Ensemble forecast experiments of summertime sea ice in the Arctic Ocean using the TOPAZ4 ice-ocean data assimilation system.

Precise information on sea ice thickness (SIT) and its prediction at medium-range (2-week) timescale is crucial for the safe maritime navigation in the Arctic Ocean. In this study, we investigate the sensitivity of medium-range prediction skill of summertime SIT distribution in the Arctic marginal seas to atmospheric forecast data, using the 51-member ECMWF operational ensemble prediction system (EPS). For a synoptic-scale cyclone event occurred in July 5-6, 2015, two-week probabilistic forecast experiments were conducted with the TOPAZ4 ice-ocean forecast system, starting on 1st July. The ensemble correlation analysis between the forecast SIT and the meteorological parameters shows that the forecast error of SIT distribution is sensitive to the sea ice drift speed until 1-week, indicating that realistic sea ice drift improves the sea ice thickness prediction. On the other hand, beyond 1 week lead, the forecast error of SIT distribution is more sensitive to surface heat flux rather than sea ice drift. The surface heat flux signal is confined to the sea ice edge region, where the shortwave radiation flux is related to the SIT change through the sea ice melting process. The shortwave radiation flux in the sea ice edge is mostly determined by the sea ice distribution, suggesting that the skillful prediction of sea ice distribution, which is largely affected by synoptic-scale disturbance, at shorter lead times indirectly affects the medium-range forecast skill. A comparison of different ensemble perturbation techniques shows that the prediction skill is better at shorter lead times (up to 1 week), when using an atmospheric EPS rather than the random perturbations used in the operational forecast system, but the random perturbations are advantageous beyond 1 week. Thus, the application of the EPS to an ice-ocean coupled forecast system leads to a more precise sea ice prediction on medium-range timescale, which we expect to become of practical use for the optimum shipping route in the Arctic Ocean.

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome.

This corrects the article DOI: 10.1038/leu.2016.276.

Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells.

L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy. The autophagy is involved in reducing reactive oxygen species (ROS) level by eliminating injured mitochondria. Inhibition of autophagy enhances L-asparaginase-induced cytotoxicity and overcomes the acquired resistance to L-asparaginase in ALL cells. The ROS-p53-positive feedback loop is an essential mechanism of this synergistic cytotoxicity. Thus, our findings provide the rationale for the future development of combined treatment of L-asparaginase and anti-autophagy drug in ALL patients.

Excess NF-κB induces ectopic odontogenesis in embryonic incisor epithelium.

Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKß, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkß). K5-Ikkß mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkß mice. The supernumerary incisors in K5-Ikkß mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.

Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil

Anti-malarial resistance in Plasmodium falciparum remains an obstacle for malaria control. Resistance-associated genes were analysed in Brazilian samples over four decades to evaluate the impact of different treatment regimens on the parasite genetic profile. Methods: Samples were collected on filter paper from patients infected in the Amazon region from 1984 to 2011.DNA was extracted with Chelex® 100 and monoinfection confirmed by PCR. SNPs in the pfcrt, pfmdr1, pfdhfr and pfdhpsgenes were assessed by PCR-RFLP. The pfmdr1 copy number was estimated using real time quantitative PCR with SYBR®Green. Parasite response was assessed ex vivo with seven concentrations of each anti-malarial. Patients were treatedaccording to Brazilian guidelines: quinine plus tetracycline or mefloquine in period 1 and ACT in period 2...

Prevention of postoperative pulmonary complications through intensive preoperative respiratory rehabilitation in patients with esophageal cancer.

