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Small-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only a limited number of examples have been reported to date. Here, we show that desmethyl desamino pateamine A (DMDA-PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, onto GNG motifs. By systematically comparing multiple eIF4A inhibitors by ribosome profiling, we found that DMDA-PatA has unique mRNA selectivity for translation repression. Unbiased Bind-n-Seq reveals that DMDA-PatA-targeted eIF4A exhibits a preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes. A combination of classical molecular dynamics simulations and quantum chemical calculations, and the subsequent development of an inactive DMDA-PatA derivative reveals that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified that DDX3, another DEAD-box protein, is an alternative DMDA-PatA target with the same effects on eIF4A. Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and the mRNA-selective inhibition of protein synthesis by small-molecule compounds. Here the authors report that DMDA-PatA, an anti-tumor compound, functions as a mRNA-selective translational inhibitor. This drug clamps the target eIF4A and DDX3 RNA-binding proteins on the GNG RNA motif, providing steric hindrance for scanning ribosomes. [ABSTRACT FROM AUTHOR]

The intraflagellar transport (IFT) machinery plays a crucial role in the bidirectional trafficking of components necessary for ciliary signaling, such as the Hedgehog, Wnt/PCR, and cAMP/PKA systems. Defects in some components of the IFT machinery cause dysfunction, leading to a wide range of human diseases and developmental disorders termed ciliopathies, such as nephronophthisis. The IFT machinery comprises three sub-complexes: BBsome, IFT-A, and IFT-B. The IFT protein 54 (IFT54) is an important component of the IFT-B sub-complex. In anterograde movement, IFT54 binds to active kinesin-II, walking along the cilia microtubule axoneme and carrying the dynein-2 complex in an inactive state, which works for retrograde movement. Several mutations in IFT54 are known to cause Senior-Loken syndrome, a ciliopathy. IFT54 possesses a divergent Calponin Homology (CH) domain termed as NN-CH domain at its N-terminus. However, several aspects of the function of the NN-CH domain of IFT54 are still obscure. Here, we report the 1H, 15N, and 13C resonance assignments of the NN-CH domain of human IFT54 and its solution structure. The NN-CH domain of human IFT54 adopts essentially the α1–α2–α3–α4–α5 topology as that of mouse IFT54, whose structure was determined by X-ray crystallographic study. The structural information and assignments obtained in this study shed light on the molecular function of the NN-CH domain in IFT54. [ABSTRACT FROM AUTHOR]

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Objectives: Endoscopy poses a high risk of severe acute respiratory syndrome coronavirus 2 infection for medical personnel due to the dispersal of aerosols from the patient. We investigated the location and size of droplets generated during esophagogastroduodenoscopy (EGD) and endoscopic submucosal dissection (ESD), the contamination of the surrounding area before and after the procedures, and the effectiveness of using an extraoral suction device (Free arm arteo; TOKYO GIKEN, Inc., Tokyo, Japan). Methods: Patients who consented to the study and underwent EGD or ESD between December 8, 2020, and April 15, 2021, at the National Cancer Center East Hospital were included. Adenosine triphosphate (ATP) hygiene monitoring tests and a particle counter were used for measurements. Results: Assessments were performed on 22 EGD and 15 ESD cases. ATP hygiene monitoring tests showed significant elevations at three sites near the patient, and two sites 1.5 m away, for EGD, and at four sites near the patient and 1.5 m away for ESD. In both ESD and EGD, extraoral suction devices reduced the extent of the contamination. Particles <5 μm in size were generated during endoscopic procedures and dispersed from both the forceps hole and the patient's mouth. The extraoral suction device did not reduce the number of particles generated. Conclusions: During endoscopic procedures, cleaning the surrounding environment is important in addition to standard precautions the endoscopist and caregivers take. The use of extraoral suction devices can also potentially reduce contamination of the surrounding environment. [ABSTRACT FROM AUTHOR]

