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In the history of peptide chemical synthesis, amino acid-protecting groups have become basic, essential, and common moieties. As the use of protecting groups for amino acids effectively suppresses unwanted side reactions and enables the desired reaction to proceed selectively, their use continues regardless of the complexities of the protection processes and the waste generated by the deprotection residues. We developed peptide bond formation between unprotected amino acids to form silacyclic dipeptides. This is the first report of the proceeding cross-condensation between an unprotected amino acid and another unprotected amino acid. The selectivity, reaction yields, and purity of the products were satisfactory. In addition, we demonstrated further elongation of these compounds and achieved convergent synthesis with peptide-peptide elongation without the use of coupling reagents. Thus, these methods showed the potential to unlock a new, more efficient synthetic path toward polypeptides.

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Efficient and straightforward peptide bond formation of N-, and C-terminal unprotected amino acids was successfully achieved by using trimethylaluminum. The coupling reaction was accomplished by pre-reaction of N-, and C-terminal unprotected amino acids and trimethylaluminum to form a five-membered ring that smoothly reacted with nucleophilic amino acid esters. This simple and highly efficient reaction system allows one-pot tripeptide synthesis without the need for expensive coupling reagents. Furthermore, peptide bond formation can be effectively achieved even for amino acids with bulky substituents at the side chain to afford the corresponding tripeptides in high yields in a one-pot manner. In addition, the reaction can be applied for further peptide elongation by the subsequent addition of amino acids and trimethylaluminum. We anticipate that this cost-effective, straightforward, and efficient protocol will be useful for the synthesis of a wide variety of peptides.

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The retinal pathology of genetically confirmed neuronal intranuclear inclusion disease (NIID) is yet unknown. We report the ocular findings in four NIID patients with NOTCH2NLC GGC repeat expansion to investigate the pathology of retinopathy. All four NIID patients were diagnosed by skin biopsy and NOTCH2NLC GGC repeat analysis. Ocular findings in patients with NIID were studied using fundus photographs, optical coherence tomographic images (OCT), and full-field electroretinograms (ERGs). The histopathology of the retina was studied on autopsy samples from two cases with immunohistochemistry. All patients had an expansion of the GGC repeat (87-134 repeats) in the NOTCH2NLC. Two patients were legally blind and had been diagnosed with retinitis pigmentosa prior to the diagnosis of NIID and assessed with whole exome sequencing to rule out comorbidity with other retinal diseases. Fundus photographs around the posterior pole showed chorioretinal atrophy in the peripapillary regions. OCT showed thinning of the retina. ERGs showed various abnormalities in cases. The histopathology of autopsy samples showed diffusely scattered intranuclear inclusions throughout the retina from the retinal pigment epithelium to the ganglion cell layer, and optic nerve glial cells. And severe gliosis was observed in retina and optic nerve. The NOTCH2NLC GGC repeat expansion causes numerous intranuclear inclusions in the retina and optic nerve cells and gliosis. Visual dysfunction could be the first sign of NIID. We should consider NIID as one of the causes of retinal dystrophy and investigate the GGC repeat expansion in NOTCH2NLC.

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Two new recyclable silicon-based hydrophobic tags were developed for installing them at the C-terminal of peptides to increase the solubility in organic solvents and the reactivity of the peptides during liquid-phase peptide synthesis (LPPS). They comprise a siloxy group containing tag and an arylsilyl group containing tag. The hydrophobicity of these tags is much greater than those of previously reported examples. The siloxy group containing tag is compatible with Fmoc-deprotection conditions (Fmoc-chemistry) and hydrogenation conditions (Cbz-chemistry), while the arylsilyl group containing one is resistant to Fmoc-deprotection conditions (Fmoc-chemistry) and Boc-deprotection conditions (Boc-chemistry). Using the siloxy group containing tag, protected DRGN-1, a peptide containing 14 amino acid residues was prepared successfully by using linear synthesis combined with one convergent synthesis step. Using the arylsilyl group containing tag, a poly alanine chain containing 7 alanine residues was synthesized. The arylsilyl group containing tag can also be installed at the N-terminal to elongate the peptides from the N-terminal to the C-terminal. The yields and the solubility of the products in organic solvents in each step were good to excellent with the assistance of these silicon-based tags.

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A new type of peptide bond formation utilizing silacyclic amino acids or peptides is described. This work has the following advantages: (1) imidazolylsilane is a highly fascinating coupling reagent for dipeptide synthesis from N-,C-terminal unprotected amino acids with amino acid tert-butyl esters; (2) deprotection of the tert-butyl ester at the C-terminus and cyclization sequentially proceed depending on reaction conditions to afford novel silacyclic dipeptides; (3) the cyclized products show a remarkable capacity as substrates of peptide elongation because the silacyclic compounds can act as both nucleophiles and electrophiles, and this capacity lead to one-pot site-selective tetra- and oligopeptide syntheses. These innovative advantages will help to simplify classical peptide synthesis significantly.