Postoperative pulmonary complications (PPCs) after esophagectomy have been reported to occur in 15.9-30% of patients and lead to increased postoperative morbidity and mortality, prolonged duration of hospital stay, and additional medical costs. The purpose of this retrospective cohort study was to investigate the possible prevention of PPCs by intensive preoperative respiratory rehabilitation in esophageal cancer patients who underwent esophagectomy. The subjects included 100 patients (87 males and 13 females with mean age 66.5 ± 8.6 years) who underwent esophagectomy. They were divided into two groups: 63 patients (53 males and 10 females with mean age 67.4 ± 9.0 years) in the preoperative rehabilitation (PR) group and 37 patients (34 males and 3 females with mean age 65.0 ± 7.8 years) in the non-PR (NPR) group. The PR group received sufficient preoperative respiratory rehabilitation for >7 days, and the NPR group insufficiently received preoperative respiratory rehabilitation or none at all. The results of the logistic regression analysis and multivariate analysis to correct for all considerable confounding factors revealed the rates of PPCs of 6.4% and 24.3% in the PR group and NPR group, respectively. The PR group demonstrated a significantly less incidence rate of PPCs than the NPR group (odds ratio: 0.14, 95% confidential interval: 0.02~0.64). [Correction added after online publication 25 June 2012: confidence interval has been changed from -1.86~ -0.22] This study showed that the intensive preoperative respiratory rehabilitation reduced PPCs in esophageal cancer patients who underwent esophagectomy.

A transcriptional variant of the LC3A gene is involved in autophagy and frequently inactivated in human cancers.

Microtubule-associated protein 1 light chain 3 has an important role in autophagy. The human LC3 gene family has five members, LC3A (variant-1: v1 and -2: v2), LC3B, LC3B2 and LC3C. Although a form of LC3B modified by phosphatidylethanolamine (form-II) is localized in autophagosomes, it is not clear whether other LC3 proteins also function in autophagy. Here, we examined the association between autophagy and human LC3 proteins during starvation- or p53-induced autophagy in Saos-2 cells. In an analysis of the intracellular distribution of each LC3 protein fused with GFP, GFP-LC3Av1 was frequently localized in autophagosomes with a punctate pattern, similar to GFP-LC3B. Further, endogenous LC3Av1 generated form-II and mostly localized in LC3B-positive autophagosomes during the induced autophagy. Interestingly, LC3Av1, not LC3B, was frequently inactivated at the transcriptional level in various human cancer cell lines (111/244 cell lines, 45.5%) and its inactivation was due to aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC) cell lines and primary tumors. Restoration of LC3Av1 expression in KYSE170 cells, an LC3Av1-inactivated ESCC cell line, showed the inhibition of tumor growth in vivo. These results suggest that LC3Av1, not only LC3B, functions in autophagy and further, LC3Av1 may be crucial in carcinogenesis.

Four-year study of lamivudine and adefovir combination therapy in lamivudine-resistant hepatitis B patients: influence of hepatitis B virus genotype and resistance mutation pattern.

To investigate the efficacy of long-term lamivudine (3TC) and adefovir dipivoxil (ADV) combination therapy in 3TC-resistant chronic hepatitis B virus (HBV) infected patients, we analysed 28 3TC-resistant patients treated with the combination therapy during 47 months (range, 9-75). At 12, 24, 36, and 48 months, the rates of virological response with undetectable HBV DNA (≤ 2.6 log copies/mL) were 56, 80, 86, and 92%, respectively. Among 17 hepatitis B e antigen (HBeAg)-positive patients, HBeAg disappeared in 24% at 12 months, 25% at 24 months, 62% at 36 months, and 88% at 48 months. When HBV genotypes were compared, patients with genotype B achieved virological response significantly more rapidly than those with genotype C (P=0.0496). One patient developed virological breakthrough after 54 months, and sequence analysis of HBV obtained from the patient was performed. An rtA200V mutation was present in the majority of HBV clones, in addition to the 3TC-resistant mutations of rtL180M+M204V. The rtN236T ADV-resistant mutation was observed in only 25% clones. In vitro analysis showed that the rtA200V mutation recovered the impaired replication capacity of the clone with the rtL180M+M204V mutations and induced resistance to ADV. Moreover, rtT184S and rtS202C, which are known entecavir-resistant mutations, emerged in some rtL180M+M204V clones without rtA200V or rtN236T. In conclusion, 3TC+ADV combination therapy was effective for most 3TC-resistant patients, especially with genotype B HBV, but the risk of emergence of multiple drug-resistant strains with long-term therapy should be considered. The mutation rtA200V with rtL180M+M204V may be sufficient for failure of 3TC+ADV therapy.