Background and objectives: The prognosis of idiopathic chronic fibrotic interstitial pneumonitis (CFIP) in patients with acute exacerbation (AE) is variable. We examined whether the imaging pattern on thoracic computed tomography (CT) or the severity of respiratory failure with AE-CFIP is associated with short-term prognosis. Methods: Patients admitted to two university hospitals were retrospectively analyzed and divided into derivation and validation cohorts. The distribution of newly appearing parenchymal abnormalities on thoracic CT was classified into peripheral, multifocal, and diffuse patterns. Respiratory failure was defined as severe if a fraction of inspired oxygen ≥ 0.5 was required to maintain percutaneous oxygen saturation ≥ 90% on admission. Factors associated with 90 day-mortality were analyzed using univariate and Cox proportional hazard regression. Results: In 59 patients with AE-CFIP of the derivation cohort, diffuse pattern on CT was associated with higher mortality within 90 days (43%) than peripheral/multifocal pattern (17%, p = 0.03). Additionally, compared with non-severe failure, severe respiratory failure was associated with higher mortality (47% vs. 21%, p = 0.06). Cox proportional hazard regression analysis demonstrated that a combination of diffuse pattern on CT and severe respiratory failure was associated with the poorest prognosis (hazard ratio [HR] 3.51 [interquartile range 1.26–9.80], p = 0.016) in the derivation cohort, which was confirmed in the validation cohort (n = 31, HR 4.30 [interquartile range 1.51–12.2], p = 0.006). Conclusion: The combination of imaging pattern on thoracic CT and severity of respiratory failure was associated with the prognosis of idiopathic AE-CFIP. [ABSTRACT FROM AUTHOR]

Ribosome biogenesis is a complicated, multistage process coordinated by ribosome assembly factors. Ribosome binding factor A (RbfA) is a bacterial one, which possesses a single structural type-II KH domain. By this domain, RbfA binds to a 16S rRNA precursor in small ribosomal subunits to promote its 5′-end processing. The human RbfA homolog, mtRbfA, binds to 12S rRNAs in the mitoribosomal small subunits and promotes its critical maturation process, the dimethylation of two highly conserved consecutive adenines, which differs from that of RbfA. However, the structural basis of the mtRbfA-mediated maturation process is poorly understood. Herein, we report the 1H, 15N, and 13C resonance assignments of the KH domain of mtRbfA and its solution structure. The mtRbfA domain adopts essentially the same α1–β1–β2–α2(kinked)–β3 topology as the type-II KH domain. Comparison with the RbfA counterpart showed structural differences in specific regions that function as a putative RNA-binding site. Particularly, the α2 helix of mtRbfA forms a single helix with a moderate kink at the Ser-Ala-Ala sequence, whereas the corresponding α2 helix of RbfA is interrupted by a distinct kink at the Ala-x-Gly sequence, characteristic of bacterial RbfA proteins, to adopt an α2-kink-α3 conformation. Additionally, the region linking α1 and β1 differs considerably in the sequence and structure between RbfA and mtRbfA. These findings suggest some variations of the RNA-binding mode between them and provide a structural basis for mtRbfA function in mitoribosome biogenesis. [ABSTRACT FROM AUTHOR]

Evidence for the utility of pharmacist-driven antimicrobial stewardship programs remains limited. This study aimed to evaluate the usefulness of our institutional pharmacist-driven prospective audit with intervention and feedback (PAF) on the treatment of patients with bloodstream infections (BSIs). The effect of pharmacist-driven PAF was estimated using an interrupted time series analysis with a quasi-experimental design. The proportion of de-escalation during BSI treatment increased by 44% after the implementation of pharmacist-driven PAF (95% CI: 30–58, p < 0.01). The number of days of therapy decreased by 16 per 100 patient days for carbapenem (95% CI: −28 to −3.5, p = 0.012) and by 15 per 100 patient days for tazobactam/piperacillin (95% CI: −26 to −4.9, p < 0.01). Moreover, the proportion of inappropriate treatment in empirical and definitive therapy was significantly reduced after the implementation of pharmacist-driven PAF. Although 30-day mortality did not change, compliance with evidenced-based bundles in the BSI of Staphylococcus aureus significantly increased (p < 0.01). In conclusion, our pharmacist-driven PAF increased the proportion of de-escalation and decreased the use of broad-spectrum antibiotics, as well as the proportion of inappropriate treatment in patients with BSI. This indicates that pharmacist-driven PAF is useful in improving the quality of antimicrobial treatment and reducing broad-spectrum antimicrobial use in the management of patients with BSI. [ABSTRACT FROM AUTHOR]

