Atlantic winter climate are highly predictable, despite a lack of agreement between individual model simulations and the poor predictive ability of raw model outputs. Crucially, current models underestimate the predictable signal (the predictable fraction of the total variability) of the North Atlantic Oscillation (the leading mode of variability in North Atlantic atmospheric circulation) by an order of magnitude. Consequently, compared to perfect models, 100 times as many ensemble members are needed in current models to extract this signal, and its effects on the climate are underestimated relative to other factors. To address these limitations, we implement a two-stage post-processing technique. We first adjust the variance of the ensemble-mean North Atlantic Oscillation forecast to match the observed variance of the predictable signal. We then select and use only the ensemble members with a North Atlantic Oscillation sufficiently close to the variance-adjusted ensemble-mean forecast North Atlantic Oscillation. This approach greatly improves decadal predictions of winter climate for Europe and eastern North America. Predictions of Atlantic multidecadal variability are also improved, suggesting that the North Atlantic Oscillation is not driven solely by Atlantic multidecadal variability. Our results highlight the need to understand why the signal-to-noise ratio is too small in current climate models10, and the extent to which correcting this model error would reduce uncertainties in regional climate change projections on timescales beyond a decade.

Utility of synthetic MRI in predicting the Ki-67 status of oestrogen receptor-positive breast cancer: a feasibility study.

AIM: To evaluate the utility of synthetic magnetic resonance imaging (MRI) of the breast in predicting the Ki-67 status in patients with oestrogen receptor (ER)-positive breast cancer. MATERIALS AND METHODS: Forty-nine patients with 50 histopathologically proven breast cancers who underwent additional synthetic MRI were enrolled in the present study. Using synthetic MRI images, T1 and T2 relaxation times and their standard deviations (SD) in the breast lesions before (T1-Pre, T2-Pre, PD-Pre, SD of T1-Pre, SD of T2-Pre, SD of PD-Pre) and after (T1-Gd, T2-Gd, PD-Gd, SD of T1-Gd, SD of T2-Gd, SD of PD-Gd) contrast agent injection were obtained. These quantitative values were compared between the low Ki-67 expression (<14%) lesions (low-proliferation group: n=23) and high Ki-67 expression (≥14%) lesions (high-proliferation group: n=27). RESULTS: The univariate analysis showed that the SD of T1-Gd (p<0.001) and T2-Gd (p=0.042) were significantly higher in the high-proliferation group than in the low-proliferation group. Multivariate analysis further showed that the SD of T1-Gd was a significant and independent predictor of Ki-67 expression, with an area under the receiver operating characteristic (AUROC) curve of 0.885. The sensitivity, specificity, and accuracy of the SD of T1-Gd with an optimal cut-off value of 98.5 were 77.8%, 87%, and 82%, respectively. CONCLUSION: The SD of T1-Gd obtained from synthetic MRI was useful to predict Ki-67 status.

Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Effect of augmented datasets on deep convolutional neural networks applied to chest radiographs.

AIM: To evaluate the effect of augmented training datasets in a deep convolutional neural network (DCNN) used for detecting abnormal chest radiographs. MATERIALS AND METHODS: Chest radiographs were corrected to conform to a DCNN dataset, with 288 abnormal and 447 normal radiographs. The radiographic images were divided into training and validation sets (441, 60%), and a test set (294, 40%). The training and validation sets were augmented to generate a total of 12,789 training and validation images. The augmentation consisted of operations such as rotation, horizontal and vertical flipping, Gaussian blur, and brightness variation, either alone or combined. The DCNN performed binary classification of the images as being abnormal or normal chest radiographs, and accuracy was used as measure to assess the model performance. RESULTS: The accuracy of the DCNN trained with the augmented dataset tended to be higher than that of the DCNN trained with the non-augmented dataset. The augmented datasets combining rotation and horizontal flipping had a high accuracy of 0.91, showing the highest accuracy among the applied augmentation techniques and combinations. CONCLUSION: Augmentation of training datasets can improve the performance of DCNN for radiographic image classification depending on the applied augmentation technique.

Itching in a trichophytin contact dermatitis mouse model and the antipruritic effect of antifungal agents.