The impact of early rehabilitation on the duration of hospitalization in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: We examined the relationship between the improved physical activity by early rehabilitation and the duration of hospitalization among patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Thirteen allo-HSCT patients with myeloablative conditioning regimens (group A) and 13 patients with nonmyeloablative conditioning regimens (group B) were assessed retrospectively in this study. All patients received physical exercise immediately after neutrophil engraftment at the class 10,000 bioclean room (class 10,000). The mean daily steps at class 10,000 were measured as a substitute for the amount of physical activity, and the duration of hospitalization as one of the clinical outcomes. RESULTS: The degree of physical activity showed a negative correlation with the duration of hospitalization in group A (r = -.71; P = .0071), regardless of complications such as acute graft-versus-host disease, infections, and cytomegalovirus reactivation. However, there was no significant association in group B (r = .09; P = .77). CONCLUSION: The improved physical activity through early rehabilitation may be an independent, favorable prognostic factor for allo-HSCT patients with myeloablative conditioning regimens.

Giant orbital Hall effect in transition metals: origin of large spin and anomalous Hall effects.

In transition metals and their compounds, the orbital degrees of freedom gives rise to an orbital current, in addition to the ordinary spin and charge currents. We reveal that considerably large spin and anomalous Hall effects observed in transition metals originate from an orbital Hall effect (OHE). To elucidate the origin of these novel Hall effects, a simple periodic s-d hybridization model is proposed as a generic model. The giant positive OHE originates from the orbital Aharonov-Bohm phase factor, and induces spin Hall conductivity that is proportional to the spin-orbit polarization at the Fermi level, which is positive (negative) in metals with more than (less than) half filling.

Sharp contrasts in low-energy quasiparticle dynamics of graphite between Brillouin zone K and H points.

The low-energy quasiparticle (QP) dynamics of graphite are governed by a coupling with the E(2g) longitudinal optical phonon of omega(LO) approximately 200 meV, which is found to dramatically depend on the electronic band dispersion epsilon(k). A discontinuity of the QP linewidth develops near omega(LO) for a linear band with a quadratic band top [near the Brillouin zone (BZ) K point], while it disappears for a pure linear band (near the BZ H point). It is also found that the effective electron-phonon coupling near the K point is stronger than near the H point by more than 50%. This finding makes possible a consistent understanding of recent angle-resolved photoemission observations near the K point.

Giant intrinsic spin and orbital hall effects in Sr2MO4 (M=Ru, Rh, Mo).

We investigate the intrinsic spin Hall conductivity (SHC) and the d-orbital Hall conductivity (OHC) in metallic d-electron systems, by focusing on the t2g-orbital tight-binding model for Sr2MO4 (M=Ru, Rh, Mo). The conductivities obtained are one or 2 orders of magnitude larger than predicted values for p-type semiconductors with approximately 5% hole doping. The origin of these giant Hall effects is the "effective Aharonov-Bohm phase" that is induced by the d-atomic angular momentum in connection with the spin-orbit interaction and the interorbital hopping integrals. The huge SHC and OHC generated by this mechanism are expected to be ubiquitous in multiorbital transition metal compounds, which opens the possibility of realizing spintronics as well as "orbitronics" devices.

Depositional records of plutonium and (137)Cs released from Nagasaki atomic bomb in sediment of Nishiyama reservoir at Nagasaki.