Background: Postoperative nausea and vomiting (PONV) delays postoperative recovery, prolongs hospital stays, and hinders patients' return to society, thus making it a major cause of increased healthcare costs. It is also the most troubling postoperative complication in female patients undergoing surgery. However, in Japan, guidelines for the management of PONV have not been established, and the management protocol for PONV is left to each institution and anesthesiologist. Therefore, we developed criteria for intraoperative management of PONV. Methods: In female surgical patients, the usefulness of the criteria was evaluated by comparing the implementation rate of intraoperative management and PONV incidence before and after the establishment of the criteria. An Apfel simplified score (Apfel score) ≥2 was set as an indication for intraoperative management of PONV. Results: The implementation rate of intraoperative management increased from 91.2 to 96.0% after the introduction of the criteria. In patients with an Apfel score of 2, the intraoperative management implementation rate significantly increased from 81.1 to 94.7% (p = 0.016), while PONV incidence significantly decreased from 44.6 to 34.1% after the introduction of the criteria (p = 0.040). Conclusions: The criteria for intraoperative management of PONV increased the implementation rate of intraoperative management and decreased PONV incidence, indicating the usefulness of the criteria. [ABSTRACT FROM AUTHOR]

Matrin-3 is a multifunctional protein that binds to both DNA and RNA. Its DNA-binding activity is linked to the formation of the nuclear matrix and transcriptional regulation, while its RNA-binding activity is linked to mRNA metabolism including splicing, transport, stabilization, and degradation. Correspondingly, Matrin-3 has two zinc finger domains for DNA binding and two consecutive RNA recognition motif (RRM) domains for RNA binding. Matrin-3 has been reported to cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) when its disordered region contains pathogenic mutations. Simultaneously, it has been shown that the RNA-binding activity of Matrin-3 mediated by its RRM domains, affects the formation of insoluble cytoplasmic granules, which are related to the pathogenic mechanism of ALS/FTD. Thus, the effect of the RRM domains on the phase separation of condensed protein/RNA mixtures has to be clarified for a comprehensive understanding of ALS/FTD. Here, we report the 1H, 15N, and 13C resonance assignments of the two RNA binding domains and their solution structures. The resonance assignments and the solution structures obtained in this work will contribute to the elucidation of the molecular basis of Matrin-3 in the pathogenic mechanism of ALS and/or FTD. [ABSTRACT FROM AUTHOR]

Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor. Here the authors show that a viral protein interferes with the binding of phosphorylated eIF2 to eIF2B, thereby suppressing the host integrated stress response (ISR). This suppression of the ISR abrogates translational changes of the host and ameliorates neurite degradation under stress. [ABSTRACT FROM AUTHOR]

In humans, YTH (YT521-B homology) domain containing protein 2 (YTHDC2) plays a crucial role in the phase-shift from mitosis to meiosis. YTH domains bind to methylated adenosine nucleotides such as m6A. In a phylogenic tree, the YTH domain of YTHDC2 (YTH2) and that of the YTH containing protein YTHDC1 (YTH1) belong to the same sub-group. However, the binding affinity of m6A differs between these proteins. Here, we report 1H, 13C and 15N resonance assignment of YTH2 and its solution structure to examine the difference of the structural architecture and the dynamic properties of YTH1 and YTH2. YTH2 adopts a β1–α1–β2–α2–β3–β4–β5–α3–β6–α4 topology, which was also observed in YTH1. However, the β4–β5 loops of YTH1 and YTH2 are distinct in length and amino acid composition. Our data revealed that, unlike in YTH1, the structure of m6A-binding pocket of YTH2 formed by the β4–β5 loop is stabilized by electrostatic interaction. This assignment and the structural information for YTH2 will provide the insight on the further functional research of YTHDC2. [ABSTRACT FROM AUTHOR]