BACKGROUND: Tinea is an infectious disease by dermatophytes, of which Trichophyton species accounts for the overwhelming majority of case. Tinea often causes itching with inflammation. In terms of pruritus by fungal infection, however, tinea has not been investigated sufficiently to date. AIM: To evaluate itch caused by Trichophyton infection and the effect of antifungal agents on the infection, by measuring scratch behaviour and profiles of inflammatory cytokines and chemokines. METHODS: We used a previously established mouse model of contact hypersensitivity induced by trichophytin, a crude extract from Trichophyton mentagrophytes. Scratching behaviour was recorded using a counting device that measured an electric current induced in a coil by movement of magnets that had been inserted into the hind paws of each animal. We investigated expression of various genes in lesional skin of mice and in normal human epidermal keratinocytes. We also investigated the antipruritic effects of the corticosteroid dexamethasone (DEX) and three antifungal agents: ketoconazole (KCZ), terbinafine (TBF) and liranaftate (LNF). RESULTS: Biphasic peaks of scratching were observed at 1 h and at 6-7 h during an observation period of 14 h after trichophytin induction. For lesional skin, RNA was extracted 24 h after trichophytin challenge, and increased expression was seen in the genes for interleukin (IL)-17A, interferon-γ, tumour necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-2 and Dectin-1, whereas there was no obvious change in the genes for IL-31 and prostaglandin (PG)E2. Furthermore, KCZ inhibited histidine decarboxylase (HDC) expression in vitro and in vivo, and inhibited scratching in the very early phase. LNF inhibited expression of thymic stromal lymphopoietin (TSLP) and IL-8 in vitro, and TSLP, TNF-α, IL-1α and MIP2 in vivo, and also scratching in the early phase. TBF did not induce any significant alterations in either gene expression or scratching. DEX suppressed expression of all the chemical mediators except HDC in vitro and in vivo, and inhibited scratching. CONCLUSION: Antifungals can inhibit itching induced by fungal infection through different mechanisms.

FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

Diagnostic capability of feature-tracking cardiovascular magnetic resonance to detect infarcted segments: a comparison with tagged magnetic resonance and wall thickening analysis.

AIM: To examine the diagnostic capabilities of feature-tracking cardiovascular magnetic resonance (FT-CMR), tagged cine magnetic resonance (MR), and wall thickening (WT) analyses to detect infarcted segments in patients with established myocardial infarction (MI). MATERIALS AND METHODS: Twenty patients with established MI were selected retrospectively and the peak endocardial circumferential strain (CS) was quantified based on the 16-segment model. According to CMR with late gadolinium enhancement, segments were categorised as transmural MI, subendocardial MI, and no MI. RESULTS: A total of 320 segments (62 transmural MI, 50 subendocardial MI, and 208 no MI) were analysed. Peak endocardial CS was significantly lower for transmural MI compared with subendocardial MI (p<0.05) and no MI (p<0.001). Cut-off values of -11.2% for CS by FTCMR, -10.9% for CS by tagged MR, and 23.8% for %WT, differentiated between infarcted and non-infarcted segments with a sensitivity of 72%, 71%, and 56%; specificity of 71%, 75%, and 67%; accuracy of 72%, 73%, and 63%; positive predictive value of 57%, 60%, and 48%; negative predictive value of 83%, 83%, and 74%; and an area-under-the-curve of 0.77, 0.79, and 0.64, respectively. CONCLUSIONS: FT-CMR was diagnostically superior to %WT, and could differentiate between subendocardial and transmural MI. Unlike tagged MR, FT-CMR did not require the acquisition of additional sequences.

Subcycle Optical Response Caused by a Terahertz Dressed State with Phase-Locked Wave Functions.

The coherent interaction of light with matter imprints the phase information of the light field on the wave function of the photon-dressed electronic state. A driving electric field, together with a stable phase that is associated with the optical probe pulses, enables the role of the dressed state in the optical response to be investigated. We observed optical absorption strengths modulated on a subcycle time scale in a GaAs quantum well in the presence of a multicycle terahertz driving pulse using a near-infrared probe pulse. The measurements were in good agreement with the analytical formula that accounts for the optical susceptibilities caused by the dressed state of the excitons, which indicates that the output probe intensity was coherently reshaped by the excitonic sideband emissions.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Terahertz-induced optical emission of photoexcited undoped GaAs quantum wells.