In a sediment core of Nishiyama reservoir at Nagasaki city, depth profiles of (240)Pu/(239)Pu isotopic ratio, (239+240)Pu and (137)Cs activities were determined. Sediments containing plutonium and (137)Cs, which were deposited immediately after a detonation of Nagasaki atomic bomb, were identified in the core. Observed below the sediments were macroscopic charcoals, providing evidence for initial deposit of the fallout of the Nagasaki atomic bomb. This is the first entire depositional records of plutonium and (137)Cs released from the Nagasaki atomic bomb together with those from atmospheric nuclear tests.

POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17.

Multiple myeloma (MM), a progressive hematological neoplasm, is thought to result from multiple genetic events affecting the terminal plasma cell. However, genetic aberrations related to MM are seldom reported. Using our in-house array-based comparative genomic hybridization system to locate candidate target genes with following their expression analysis, we identified POU2AF1 at 11q23.1 as a probable amplification target in MM cell lines. POU2AF1 is a B-cell-specific transcriptional co-activator, which interacts with octamer-binding transcription factors Oct-1 and Oct-2, and augments their function. Downregulation of POU2AF1 expression by specific small-interfering RNA (siRNA) inhibited MM cell growth, whereas ectopic expression of POU2AF1 promoted growth of MM cells. Among putative transcriptional targets for POU2AF1, B-cell maturation factor, TNFRSF17, enhanced its transcription by POU2AF1, and POU2AF1 directly bound to an octamer site within the 5' region of TNFRSF17. Expression level of TNFRSF17 was closely correlated with that of POU2AF1 in cell lines and primary samples of MM, and decreasing TNFRSF17 expression by means of TNFRSF17 siRNA inhibited MM cell growth. Taken together, our results suggest that POU2AF1, when activated by amplification or other mechanisms, may contribute to progression of MM by accelerating growth of MM cells through direct transactivation of one of its target genes, TNFRSF17.

Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas.

We previously identified a cluster of prostanoid receptor genes, prostaglandin D2 receptor (PTGDR) and prostaglandin E receptor 2 (PTGER2), as possible targets for DNA methylation in advanced types of neuroblastoma (NB) using bacterial artificial chromosome array-based methylated CpG island amplification method. Among them, in this study, we found that PTGER2 was frequently silenced in NB cell lines, especially in those with MYCN amplification, through epigenetic mechanisms. In NB cell lines, DNA methylation pattern within a part of CpG island was inversely correlated with PTGER2 expression, and histone H3 and H4 deacetylation and histone H3 lysine 9 methylation within the putative promoter region were more directly correlated with silencing of this gene. Methylation of PTGER2 was observed more frequently in advanced-type of primary NBs compared with early-stage tumors. Growth of NB cells lacking endogenous PTGER2 expression was inhibited by restoration of the gene product by transient and stable transfection. A PTGER2-selective agonist, butaprost, increased intracellular cyclic adenosine monophosphate (cAMP) level, inhibited cell growth and induced apoptosis of NB cells stably expressing exogenous PTGER2. 8-Bromo-cAMP also inhibited growth of NB cells lacking PTGER2 expression, but not cells expressing this gene. Taken together, it is suggested that NB cells may lose responsiveness to PTGER2-mediated growth inhibition/apoptosis through epigenetic silencing of PTGER2 and/or disruption of downstream cAMP-dependent pathway during the neuroblastomagenesis.

Frequent methylation-associated silencing of a candidate tumor-suppressor, CRABP1, in esophageal squamous-cell carcinoma.