Paracostibite (CoSbS) is a promising candidate for n-type thermoelectric materials. In this study, a nanostructured CoSbS pellet was fabricated using chemically synthesized Co–Sb–S nanoparticles as building blocks. The CoSbS pellet showed the highest electrical conductivity (σ = 141 S/cm at 661 K) and lowest thermal conductivity [κ ≅ 2 W/(m K)] among the reported CoSbS. Detailed analysis of the electrical transport process in a wide temperature range (3 K–661 K) revealed the existence of a donor level. At a temperature less than 170 K, the resistivity showed Mott variable-range hopping behavior, while the band conduction became dominant as the temperature increased. Nanograins in the pellet significantly enhanced phonon scattering, resulting in suppression of κ. The maximum dimensionless figure of merit value was 0.05 at 661 K, which is comparable with previously reported values for CoSbS TE materials. [ABSTRACT FROM AUTHOR]

Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO4) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm infants in a retrospective cohort study. We used a nationwide obstetrical database from 2014. A total of 4,622 live preterm infants born at 32–36 gestational weeks participated. Fourteen risk factors based on both clinical relevance and univariate analysis were adjusted in multivariable logistic regression analyses. Neonatal hyperkalemia and hypoglycemia occurred in 7.6% (284/3,732) and 32.4% (1,458/4,501), respectively. Occurrence of hyperkalemia was associated with concomitant usage of ritodrine and MgSO4 compared with no usage (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.09–2.15). Occurrence of hypoglycemia was associated with ritodrine alone (aOR 2.58 [CI 2.21–3.01]) and with concomitant usage of ritodrine and MgSO4 (aOR 2.59 [CI 2.13–3.15]), compared with no usage, and was associated with long-term usage (≥ 48 hours) of ritodrine and cessation directly before delivery. In conclusion, in late preterm infants, usage of ritodrine together with MgSO4 was associated with occurrence of critical neonatal hyperkalemia, and long-term usage of ritodrine and cessation directly before delivery were associated with neonatal hypoglycemia. [ABSTRACT FROM AUTHOR]

The use of allogeneic, pluripotent stem‐cell‐derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator‐initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)‐homozygous‐induced pluripotent stem cell (iPSC)‐derived anti–glypican‐3 (GPC3) chimeric antigen receptor (CAR)‐expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety and producibility. In this paper, we describe our methods for the stable, feeder‐free production of CAR‐expressing NK/ILC cells from CAR‐transduced iPSC with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8‐3.6 × 106 iPSC within 7 weeks was 1.8‐4.0 × 109. These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity and interferon gamma (IFN‐γ) production against GPC3‐expressing tumor cells. When the CAR‐NK/ILC cells were injected into a GPC3‐positive, ovarian‐tumor‐bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival of the animals. When the cells were injected into immunodeficient mice during non–clinical safety tests, no acute systemic toxicity or tumorigenicity of the final product or residual iPSC was observed. In addition, our test results for the CAR‐NK/ILC cells generated with clinical manufacturing standards are encouraging, and these methods should accelerate the development of allogeneic pluripotent stem cell‐based immune cell cancer therapies. [ABSTRACT FROM AUTHOR]

Human lymphocyte antigen (HLA) class I molecules play a central role in cytotoxic T lymphocytes (CTL)‐based antitumor immunity. However, the expression rate of HLA class I in cancer cells remains a topic of discussion. We compared HLA class I expression levels between cancer cells and surrounding non–tumorous hepatocytes in 20 early‐stage hepatocellular carcinoma (HCC) patients by immunohistochemistry using EMR 8‐5. The expression levels of HLA class I were classified as negative, incomplete positive or complete positive. Similarly, for various types of solid cancers, HLA class I expression was examined. For the HLA class I expression in cancer cells, among 20 HCC patients, 13 were complete positive, 3 were incomplete positive, and 4 were negative. In addition, 15 (75.0%) had higher expression levels of HLA class I in cancer cells compared with that in surrounding non–tumorous hepatocytes. An interferon‐γ (IFN‐γ) enzyme‐linked immunospot (ELISPOT) assay indicated that cancer cells with positive expression of HLA class I had strong sensitivity to antigen‐specific CTL. We suggested that HLA class I expression in cancer cells could be involved in the clinical prognosis of HCC patients. Similarly, 66.7%, 100.0%, 66.7% and 62.5% of patients with early‐stage pancreatic, gallbladder, esophageal and breast cancers, respectively, had higher expression levels of HLA class I in cancer cells than in surrounding normal tissue cells. We suggest that in several early‐stage solid cancers, including HCC, HLA class I expression levels in cancer cells are higher than that in surrounding normal tissue cells, which could result in the anti–tumor effect of CTL‐based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