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The application of remote sensing in plant breeding can provide rich information about the growth processes of plants, which leads to better understanding concerning crop yield. It has been shown that traits measured by remote sensing were also beneficial for genomic prediction (GP) because the inclusion of remote sensing data in multitrait models improved prediction accuracies of target traits. However, the present multitrait GP model cannot incorporate high-dimensional remote sensing data due to the difficulty in the estimation of a covariance matrix among the traits, which leads to failure in improving its prediction accuracy. In this study, we focused on growth models to express growth patterns using remote sensing data with a few parameters and investigated whether a multitrait GP model using these parameters could derive better prediction accuracy of soybean [Glycine max (L.) Merr.] biomass. A total of 198 genotypes of soybean germplasm were cultivated in experimental fields, and longitudinal changes of their canopy height and area were measured continuously via remote sensing with an unmanned aerial vehicle. Growth parameters were estimated by applying simple growth models and incorporated into the GP of biomass. By evaluating heritability and correlation, we showed that the estimated growth parameters appropriately represented the observed growth curves. Also, the use of these growth parameters in the multitrait GP model contributed to successful biomass prediction. We conclude that the growth models could describe the genetic variation of soybean growth curves based on several growth parameters. These dimension-reduction growth models will be indispensable for extracting useful information from remote sensing data and using this data in GP and plant breeding.

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The development of methods for amide bond formation without recourse to typical condensation reagents has become an emerging research area and has been actively explored in the past quarter century. Inspired by the structure of vitamin B12, we have developed a metal-templated macrolactamisation that generates a new wave towards classical macrolactam synthesis. Further, distinct from the extensively used methods with condensation reagents or catalysts based on catalyst/reagent control our metal-catalysed methods based on substrate control can effectively address long-standing challenges such as racemisation in the field of peptide chemistry. In addition, the substrate-controlled strategy demonstrates the feasibility of "remote" peptide bond-forming reaction catalysed by a metal-ligand complex. Moreover, an originally designed hydrosilane/aminosilane system can avoid not only racemisation but also unnecessary waste production. This feature article documents our discovery and application of our original approaches in amide bond formation.

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Non-additive (dominance and epistasis) effects have remarkable influences on hybrid performance, e.g., via heterosis. Nevertheless, only additive effects are often considered in genomic predictions (GP). In this study, we demonstrated the importance of dominance effects in the prediction of hybrid performance in bioenergy sorghum [Sorghum bicolor (L.) Moench]. The dataset contained more than 400 hybrids between 200 inbred lines and two testers. The hybrids exhibited considerable heterosis in culm length and fresh weight, and the degree of heterosis was consistent with the genetic distance from the corresponding tester. The degree of heterosis was further different among subpopulations. Conversely, Brix exhibited limited heterosis. Regarding GP, we examined three statistical models and four training dataset types. In most of the dataset types, genomic best linear unbiased prediction (GBLUP) with additive effects had lower prediction accuracy than GBLUP with additive and dominance effects (GBLUP-AD) and Gaussian kernel regression (GK). The superiority of GBLUP-AD and GK depended on the level of dominance variance, which was high for culm length and fresh weight, and low for Brix. Considering subpopulations, the influence of dominance was more complex. Our findings highlight the importance of considering dominance effects in GP models for sorghum hybrid breeding.

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A Lewis-acid-catalyzed method for the substrate-directed formation of peptide bonds has been developed, and this powerful approach is utilized for the new "remote" activation of carboxyl groups under solvent-free conditions. The presented method has the following advantages: (1) the high-yielding peptide synthesis uses a tantalum catalyst for any amino acids; (2) the reaction proceeds without any racemization; (3) the new substrate-directed chemical ligation using the titanium catalyst is applicable to convergent peptide synthesis. These advantages overcome some of the unresolved problems in classical peptide synthesis.

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In the presence of palladium on carbon (Pd/C) as a catalyst, hydrogenation of aliphatic nitriles in cyclohexane efficiently proceeded at 25-60 °C under ordinary hydrogen gas pressure to afford the corresponding tertiary amines. However, the use of rhodium on carbon (Rh/C) led to the highly selective generation of secondary amines. Hydrogenation of aromatic nitriles and cyclohexanecarbonitrile selectively produced secondary amines in the presence of either Pd/C or Rh/C.