Epigenetic alterations and the resulting inactivation of tumor suppressor genes often contribute to the development of various cancers. To identify novel candidates that may be silenced by aberrant methylation in esophageal squamous-cell carcinoma (ESCC), we analysed ESCC cell lines by a recently developed method known as bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA), and selected candidates through BAMCA-assisted strategy. In the course of this program, we identified frequent CpG methylation-dependent silencing of the gene encoding cellular retinoic acid binding protein 1 (CRABP1) in our panel of ESCC cell lines. Expression of CRABP1 mRNA was restored in gene-silenced ESCC cells after treatment with 5-aza 2'-deoxycytidine. The DNA methylation status of the CRABP1 CpG island with clear promoter activity correlated inversely with expression of this gene. CpG methylation of CRABP1 was frequently observed in primary ESCC tissues as well. Restoration of CRABP1 expression in ESCC cells lacking the protein reduced cell growth by inducing arrest at G(0)-G(1), whereas knockdown of the gene in cells expressing CRABP1 promoted cell growth. Among 113 primary ESCC tumors, the absence of immunoreactive CRABP1 was significantly associated with de-differentiation of cancer cells and with distant lymph-node metastases in the patients. These results indicate that CRABP1 appears to have a tumor-suppressor function in esophageal epithelium, and its epigenetic silencing may play a pivotal role during esophageal carcinogenesis. Its expression status in biopsies or resected tumors might serve as an index for identifying ESCC patients for whom combined therapeutic modalities would be recommended.

A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity.

Anaplastic thyroid cancer (ATC) is one of the most lethal of all human tumors, but cytogenetic information concerning ATC is extremely limited. Using our in-house array-based comparative genomic hybridization and 14 ATC cell lines with further fluorescence in situ hybridization analysis, we demonstrated amplification of the DUSP26 gene, known by another report as MAP kinase phosphatase-8. DUSP26 was overexpressed in ATC cell lines and primary ATC tumor samples. When overexpressed, either exogenously or endogenously, DUSP26 promoted growth of the ATC cells. DUSP26 encodes a protein containing a dual-specificity phosphatase domain that can dephosphorylate itself. DUSP26 effectively dephosphorylates p38 and has a little effect on extracellular signal-regulated kinase in ATC cells. DUSP26 protein formed a physical complex with p38, and promoted survival of ATC cells by inhibiting p38-mediated apoptosis. Our findings suggest that DUSP26 may act as an oncogene in ATC, and might be a useful diagnostic marker and therapeutic target of this disease.

Ultrafast Fano resonance between optical phonons and electron-hole pairs at the onset of quasiparticle generation in a semiconductor.

Based on the many-body time-dependent approach applied to the ultrafast time region, we investigate the dynamics of creation of an optical phonon incorporating with the electron-hole continuum in a semiconductor. In the transient Fano resonance, due to an interference between those sharp (optical phonon) and continuum (electron-hole pair) quasiparticles, we find the robust destructive interference at birth of them, i.e., tau approximately 0 if the created phonon is coherent under the irradiation of ultrashort optical pulses. The origin is found to be the potential scattering of the electron-hole pair by the q=0 coherent phonon. This finding agrees well with the recent experiment.

Calpain inhibition by alpha-ketoamide and cyclic hemiacetal inhibitors revealed by X-ray crystallography.

Calpains are intracellular calcium-activated cysteine proteases whose unregulated proteolysis following the loss of calcium homeostasis can lead to acute degeneration during ischemic episodes and trauma, as well as Alzheimer's disease and cataract formation. The determination of the crystal structure of the proteolytic core of mu-calpain (muI-II) in a calcium-bound active conformation has made structure-guided design of active site inhibitors feasible. We present here high-resolution crystal structures of rat muI-II complexed with two reversible calpain-specific inhibitors employing cyclic hemiacetal (SNJ-1715) and alpha-ketoamide (SNJ-1945) chemistries that reveal new details about the interactions of inhibitors with this enzyme. The SNJ-1715 complex confirms that the free aldehyde is the reactive species of the cornea-permeable cyclic hemiacetal. The alpha-ketoamide warhead of SNJ-1945 binds with the hydroxyl group of the tetrahedral adduct pointing toward the catalytic histidine rather than the oxyanion hole. The muI-II-SNJ-1945 complex shows residue Glu261 displaced from the S1' site by the inhibitor, resulting in an extended "open" conformation of the domain II gating loop and an unobstructed S1' site. This conformation offers an additional template for structure-based drug design extending to the primed subsites. An important role for the highly conserved Glu261 is proposed.