Development of biomimetic catalytic oxidation methods and non-salt methods using transition metal-based acid and base ambiphilic catalysts

This review focuses on the development of ruthenium and flavin catalysts for environmentally benign oxidation reactions based on mimicking the functions of cytochrome P-450 and flavoenzymes, and low valent transition-metal catalysts that replace conventional acids and bases. Several new concepts and new types of catalytic reactions based on these concepts are described

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes.

CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM

Spin texture induced by non-magnetic doping and spin dynamics in 2D triangular lattice antiferromagnet h-Y(Mn,Al)O3

Novel effects induced by nonmagnetic impurities in frustrated magnets and quantum spin liquid represent a highly nontrivial and interesting problem. A theoretical proposal of extended modulated spin structures induced by doping of such magnets, distinct from the well-known skyrmions has attracted significant interest. Here, we demonstrate that nonmagnetic impurities can produce such extended spin structures in h-YMnO3, a triangular antiferromagnet with noncollinear magnetic order. Using inelastic neutron scattering (INS), we measured the full dynamical structure factor in Al-doped h-YMnO3 and confirmed the presence of magnon damping with a clear momentum dependence. Our theoretical calculations can reproduce the key features of the INS data, supporting the formation of the proposed spin textures. As such, our study provides the first experimental confirmation of the impurity-induced spin textures. It offers new insights and understanding of the impurity effects in a broad class of noncollinear magnetic systems.Comment: 18 pages, 4 figures and supplementary Information. Accepted for publication in Nature Communication

Nitrides as ammonia synthesis catalysts and as potential nitrogen transfer reagents

In this article, an overview of the application of selected metal nitrides as ammonia synthesis catalysts is presented. The potential development of some systems into nitrogen transfer reagents is also described

Comparison of the intracellular trafficking itinerary of ctla-4 orthologues.

CTLA-4 is an essential inhibitor of T cell immune responses. At steady state, most CTLA-4 resides in intracellular compartments due to constitutive internalisation mediated via a tyrosine based endocytic motif (YVKM) within the cytoplasmic domain. This domain is highly conserved in mammals suggesting strong selective pressure. In contrast, the C-terminal domain varies considerably in non-mammals such as fish, xenopus and birds. We compared the ability of the C-terminus of these species to direct the trafficking of CTLA-4 with human CTLA-4. Using a chimeric approach, endocytosis was found to be conserved between human, xenopus and chicken CTLA-4 but was reduced substantially in trout CTLA-4, which lacks the conserved YXXM motif. Nevertheless, we identified an alternative YXXF motif in trout CTLA-4 that permitted limited endocytosis. Post-internalisation, CTLA-4 was either recycled or targeted for degradation. Human and chicken CTLA-4, which contain a YVKM motif, showed efficient recycling compared to xenopus CTLA-4 which contains a less efficient YEKM motif. Specific mutation of this motif in human CTLA-4 reduced receptor recycling. These findings suggest evolutionary development in the endocytic and recycling potential of CTLA-4, which may facilitate more refined functions of CTLA-4 within the mammalian immune system

新しい介護負担評価尺度(ABC-16)の妥当性

目的：本研究の目的は、新たに作成された自己記入式介護負担評価尺度(ABC-16) の妥当性を検討することである方法：対象者は、第1群では51名（平均年齢63±11歳）、第2群では31名（平均年齢58±14歳）の家族介護者である。結果：第1群におけるABC-16総計の平均点は14.98±7.52であった。第1群では高い妥当性（内的整合性、α=0.821) を示し、かつ4つの領域間に有意の相関が得られた(P<0.05)。重回帰分析によりABC-16と介護者のQOL (P=0.034) および夜間介護(P=0.001) とにおいて強い関連が見られた。第2群は第1群の結果とほぽ同様の結果が得られ、ABC-16の交差妥当性のあることが示唆された。結論： ABC-16は高い妥当性を有する大変優れた介護負担評価尺度であることが示された。Aims: The aim of this study is to evaluate the validation of a newly developed self-administered assessment of the burden on caregivers (ABC-16). Methods: The subjects were 51 family caregivers (mean age 63 ± 11 years) for the first trial and 31 family caregivers (mean age 58 ± 14 years) for the second trial. The ABC-16 consists of 16 items and is designed to cover 4 dimensions (the care receiver\u27s burden, burden on social life, financial burden, and burden on health). Results: In the first trial, the mean and standard deviation of the total score of the ABC-16 was 14.98 ± 7.52. The first trial showed high reliability; the internal consistency was α=0.821 and significant correlations among the four dimensions were found (P<0.05). A multiple regression analysis showed strong correlations between the ABC-16 and the QOL of the caregivers (P=0.034), and the caregiving during the night (P=0.001). The second trial showed findings similar to those in the first trial, which suggested the good cross validation of the ABC-16. Conclusions: It is suggested that the ABC-16 is an excellent tool for assessing the care burden with high validity