To mitigate the damage caused by debris flows resulting from heavy precipitation and to aid in evacuation plan preparation, areas at risk should be mapped on a scale appropriate for affected individuals and communities. We tested the effectiveness of simply identifying debris-flow hazards through automated derivation of surface curvatures using LiDAR digital elevation models. We achieved useful correspondence between plan curvatures and areas of existing debris-flow damage in two localities in Japan using the analysis of digital elevation models (DEMs). We found that plan curvatures derived from 10m DEMs may be useful to indicate areas that are susceptible to debris flow in mountainous areas. In residential areas located on gentle sloping debris flow fans, the greatest damage to houses was found to be located in the elongated depressions that are connected to mountain stream valleys. Plan curvature derived from 5m DEM was the most sensitive indicators for susceptibility to debris flows. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical features and surgical outcomes of macular dragging or tractional retinal detachment that occurred as a result of fibrovascular tissue (FT) progression toward the posterior retina in eyes with familial exudative vitreoretinopathy (FEVR). Methods: The medical records of 4 patients (2 girls, 2 boys) with FEVR were reviewed retrospectively. Results: All 4 patients had retinal dragging or radial retinal folds with FT in the peripheral retina in at least 1 eye at the initial visit. During the follow-up period, all the patients had FT that progressed toward the posterior pole and developed from the peripheral FT, resulting in macular dragging or posterior tractional retinal detachment. Vitrectomy with or without scleral buckling and laser photocoagulation were performed in all 4 cases, with removal of the FT in the posterior pole and segmentation of the FT between the posterior and peripheral FT. The traction resolved postoperatively and the retina extended in all 4 cases. Conclusions: In 4 cases with FEVR, the FT developed from the peripheral FT, progressed toward the posterior retina, and generated traction. Vitrectomy with focal removal and segmentation of the FT in the posterior pole might be a good surgical option in such eyes. [ABSTRACT FROM AUTHOR]

The spliceosomal protein SF3b49, a component of the splicing factor 3b (SF3b) protein complex in the U2 small nuclear ribonucleoprotein, contains two RNA recognition motif (RRM) domains. In yeast, the first RRM domain (RRM1) of Hsh49 protein (yeast orthologue of human SF3b49) reportedly interacts with another component, Cus1 protein (orthologue of human SF3b145). Here, we solved the solution structure of the RRM1 of human SF3b49 and examined its mode of interaction with a fragment of human SF3b145 using NMR methods. Chemical shift mapping showed that the SF3b145 fragment spanning residues 598-631 interacts with SF3b49 RRM1, which adopts a canonical RRM fold with a topology of β1-α1-β2-β3-α2-β4. Furthermore, a docking model based on NOESY measurements suggests that residues 607-616 of the SF3b145 fragment adopt a helical structure that binds to RRM1 predominantly via α1, consequently exhibiting a helix-helix interaction in almost antiparallel. This mode of interaction was confirmed by a mutational analysis using GST pull-down assays. Comparison with structures of all RRM domains when complexed with a peptide found that this helix-helix interaction is unique to SF3b49 RRM1. Additionally, all amino acid residues involved in the interaction are well conserved among eukaryotes, suggesting evolutionary conservation of this interaction mode between SF3b49 RRM1 and SF3b145. [ABSTRACT FROM AUTHOR]