Intense terahertz (THz) pulse induces photoluminescence (PL) flash from undoped high-quality GaAs/AlGaAs quantum wells under continuous wave laser excitation. The number of excitons increases 10,000-fold from that of the steady state under only laser excitation. The THz electric field dependence and the relaxation dynamics of the PL flash intensity suggest that the strong electric field of the THz pulse ionizes impurity states during the 1 ps period of the THz pulse and release carriers from a giant reservoir containing impurity states in the AlGaAs layers.

Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.

Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.

Correlation with larval body size of mRNA levels of growth hormone, growth hormone receptor I and insulin-like growth factor I in larval torafugu Takifugu rubripes.

The full-length of insulin-like growth factor (IGF) complementary (c)DNAs encoded by igf-I and igf-II from torafugu pufferfish Takifugu rubripes were cloned in the present study. The deduced amino acid sequences of the two genes showed c. 80% identity each with those of Igf-I and Igf-II from other teleosts, respectively. Two growth hormone (GH) receptors, ghr1 and ghr2, were also cloned in silico using the T. rubripes Fugu genome database. The transcripts of T. rubripes igf-I were detected in slow muscle, heart, skin, gill, liver and intestine but not in fast muscle, spleen and testis of adult fish, whereas those of igf-II were found in all tissues examined. Subsequently, the accumulated messenger (m)RNA levels of igf-I and igf-II were investigated in an F(2) population derived from a male of an apparent fast-growing T. rubripes strain and a wild female T. rubripes together with those of other growth-related genes encoding Gh, Ghr1 and Ghr2, and with those of prolactin (Prl) and leptin (Lep) previously reported. The accumulated mRNA levels of igf-I, gh and ghr1 were significantly correlated to growth rate at larval stages in the population, but not for those of igf-II, prl, ghr2 and lep. Although it is unclear whether or not this phenotype is directly related to the heredity of the fast-growing strain, the findings suggest that the expression of igf-I, gh and ghr1 is involved in the regulation of growth rate at larval stages in T. rubripes.

[Leiomyosarcoma of the middle mediastinum; report of a case].

The case was 74-year-old woman. A tumor at the aortic window was found while retrieving the cause of the hoarseness, and the surgical biopsy was performed. The diagnosis of the leiomyosarcoma was obtained by pathology, and it probably originated from the middle mediastinal tissue. The radical operation was not selected, and the radiation therapy was performed. She did not suffered from symptoms associated with cardiopulmonary dysfunction, but she died of the cerebral metastasis in 5 months after the biopsy.

Over-expression of Caj1, a plasma membrane associated J-domain protein in Saccharomyces cerevisiae, stabilizes amino acid permeases.

Hsp70: J-domain protein (JDP) machines, along with the cellular protein degradation systems play a central role in regulating cellular proteostasis. An equally robust surveillance system operates at the plasma membrane too that affects proper sorting, stability as well as the turnover of membrane proteins. Although plausible, a definitive role of the Hsp70: JDP machine in regulating the stability of plasma membrane proteins is not well understood in Saccharomyces cerevisiae. Here we show that a moderate over-expression of Caj1, one of the thirteen JDPs residing in the nucleo-cytosolic compartment of S. cerevisiae reduced the cold sensitivity of tryptophan auxotrophic yeast cells by stabilizing tryptophan permeases, Tat1 and Tat2 in a J-domain dependent manner. Concomitantly, higher Caj1 levels also caused slow growth and increased plasma membrane damage at elevated temperatures possibly due to the stabilization of thermolabile plasma membrane proteins. Finally, we show that although majorly cytosolic, Caj1 also co-localizes with the membrane dye FM4-64 at the cellular periphery suggesting that Caj1 might interact with the plasma membrane. Based on the results presented in this study, we implicate the Hsp70: Caj1 chaperone machine in regulating the stability or turnover of plasma membrane proteins in budding yeast.

Determination of Lycopene Concentration in Fresh Tomatoes by Spectrophotometry: A Collaborative Study.