Magnetoencephalography in Pediatric Lesional Epilepsy Surgery

This study was performed to assess the usefulness of magnetoencephalography (MEG) as a presurgical evaluation modality in Korean pediatric patients with lesional localization-related epilepsy. The medical records and MEG findings of 13 pediatric patients (6 boys and 7 girls) with localization-related epilepsy, who underwent epilepsy surgery at Seoul National University Children's Hospital, were retrospectively reviewed. The hemispheric concordance rate was 100% (13/13 patients). The lobar or regional concordance rate was 77% (10/13 patients). In most cases, the MEG spike sources were clustered in the proximity of the lesion, either at one side of the margin (nine patients) or around the lesion (one patient); clustered spike sources were distant from the lesion in one patient. Among the patients with clustered spike sources near the lesion, further extensions (three patients) and distal scatters (three patients) were also observed. MEG spike sources were well lateralized and localized even in two patients without focal epileptiform discharges in the interictal scalp electroencephalography. Ten patients (77%) achieved Engel class I postsurgical seizure outcome. It is suggested that MEG is a safe and useful presurgical evaluation modality in pediatric patients with lesion localization-related epilepsy

PHYSICAL ACTIVITY LEVEL DOES NOT INFLUENCE THE NEUROMUSCULAR FATIGUE IN ADULTS

Introduction: Fatigue during voluntary muscle contractions is a complex and multifactorial phenomenon associated with central changes and adaptations of the neuromuscular system. Objective: The purpose of this study was to evaluate the fatigue induced by intermittent successive extension of the knee between active and inactive university students. Method: Twenty healthy men (≥18 years), voluntarily participated in this study. To determine the maximum voluntary isometric contraction (MVIC) of the knee extensors muscle group, three sets of isometric contractions of knee extension were performed for five seconds with five minutes of rest between sets. The fatigue protocol consisted of 10 sets of 10 maximal concentric contractions of the extensor on the right knee, performed at 75% of MVIC with an interval of 45". Results: Significant reductions were observed (p<0.01), both in isometric strength (-34±4%) and the dynamic strength (-40 ± 3%). In addition, the slope of relationship strength x repetition was -0.79±0.07 Nm/repetitions and the magnitude of the effect reached -8.90. Conclusion: The protocol was useful to induce peripheral fatigue, although muscle strength is greater in the active group. In both isometric and dynamic action, muscle fatigue did not differ between groups

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Introduction: Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes. Methods: Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively. Results: Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events. Conclusion: These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies. Funding: Janssen Research & Development

Temperature Control of Fimbriation Circuit Switch in Uropathogenic Escherichia coli: Quantitative Analysis via Automated Model Abstraction

Uropathogenic Escherichia coli (UPEC) represent the predominant cause of urinary tract infections (UTIs). A key UPEC molecular virulence mechanism is type 1 fimbriae, whose expression is controlled by the orientation of an invertible chromosomal DNA element—the fim switch. Temperature has been shown to act as a major regulator of fim switching behavior and is overall an important indicator as well as functional feature of many urologic diseases, including UPEC host-pathogen interaction dynamics. Given this panoptic physiological role of temperature during UTI progression and notable empirical challenges to its direct in vivo studies, in silico modeling of corresponding biochemical and biophysical mechanisms essential to UPEC pathogenicity may significantly aid our understanding of the underlying disease processes. However, rigorous computational analysis of biological systems, such as fim switch temperature control circuit, has hereto presented a notoriously demanding problem due to both the substantial complexity of the gene regulatory networks involved as well as their often characteristically discrete and stochastic dynamics. To address these issues, we have developed an approach that enables automated multiscale abstraction of biological system descriptions based on reaction kinetics. Implemented as a computational tool, this method has allowed us to efficiently analyze the modular organization and behavior of the E. coli fimbriation switch circuit at different temperature settings, thus facilitating new insights into this mode of UPEC molecular virulence regulation. In particular, our results suggest that, with respect to its role in shutting down fimbriae expression, the primary function of FimB recombinase may be to effect a controlled down-regulation (rather than increase) of the ON-to-OFF fim switching rate via temperature-dependent suppression of competing dynamics mediated by recombinase FimE. Our computational analysis further implies that this down-regulation mechanism could be particularly significant inside the host environment, thus potentially contributing further understanding toward the development of novel therapeutic approaches to UPEC-caused UTIs