Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug-induced thrombocytopenia.

Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.

Safety and Seropositivity after Live Attenuated Vaccine in Adult Patients Receiving Hematopoietic Stem Cell Transplantation.

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.

[Recurring Sweet syndrome in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia].

Sweet syndrome is a rare inflammatory disease with rapid onset of painful, edematous skin eruptions, and neutrophilia. Concerning hematological disorders, Sweet syndrome often presents in patients with myeloid diseases, but it is rarely observed in patients with lymphoid diseases. Here we describe a 72-year-old male with Philadelphia chromosome-positive acute lymphoblastic leukemia who suffered recurring Sweet syndrome. Following induction chemotherapy, granulocyte colony-stimulating factors (G-CSFs) were administered due to febrile neutropenia. A few weeks thereafter, skin eruption emerged on the palmar and dorsal surfaces of his hands, and skin biopsy confirmed Sweet syndrome. His symptoms improved with the short-term use of prednisolone. After recovering from the neutropenia, the patient received percutaneous coronary intervention (PCI) due to unstable angina that developed after the induction chemotherapy. During PCI, coronary artery dissection caused cardiopulmonary arrest. The patient recovered with intensive care. However, blood tests on the following day revealed marked neutrophilia. The skin eruption re-emerged on both hands, which was consistent with Sweet syndrome. Sweet syndrome repeatedly occurred after the recovery of neutropenia due to chemotherapy. We suggest that the intrinsic increase in G-CSF in response to inflammation might have caused recurring Sweet syndrome in this patient.

Caenibacillus caldisaponilyticus gen. nov., sp. nov., a thermophilic, spore-forming and phospholipid-degrading bacterium isolated from acidulocompost.

A thermophilic and phospholipid-degrading bacterium, designated strain B157T, was isolated from acidulocompost, a garbage compost processed under acidic conditions at moderately high temperature. The organism was Gram-stain-positive, aerobic, spore-forming and rod-shaped. Growth was observed to occur at 40-65 °C and pH 4.8-8.1 (optimum growth: 50-60 °C, pH 6.2). The strain was catalase- and oxidase-positive. The cell wall contained meso-diaminopimelic acid, alanine, glutamic acid and galactose. The predominant respiratory quinone was menaquinone-7 (MK-7) and the major fatty acids were anteiso-C17 : 0 and iso-C17 : 0. Comparative 16S rRNA gene sequence analysis showed that strain B157T was related most closely to Tuberibacillus calidus 607T (94.8 % identity), and the phylogenetic analysis revealed that it belonged to the family Sporolactobacillaceae. The DNA G+C content was determined as 51.8 mol%. In spite of many similarities with the type strains of members of the family Sporolactobacillaceae, genotypic analyses suggest that strain B157T represents a novel species of a new genus, Caenibacilluscaldisaponilyticus gen. nov., sp. nov. The type strain of Caenibacilluscaldisaponilyticus is B157T (=NBRC 111400T=DSM 101100T).

Phytochrome C is a key factor controlling long-day flowering in barley.

The spring-type near isogenic line (NIL) of the winter-type barley (Hordeum vulgare ssp. vulgare) var. Hayakiso 2 (HK2) was developed by introducing VERNALIZATION-H1 (Vrn-H1) for spring growth habit from the spring-type var. Indo Omugi. Contrary to expectations, the spring-type NIL flowered later than winter-type HK2. This phenotypic difference was controlled by a single gene, which cosegregated only with phytochrome C (HvPhyC) among three candidates around the Vrn-H1 region (Vrn-H1, HvPhyC, and CASEIN KINASE IIα), indicating that HvPhyC was the most likely candidate gene. Compared with the late-flowering allele HvPhyC-l from the NIL, the early-flowering allele HvPhyC-e from HK2 had a single nucleotide polymorphism T1139C in exon 1, which caused a nonsynonymous amino acid substitution of phenylalanine at position 380 by serine in the functionally essential GAF (3', 5'-cyclic-GMP phosphodiesterase, adenylate cyclase, formate hydrogen lyase activator protein) domain. Functional assay using a rice (Oryza sativa) phyA phyC double mutant line showed that both of the HvPhyC alleles are functional, but HvPhyC-e may have a hyperfunction. Expression analysis using NILs carrying HvPhyC-e and HvPhyC-l (NIL [HvPhyC-e] and NIL [HvPhyC-l], respectively) showed that HvPhyC-e up-regulated only the flowering promoter FLOWERING LOCUS T1 by bypassing the circadian clock genes and flowering integrator CONSTANS1 under a long photoperiod. Consistent with the up-regulation, NIL (HvPhyC-e) flowered earlier than NIL (HvPhyC-l) under long photoperiods. These results implied that HvPhyC is a key factor to control long-day flowering directly.