The crystal structure of Schizosaccharomyces pombe guanine nucleotide exchange factor eIF2B, providing a structural framework for the eIF2B-mediated mechanism of stress-induced translational control.Translation initiation factor 2B structure: The guanine nucleotide exchange factor, eIF2B, is key to eukaryotic translation initiation, acting on the γ subunit of eIF2. During stress, the α subunit of eIF2 is phosphorylated; this inhibits the activity of eIF2B, resulting in downregulation of general translation. Shigeyuki Yokoyama and colleagues have now solved the structure of the ten-subunit eIF2B complex of fission yeast. The regulatory hexameric core is bounded on opposite faces by dimeric catalytic subcomplexes. The sites of interaction with the eIF2α and eIF2γ subunits are identified. Modelling reveals how phosophorylation of the α subunit affects its binding to eIF2B, and how assembly on the non-productive eIF2–eIF2B complex inhibits nucleotide exchange on eIF2γ.Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the eukaryotic translation initiation factor 2B (eIF2B)1,2. eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of α-, β- and γ-subunits. eIF2B exchanges GDP for GTP on the γ-subunit of eIF2 (eIF2γ), and is inhibited by stress-induced phosphorylation of eIF2α. eIF2B is a heterodecameric complex of two copies each of the α-, β-, γ-, δ- and ε-subunits3; its α-, β- and δ-subunits constitute the regulatory subcomplex4, while the γ- and ε-subunits form the catalytic subcomplex5. The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the α2β2δ2 hexameric regulatory subcomplex binds two γε dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2α-binding and eIF2γ-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2γ-binding interface is located close to the conserved ‘NF motif’, which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2α, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2α phosphorylation generates the ‘nonproductive’ eIF2–eIF2B complex5, which prevents nucleotide exchange on eIF2γ, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced translational control. [ABSTRACT FROM AUTHOR]

Combining different properties derived from different materials into a single nanoparticle allows diverse applications in many fields. In terms of plasmonic and magnetic properties, Ag and FeCo are the best candidates due to their optimal physical properties – Ag has the highest scattering cross-section of all plasmonic materials and FeCo has the highest saturation magnetization of all magnetic materials. Recently we have succeeded in synthesizing magnetic–plasmonic hybrid Ag@FeCo@Ag core–shell–shell nanoparticles; however, the formation mechanism of the hybrid nanoparticles was still unclear. In this study, we investigated the formation mechanism of the Ag@FeCo@Ag double shell nanoparticles. Understanding the formation mechanism will help in tuning the physical properties of the Ag@FeCo@Ag nanoparticles and in designing novel heterostructured nanoparticles. [ABSTRACT FROM AUTHOR]

Key Clinical Message Autologous formalin-fixed tumor vaccine ( AFTV) suppressed re-recurrence for more than 32 months of multiple-recurrent hepatocellular carcinoma based on hepatitis C virus-induced liver cirrhosis in a case with previous recurrence interval, 51-, 28-, 12-, and 4-months. We detected glypican-3-specific cytotoxic T lymphocytes in the peripheral blood at 12 months after AFTV. [ABSTRACT FROM AUTHOR]

ABSTRACT The family of cytoplasmic polyadenylation element binding proteins CPEB1, CPEB2, CPEB3, and CPEB4 binds to the 3′-untranslated region (3′-UTR) of mRNA, and plays significant roles in mRNA metabolism and translation regulation. They have a common domain organization, involving two consecutive RNA recognition motif (RRM) domains followed by a zinc finger domain in the C-terminal region. We solved the solution structure of the first RRM domain (RRM1) of human CPEB3, which revealed that CPEB3 RRM1 exhibits structural features distinct from those of the canonical RRM domain. Our structural data provide important information about the RNA binding ability of CPEB3 RRM1. Proteins 2014; 82:2879-2886. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Tissue-specific alternative pre-mRNA splicing is often cooperatively regulated by multiple splicing factors, but the structural basis of cooperative RNA recognition is poorly understood. In Caenorhabditis elegans, ligand binding specificity of fibroblast growth factor receptors (FGFRs) is determined by mutually exclusive alternative splicing of the sole FGFR gene, egl-15. Here we determined the solution structure of a ternary complex of the RNA-recognition motif (RRM) domains from the RBFOX protein ASD-1, SUP-12 and their target RNA from egl-15. The two RRM domains cooperatively interact with the RNA by sandwiching a G base to form the stable complex. Multichromatic fluorescence splicing reporters confirmed the requirement of the G and the juxtaposition of the respective cis elements for effective splicing regulation in vivo. Moreover, we identified a new target for the heterologous complex through an element search, confirming the functional significance of the intermolecular coordination. [ABSTRACT FROM AUTHOR]