BACKGROUND: Lycopene has been the object of considerable research attention recently, and the effects of the intake of lycopene, or of tomato products, have been studied in various ways. In Japan, interest in the health-promoting function of food components has increased. OBJECTIVE: Developing a method to determine lycopene contents in tomato that meets the Japanese Agricultural Standard (JAS). METHOD: In the proposed JAS method, the test sample consists of fresh tomatoes; a hexane-acetone mixture is utilized as the extraction solvent. A collaborative study was conducted to evaluate the interlaboratory performance of the method. RESULTS: Ten laboratories participated and analyzed six test materials characterized by a lycopene content between 39 and 170 mg/kg as blind duplicates. After removing statistical outliers, RSDr ranged from 1.2 to 3.0% and RSDR ranged from 2.4 to 4.2%. The HorRat values were calculated and found to be in the 0.26-0.49 range. CONCLUSIONS: The method for determining the lycopene content in tomato was evaluated by means of a collaborative study, and the reproducibility of this method was found to be acceptable. HIGHLIGHTS: Intended for standardization in Japan, a method to determine lycopene content in tomato has been developed and shown to have acceptable precision in a collaborative study.

Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors.

The gene encoding alpha 6(IV) collagen, COL4A6, was identified on the human X chromosome in a head-to-head arrangement and within 452 base pairs of the alpha 5(IV) collagen gene, COL4A5. In earlier studies, intragenic deletions of COL4A5 were detected in a subset of patients with Alport syndrome (AS), a hereditary defect of basement membranes. In some families, AS cosegregates with diffuse leiomyomatosis (DL), a benign smooth muscle tumor diathesis. Here it is shown that patients with AS-DL harbor deletions that disrupt both COL4A5 and COL4A6. Thus, type IV collagen may regulate smooth muscle differentiation and morphogenesis.

PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans.

OBJECTIVE: The existence of mesenchymal stem cells (MSCs) in SF was previously reported. However, the behaviour and properties of MSCs derived from SF have not been fully elucidated. METHODS: Human SFs were obtained from 19 knee joints with anterior cruciate ligament injury around the time of reconstruction surgery, and from three healthy volunteers. SF was plated, cultured and examined for colony-forming number, in vitro differentiation, surface epitopes and gene profiles. Also, rabbit synovium-MSCs were injected into the knee joint in a rabbit partial anterior cruciate ligament defect model, and the injected cells were traced. RESULTS: SF-MSCs from IA ligament injury patients were 100 times more in number than those from healthy volunteers. Total colony number was positively correlated with post-injury period. No significant differences were observed among the cells derived from SF around the time of the surgery in relation to surface epitopes and differentiation potentials. Cluster analysis of gene profiles demonstrated that SF-MSCs were more similar to synovium MSCs than bone marrow MSCs. In rabbit experiments, the MSCs injected into the knee in which IA ligament was partially defective were observed more on the defected area than on the intact area of the ligament at 24 h. CONCLUSION: We demonstrated that SF-MSCs, similar to synovium MSCs, increased in number after IA ligament injury and surgery without marked alteration of the properties.

Effect of matrix metalloproteinase-3 functional SNP on serum matrix metalloproteinase-3 level and outcome measures in Japanese RA patients.

OBJECTIVE: A bi-allelic polymorphism on the promoter region, -1612 ins/del A, was found to influence the production of MMP-3. Since MMP-3 plays a particularly pivotal role in joint destruction, the MMP-3 gene is thought to be an interesting target gene of disease severity in RA. We attempt to determine whether the MMP-3 promoter polymorphism is associated with serum titre of MMP-3, disease activity and severity in Japanese RA patients. METHODS: DNA samples were obtained from 1504 RA patients as part of the Institute of Rheumatology Rheumatoid Arthritis observational cohort study. From the 2006 spring data, serum MMP-3 levels of 820 patients were available by enzyme immunoassay. Joint damage score at 5-yr disease duration could be measured using the Sharp/van der Heijde method in 162 patients. Genotyping of -1612 ins/del A was performed using fluorescent-labelled fragment analysis. Differences in serum MMP-3 level and joint damage score among genotypes of -1612 ins/del A polymorphism were analysed by linear regression analysis. RESULTS: No significant differences were found among MMP-3 genotypes on patient characteristics including disease activity score (P = 0.51) or health assessment questionnaire (P = 0.99). A significant effect of risk allele on serum MMP-3 level was observed (P = 0.038), while no significant effect was observed on radiographic joint damage (P = 0.47). CONCLUSION: We conclude that MMP-3 functional polymorphism is associated with serum MMP-3 titre, but is not a direct predictor for outcome measures in Japanese RA patients.