In the study of English denominal adjectives, scholarly attention has predominantly centred on those with Latinate suffixes (e.g., -al, -ary, and -ic/-ical), which are well-known as relational ...adjectives (RAdjs) and are extensively scrutinised in the existing literature. Conversely, those with English native suffixes (e.g., -en, -ern, -y, and -ed) have not undergone thorough examination to date. In the present study, I delve specifically into denominal adjectives with the suffix -ed (-ed Adjs), such as bearded, long-tailed, and shirt-sleeved. I present a novel basic picture of these adjectives, setting forth the following two central propositions: (i) -ed Adjs are a type of RAdj and (ii) undergo conversion to qualitative adjectives (QAdjs) (e.g., bearded man vs. bearded rock) akin to the better-known Latinate RAdjs (e.g., grammatical error vs. grammatical sentence). The analysis is conducted by examining suffixal etymology (i.e., Latinate or Germanic), suffixal properties (i.e., all-purpose or dedicated), and the driving factor for QAdj-forming conversion (i.e., the modal attribute true). These propositions and analyses collectively enrich our comprehensive understanding of the semantic and morphosyntactic properties of -ed Adjs within the realm of English morphology.
Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine ...receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4+ T‐cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4+ Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti‐CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody‐dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti‐CCR4 mAb in patients with CCR4+ T‐cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti‐CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4+ tumor cells, but also to overcome the suppressive effect of CCR4+ Treg cells on the host immune response to tumor cells. (Cancer Sci 2006; 97: 1139–1146)
Motivation: Intrinsically disordered regions in proteins have no unique stable structures without their partner molecules, thus these regions sometimes prevent high-quality structure determination. ...Furthermore, proteins with disordered regions are often involved in important biological processes, and the disordered regions are considered to play important roles in molecular interactions. Therefore, identifying disordered regions is important to obtain high-resolution structural information and to understand the functional aspects of these proteins. Results: We developed a new prediction method for disordered regions in proteins based on the meta approach and implemented a web-server for this prediction method named ‘metaPrDOS’. The method predicts the disorder tendency of each residue using support vector machines from the prediction results of the seven independent predictors. Evaluation of the meta approach was performed using the CASP7 prediction targets to avoid an overestimation due to the inclusion of proteins used in the training set of some component predictors. As a result, the meta approach achieved higher prediction accuracy than all methods participating in CASP7. Availability: http://prdos.hgc.jp/meta/ Contact: t-ishida@hgc.jp
Evading immune surveillance is one of the common hallmarks of cancer. Herein we describe two major evasion mechanisms in lymphoma, focusing on regulatory T (Treg) cells and C‐C chemokine receptor 4 ...(CCR4) expressed on these cells. First, the tumor cells themselves function as Treg cells, characterized by expression of CCR4, contributing to tumor survival by downregulating host immunity. Second, CCR4 ligands are produced by tumor cells, which attract other CCR4+ Treg cells to the vicinity of the tumor. CCR4+ adult T‐cell leukemia//lymphoma is an example of the former phenomenon, and Hodgkin lymphoma of the latter, for which an almost identical immunopathogenesis has been reported in many types of cancer. Awareness of the importance of CCR4 allows the rational design of more effective cancer treatments. Accordingly, we have developed a defucosylated anti‐CCR4 mAb, the first therapeutic agent targeting CCR4 to be used clinically for cancer. The therapeutic anti‐CCR4 mAb represents a promising treatment method for patients with CCR4+ neoplasms by directly killing the cancer cells, but could also be used as a novel treatment strategy for many types of CCR4− cancers to overcome the suppressive effect of CCR4+ Treg cells. (Cancer Sci 2011; 102: 44–50)
This paper makes an intensive comparison in operating performance between a modular multilevel double-star chopper-cells (DSCC) inverter and a modular multilevel triple-star bridge-cells (TSBC) ...converter. Both inverter and converter are intended to drive medium-voltage motors in industrial applications. First, it makes numerical comparisons, thus, resulting in revealing that the torque and frequency of a driven motor produce a significant effect on capacitor-voltage fluctuation and arm or cluster current in the individual DSCC inverter and TSBC converter. Next, a three-phase DSCC inverter and a three-phase TSBC converter with the same rating as 400 V and 15 kW are designed and compared to drive the following two general purposes and specially-designed induction motors; one is rated at the 380-V, 15-kW, 50-Hz four-pole motor, and the other is at the 320-V, 15-kW, 38-Hz six-pole motor. This experimental comparison based on the two downscaled drive systems confirms the validity of the numerical comparison. Finally, this paper concludes that the DSCC inverter is more suitable for driving medium-voltage high-speed motors loaded with quadratic-torque-to-speed profiles like fans, blowers, pumps, and centrifugal compressors. On the other hand, the TSBC converter is more suitable for driving medium-voltage low-speed high-torque motors like mills, kilns, conveyors, and extruders.
FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of ...CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients.
We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed.
The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.
The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.
The proper application of retrosynthesis to identify possible transformations for a given target compound requires a lot of chemistry knowledge and experience. However, because the complexity of this ...technique scales together with the complexity of the target, efficient application on compounds with intricate molecular structures becomes almost impossible for human chemists. The idea of using computers in such situations has existed for a long time, but the accuracy was not sufficient for practical applications. Nevertheless, with the steady improvement of machine learning and artificial intelligence in recent years, computer-assisted retrosynthesis has been gaining research attention again. Because of the overall lack of chemical reaction data, the main challenge for the recent retrosynthesis methods is low exploration ability during the analysis of target and intermediate compounds. The main goal of this research is to develop a novel, template-free approach to address this issue. Only individual molecular substructures of the target are used to determine potential disconnection sites, without relying on additional information such as chemical reaction class. The model for the identification of potential disconnection sites is trained on novel molecular substructure fingerprint representations. For each of the disconnections suggested using the model, a simple structural similarity-based reactant retrieval and scoring method is applied, and the suggestions are completed. This method achieves 47.2% top-1 accuracy for the single-step retrosynthesis task on the processed United States Patent Office dataset. Furthermore, if the predicted reaction class is used to narrow down the reactant candidate search space, the performance is improved to 61.4% top-1 accuracy.
Abstract
In vascular plants, roots anchor themselves into the soil and take up water and nutrients to provide them to the shoots. Therefore, continuous growth and development of the roots are ...important for plant life. To achieve this, photosynthesizing leaves must be able to supply sufficient photoassimilates to the roots. However, the mechanisms by which plants maintain carbon levels in roots remain elusive. Here, we focused on the Arabidopsis (Arabidopsis thaliana) CLAVATA3/ESR-related 2 (CLE2) peptide, which was detected in Arabidopsis xylem exudate, and its homologs. CLE2 and CLE3 genes responded to carbon-deficient conditions. Loss- and gain-of-function mutant analyses showed that CLE genes positively affected root sucrose level. Mutations in the CLE genes resulted in a high shoot/root ratio under sucrose-free conditions. Grafting experiments demonstrated the systemic effect of CLE peptide genes. These findings provide insights into the molecular basis for the relationship between roots and leaves in maintenance of the root sucrose levels and growth.
In protein tertiary structure prediction, model quality assessment programs (MQAPs) are often used to select the final structural models from a pool of candidate models generated by multiple ...templates and prediction methods. The 3-dimensional convolutional neural network (3DCNN) is an expansion of the 2DCNN and has been applied in several fields, including object recognition. The 3DCNN is also used for MQA tasks, but the performance is low due to several technical limitations related to protein tertiary structures, such as orientation alignment. We proposed a novel single-model MQA method based on local structure quality evaluation using a deep neural network containing 3DCNN layers. The proposed method first assesses the quality of local structures for each residue and then evaluates the quality of whole structures by integrating estimated local qualities. We analyzed the model using the CASP11, CASP12, and 3D-Robot datasets and compared the performance of the model with that of the previous 3DCNN method based on whole protein structures. The proposed method showed a significant improvement compared to the previous 3DCNN method for multiple evaluation measures. We also compared the proposed method to other state-of-the-art methods. Our method showed better performance than the previous 3DCNN-based method and comparable accuracy as the current best single-model methods; particularly, in CASP11 stage2, our method showed a Pearson coefficient of 0.486, which was better than those of the best single-model methods (0.366-0.405). A standalone version of the proposed method and data files are available at https://github.com/ishidalab-titech/3DCNN_MQA.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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