Antigen-specific cancer immunotherapy is a promising strategy for improving cancer treatment. Recently, many tumor-associated antigens and their epitopes recognized by cytotoxic T lymphocytes (CTLs) have been identified. However, the density of endogenously presented antigen-derived peptides on tumor cells is generally sparse, resulting in the inability of antigen-specific CTLs to work effectively. We hypothesize that increasing the density of an antigen-derived peptide would enhance antigen-specific cancer immunotherapy. Here, we demonstrated that intratumoral peptide injection leads to additional peptide loading onto major histocompatibility complex class I molecules of tumor cells, enhancing tumor cell recognition by antigen-specific CTLs. In in vitro studies, human leukocyte antigen (HLA)-A*02:01-restricted glypican-3 (FVGEFFTDV) and cytomegalovirus (NLVPMVATV) peptide-specific CTLs showed strong activity against all peptide-pulsed cell lines, regardless of whether the tumor cells expressed the antigen. In in vivo studies using immunodeficient mice, glypican-3 and cytomegalovirus peptides injected into a solid mass were loaded onto HLA class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, intratumoral injection of ovalbumin peptide (SIINFEKL) was effective for tumor growth inhibition and survival against ovalbumin-negative tumors without adverse reactions. Moreover, we demonstrated an antigen-spreading effect that occurred after intratumoral peptide injection. Intratumoral peptide injection enhances tumor cell antigenicity and may be a useful option for improvement in antigen-specific cancer immunotherapy against solid tumors. [ABSTRACT FROM AUTHOR]

Abstract: The WWE domain is often identified in proteins associated with ubiquitination or poly-ADP-ribosylation. Structural information about WWE domains has been obtained for the ubiquitination-related proteins, such as Deltex and RNF146, but not yet for the poly-ADP-ribose polymerases (PARPs). Here we determined the solution structures of the WWE domains from PARP11 and PARP14, and compared them with that of the RNF146 WWE domain. NMR perturbation experiments revealed the specific differences in their ADP-ribose recognition modes that correlated with their individual biological activities. The present structural information sheds light on the ADP-ribose recognition modes by the PARP WWE domains. [Copyright &y& Elsevier]

The oxidation of solution-synthesized iron (Fe) and iron carbide (Fe2C) nanoparticles was studied in an environmental scanning transmission electron microscope (ESTEM) at elevated temperatures under oxygen gas. The nanoparticles studied had a native oxide shell present, that formed after synthesis, an ~3 nm iron oxide (FexOy) shell for the Fe nanoparticles and ~2 nm for the Fe2C nanoparticles, with small void areas seen in several places between the core and shell for the Fe and an ~0.8 nm space between the core and shell for the Fe2C. The iron nanoparticles oxidized asymmetrically, with voids on the borders between the Fe core and FexOy shell increasing in size until the void coalesced, and finally the Fe core disappeared. In comparison, the oxidation of the Fe2C progressed symmetrically, with the core shrinking in the center and the outer oxide shell growing until the iron carbide had fully disappeared. Small bridges of iron oxide formed during oxidation, indicating that the Fe transitioned to the oxide shell surface across the channels, while leaving the carbon behind in the hollow core. The carbon in the carbide is hypothesized to suppress the formation of larger crystallites of iron oxide during oxidation, and alter the diffusion rates of the Fe and O during the reaction, which explains the lower sensitivity to oxidation of the Fe2C nanoparticles. [ABSTRACT FROM AUTHOR]