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Carbon monoxide (CO) and styrene derivatives that can be both generated by a palladium on carbon (Pd/C)-catalyzed carbon-carbon (C-C) bond cleavage reaction of cinnamaldehyde derivatives were effectively utilized in further palladium-catalyzed C-C bond forming reactions in a direct and practical way. CO derived from simple and affordable CO carriers such as cinnamaldehyde or terephthalaldehyde was efficiently employed in the in situ CO fixation with various aromatic iodides through a palladium-catalyzed carbonylation followed by an inter- or intramolecular coupling reaction with alcohols to afford the corresponding esters or lactones, respectively. Styrene derivatives were also efficient substrates in an in situ Mizoroki-Heck-type cross-coupling reaction with aryl iodides, leading to the effective formation of asymmetric stilbenes. The decarbonylation of cinnamaldehyde derivatives and the subsequent independent syntheses of both esters/lactones and 1,2-diarylethenes could be achieved in a virtual one-pot and in situ reaction using a H-shaped pressure-tight glass-sealed tube consisting of two independent but laterally connected reaction tubes in the gas space.

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Profiling elemental contents in wheat grains and clarifying the underlying genetic systems are important for the breeding of biofortified crops. Our objective was to evaluate the genetic potential of 269 Afghan wheat landraces for increasing elemental contents in wheat cultivars. The contents of three major (Mg, K, and P) and three minor (Mn, Fe, and Zn) elements in wheat grains were measured by energy dispersive X-ray fluorescence spectrometry. Large variations in elemental contents were observed among landraces. Marker-based heritability estimates were low to moderate, suggesting that the elemental contents are complex quantitative traits. Genetic correlations between two locations (Japan and Afghanistan) and among the six elements were estimated using a multi-response Bayesian linear mixed model. Low-to-moderate genetic correlations were observed among major elements and among minor elements respectively, but not between major and minor elements. A single-response genome-wide association study detected only one significant marker, which was associated with Zn, suggesting it will be difficult to increase the elemental contents of wheat by conventional marker-assisted selection. Genomic predictions for major elemental contents were moderately or highly accurate, whereas those for minor elements were mostly low or moderate. Our results indicate genomic selection may be useful for the genetic improvement of elemental contents in wheat.

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We herein describe the first known case of diffuse alveolar hemorrhage (DAH) associated with the administration of Makyo-kanseki-to, a Chinese herbal drug. A 64-year-old man with bronchial asthma presented with persistent cough. Makyo-kanseki-to was prescribed as an adjunctive treatment for bronchial asthma. Immediately after drug ingestion, the patient expectorated bloody sputum. DAH was diagnosed based on the presence of bilateral ground-glass opacity which was identified on chest computed tomography and bloody bronchoalveolar lavage fluid. We diagnosed that the administration of Makyo-kanseki-to was the responsible medication because the hemorrhage developed immediately after drug ingestion and resolved after the cessation of such medication with no subsequent recurrence.

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Background. Submacular hemorrhage can occur after blunt trauma to the eye. Intravitreal tissue plasminogen activator (tPA) and gas injection are often used for treatment and are effective for submacular hemorrhage caused by age-related macular degeneration. This report describes the clinical outcome in a child with submacular hemorrhage caused by traumatic choroidal rupture who underwent successful intravitreal tPA injection and pneumatic displacement. Case Presentation. A 10-year-old boy developed sudden decrease of vision and a central scotoma in his right eye after trauma. Submacular hemorrhage was found in the eye. Visual acuity was 20/70 OD. Tissue plasminogen activator (12.5 µg in 0.05 mL) and 0.3 mL of pure sulfur hexafluoride were injected into the vitreous cavity under general anesthesia. After surgery, the patient was instructed to maintain a prone position. Displacement of the submacular hemorrhage from the fovea revealed a choroidal rupture, presumed to be the cause of the hemorrhage. After 4 months of follow-up, visual acuity was restored and final visual acuity is 20/16. Conclusion. Intravitreal tPA and gas injection can be an effective treatment for children with submacular hemorrhage.

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We have demonstrated a palladium on carbon-catalyzed approach to regioselectively alter the cleavage sites of the C-C bonds of cinnamaldehyde derivatives by a slight change in the reaction conditions in isopropanol under an O2 atmosphere. Styrene derivatives could be selectively formed by the addition of Na2CO3 in association with the dissociation of carbon monoxide, while benzaldehyde derivatives were generated by the addition of CuCl and morpholine instead of Na2CO3.