Novel Computational Design of Polymer Micromachined Insect-Mimetic Wings for Flapping-Wing Nano Air Vehicles.

The flapping wings of insects undergo large deformations caused by aerodynamic forces, resulting in cambering. Insect-mimetic micro wings for flapping-wing nano air vehicles mimic these characteristic deformations. In this study, a 2.5-dimensional insect-mimetic micro wing model for flapping-wing nano air vehicles is proposed to realize this type of wing. The proposed model includes a wing membrane, a leading edge, a center vein, and a root vein, all of which are modeled as shell elements. The proposed wing is a 2.5-dimensional structure and can thus be fabricated using polymer micromachining. We conducted a design window search to demonstrate the capabilities of the wing. The design windows, which are areas of desirable design solutions in the design parameter space, are iteratively searched using nonlinear finite-element analysis under quasi-steady aerodynamic modeling. Here, thickness is selected as a design parameter. The properties of real insects, polymer materials, and fabrication conditions are used to determine the other parameters. A fabricable design solution that generates sufficient camber is found from the design windows.

Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug-induced thromboembolism.

ABSTRACT: Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography-mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

Vein-Membrane Interaction in Cambering of Flapping Insect Wings.

It is still unclear how elastic deformation of flapping insect wings caused by the aerodynamic pressure results in their significant cambering. In this study, we present that a vein-membrane interaction (VMI) can clarify this mechanical process. In order to investigate the VMI, we propose a numerical method that consists of (a) a shape simplification model wing that consists of a few beams and a rectangular shell structure as the structural essence of flapping insect wings for the VMI, and (b) a monolithic solution procedure for strongly coupled beam and shell structures with large deformation and large rotation to analyze the shape simplification model wing. We incorporate data from actual insects into the proposed numerical method for the VMI. In the numerical analysis, we demonstrate that the model wing can generate a camber equivalent to that of the actual insects. Hence, the VMI will be a mechanical basis of the cambering of flapping insect wings. Furthermore, we present the mechanical roles of the veins in cambering. The intermediate veins increase the out-of-plane deflection of the wing membrane due to the aerodynamic pressure in the central area of the wing, while they decrease it in the vicinity of the trailing edge. As a result, these veins create the significant camber. The torsional flexibility of the leading-edge veins increases the magnitude of cambering.

Iron-catalyzed decarbonylation reaction of aliphatic carboxylic acids leading to α-olefins.

The catalytic decarbonylation reaction of aliphatic carboxylic acids can be carried out in the presence of an iron complex, and it proceeds smoothly to give α-olefins with high selectivity.

A two-dimensional computational study on the fluid-structure interaction cause of wing pitch changes in dipteran flapping flight.

In this study, the passive pitching due to wing torsional flexibility and its lift generation in dipteran flight were investigated using (a) the non-linear finite element method for the fluid-structure interaction, which analyzes the precise motions of the passive pitching of the wing interacting with the surrounding fluid flow, (b) the fluid-structure interaction similarity law, which characterizes insect flight, (c) the lumped torsional flexibility model as a simplified dipteran wing, and (d) the analytical wing model, which explains the characteristics of the passive pitching motion in the simulation. Given sinusoidal flapping with a frequency below the natural frequency of the wing torsion, the resulting passive pitching in the steady state, under fluid damping, is approximately sinusoidal with the advanced phase shift. We demonstrate that the generated lift can support the weight of some Diptera.