Copper selenide-sulfide nanostructures were synthesized using metal-organic chemical routes in the presence of Cu- and Se-precursors as well as S-containing compounds. Our goal was first to examine if the initial Cu/Se 1:1 molar proportion in the starting reagents would always lead to equiatomic composition in the final product, depending on other synthesis parameters which affect the reagents reactivity. Such reaction conditions were the types of precursors, surfactants and other reagents, as well as the synthesis temperature. The use of 'hot-injection' processes was avoided, focusing on 'non-injection' ones; that is, only heat-up protocols were employed, which have the advantage of simple operation and scalability. All reagents were mixed at room temperature followed by further heating to a selected high temperature. It was found that for samples with particles of bigger size and anisotropic shape the CuSe composition was favored, whereas particles with smaller size and spherical shape possessed a Cu2−xSe phase, especially when no sulfur was present. Apart from elemental Se, Al2Se3 was used as an efficient selenium source for the first time for the acquisition of copper selenide nanostructures. The use of dodecanethiol in the presence of trioctylphosphine and elemental Se promoted the incorporation of sulfur in the materials crystal lattice, leading to Cu-Se-S compositions. A variety of techniques were used to characterize the formed nanomaterials such as XRD, TEM, HRTEM, STEM-EDX, AFM and UV-Vis-NIR. Promising results, especially for thin anisotropic nanoplates for use as electrocatalysts in nitrogen reduction reaction (NRR), were obtained. [ABSTRACT FROM AUTHOR]

A 77-year-old Japanese woman initially presented with non-Hodgkin's lymphoma involving her neck, axillary and inguen lymph nodes. She had edematous erythema and nodules limited to the skin in zosteriform distribution on the left side chest wall along the T4–5 dermatome. In addition, since 1970, we have mainly been collecting English-language articles on malignant skin tumors and skin metastasis described as zosteriform in the title, and we have reviewed a total of 29 cases, including our own. It should be mentioned that 59% of the cases reported had been diagnosed with herpes zoster at the time of the initial examination and that many of them had received drug therapy (e.g. acyclovir). We wish to add the dermatomic eruption mimicking zoster sine herpete to the list of possible presentations of cutaneous malignancies. [ABSTRACT FROM AUTHOR]

The NMR structure of a 12-mer RNA derived from the helix 6 of SRP RNA from Pyrococcus furiosus , whose loop-closing base pair is U:G, was determined, and the structural and thermodynamic properties of the RNA were compared with those of a mutant RNA with the C:G closing base pair. Although the structures of the two RNAs are similar to each other and adopt the GNRR motif, the conformational stabilities are significantly different to each other. It was suggested that weaker stacking interaction of the GAAG loop with the U:G closing base pair in 12-mer RNA causes the lower conformational stability. [ABSTRACT FROM AUTHOR]

A polarization-sensitive Fourier domain optical coherence tomography (PS-FD-OCT) system is demonstrated. This OCT system is based on a spectral interferometer, does not require mechanical axial scanning, and enables phase information to be used in an OCT image. Owing to this phase information, the system requires only two measurements for determining the Jones matrix images and Müller images of biological samples. This system reveals the birefringence properties of the inner surface of a porcine esophagus. [ABSTRACT FROM AUTHOR]

The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively;p= 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively;p= 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine. [ABSTRACT FROM AUTHOR]

Ultrasonic medical equipment is used in not only diagnosis but also therapy such as that for treating hyperthermia. Many researchers are also studying high-frequency ultrasonic imaging systems with interluminal or catheter transducers. In both applications, an acoustic lens might improve the characteristics of ultrasonic medical probes. In this paper, a small acoustic lens for an ultrasonic catheter-type probe is described. The conventional three-dimensional finite-difference time-domain (3D FDTD) with orthogonal coordinates requires a large memory and a long calculation time to estimate the characteristics of the lens. To overcome these disadvantages, a simple two-dimensional (2D) FDTD calculation based on symmetry is proposed in this paper. A virtual spherical sound source whose amplitude distribution is equal to that of the sound propagation field of an actual sound source is also used to simplify the calculation. A numerical model of the lens with a lens holder is constructed. The experimental results agree well with the calculated results with the lens holder. [ABSTRACT FROM AUTHOR]