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This study was carried out with the aim of developing the methodology to determine elemental composition in wheat and identify the best germplasm for further research. Orphan and genetically diverse Afghan wheat landraces were chosen and EDXRF was used to measure the content of some of the elements to establish elemental composition in grains of 266 landraces using 10 reference lines. Four elements, K, Mg, P, and Fe, were measured by standardizing sample preparation. The results of hierarchical cluster analysis using elemental composition data sets indicated that the Fe content has an opposite pattern to the other elements, especially that of K. By systematic analysis the best wheat germplasms for P content and Fe content were identified. In order to compare the sensitivity of EDXRF, the ICP method was also used and the similar results obtained confirmed the EDXRF methodology. The sampling method for measurement using EDXRF was optimized resulting in high-throughput profiling of elemental composition in wheat grains at low cost. Using this method, we have characterized the Afghan wheat landraces and isolated the best genotypes that have high-elemental content and have the potential to be used in crop improvement.

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BACKGROUND: The serum level of eosinophil-derived neurotoxin (EDN), a protein present in eosinophil granules, correlates with the severity of childhood asthma. However, the relationship between the serum EDN level and the severity of adult asthma has not been sufficiently investigated. OBJECTIVE: This study aimed to elucidate the correlation between the serum EDN level and markers of severity in adult asthma. METHODS: The subjects comprised 83 adult patients who had asthma and who were undergoing treatment. Of these patients, 40 were positive for house-dust-specific immunoglobulin E (IgE) antibodies; 9 patients with severe adult asthma who were treated with omalizumab were included in the study. We measured the blood eosinophil count, serum EDN, and eosinophil cationic protein levels before investigating the correlations of these parameters with lung function and symptom score. RESULTS: There were no significant correlations between the blood eosinophil count or serum EDN or eosinophil cationic protein level with lung function and the symptom score in patients with asthma. However, serum EDN level was inversely correlated with the decrease percentage forced expiratory volume in 1 second (%FEV1) in patients positive for house-dust-specific IgE antibody (R = -0.54; p < 0.05), whereas no such correlation was observed in patients with negative results for house-dust-specific IgE antibody (R = 0.11; p = 0.468). A significant correlation was observed between a decrease in serum EDN level from baseline and lung function improvement after 8 weeks of omalizumab therapy (R = -0.77; p = 0.015). CONCLUSION: Serum EDN level may be a useful marker for monitoring persistent airflow limitation in adult patients with asthma who had positive results for house-dust-specific IgE antibodies.

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BACKGROUND: Omalizumab, a monoclonal anti-IgE antibody, is currently indicated for the treatment of moderate-to-severe allergic asthma. To measure active IgE levels in sera from patients treated with omalizumab, the IgE subfraction in complex with omalizumab should be eliminated from total IgE, and free IgE levels can then be determined. With the aim of therapeutic monitoring for anti-IgE therapy, we developed a new ELISA for free IgE. METHODS: We used recombinant human soluble FcεRIα as a capture antigen and a biotinylated polyclonal anti-IgE antibody for detection. Using the newly developed ELISA, we measured the serum free IgE levels weekly in four asthmatic patients after their first omalizumab injection. We also measured the serum free IgE levels in 54 patients treated with omalizumab for over 4 weeks. RESULTS: This assay was technically robust, the mean recovery rate in serum was 93.16% ± 5.34%. For all patients, omalizumab treatment significantly reduced serum free IgE levels prior to the second omalizumab injection. To maintain the benefit of omalizumab, serum free IgE concentrations should be <50 ng/ml. However, in 14 of 54 patients treated with omalizumab for over 4 weeks, serum free IgE concentrations measured by our ELISA were >50 ng/ml. CONCLUSIONS: Our data suggest that the measurement of free IgE levels using our newly developed ELISA would be useful for monitoring serum free IgE levels during omalizumab therapy.

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BACKGROUND: Increased osmolality of the airway surface fluid due to water loss associated with hyperventilation is considered to be a cause of exercise-induced asthma (EIA). AIM: We investigated the influence of changes in osmolality on airway epithelial ion transport in guinea pigs. METHODS: We explored from measuring open circuit potential difference in challenge with hypertonic saline or mannitol. RESULTS: Diphenylamine-2-carboxylate (DPC), amiloride, and disodium cromoglycate (DSCG) prevented an increase of the potential difference (PD) after exposure of tracheal mucosa to 0.9-10.8% hypertonic saline solutions (HSSs) (p < 0.05, p < 0.01, and p < 0.01, respectively on 1.8%). An increase of the PD was observed after a single dose of 1.8% hypertonic saline solution (HSS) was applied to the mucosa, but no increase was observed after a single exposure to a 585 mOsm/kg aqueous mannitol solution (585AMS). The results remained the same when a Cl-free solution was used as the perfusate. The change of airway epithelial cell thickness was only suppressed significantly by DPC (p < 0.01) after 1.8% HSS challenge. CONCLUSIONS: Not only the change of osmolality, but also changes of the Cl- and Na+ concentrations in airway surface fluid seem to have an important influence on the PD. cAMP-dependent Cl- channel may have a role, and the same mechanism may provoke EIA.

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