▪ Abstract In eukaryotic cells, most proteins in the cytosol and nucleus are degraded via the ubiquitin-proteasome pathway. The 26S proteasome is a 2.5-MDa molecular machine built from ∼31 different subunits, which catalyzes protein degradation. It contains a barrel-shaped proteolytic core complex (the 20S proteasome), capped at one or both ends by 19S regulatory complexes, which recognize ubiquitinated proteins. The regulatory complexes are also implicated in unfolding and translocation of ubiquitinated targets into the interior of the 20S complex, where they are degraded to oligopeptides. Structure, assembly and enzymatic mechanism of the 20S complex have been elucidated, but the functional organization of the 19S complex is less well understood. Most subunits of the 19S complex have been identified, however, specific functions have been assigned to only a few. A low-resolution structure of the 26S proteasome has been obtained by electron microscopy, but the precise arrangement of subunits in the 19S co...

The 26S Proteasome: A Molecular Machine Designed for Controlled Proteolysis

Fluorescent probes are one of the cornerstones of real-time imaging of live cells and a powerful tool for cell biologists. They provide high sensitivity and great versatility while minimally perturbing the cell under investigation. Genetically-encoded reporter constructs that are derived from fluorescent proteins are leading a revolution in the real-time visualization and tracking of various cellular events. Recent advances include the continued development of 'passive' markers for the measurement of biomolecule expression and localization in live cells, and 'active' indicators for monitoring more complex cellular processes such as small-molecule-messenger dynamics, enzyme activation and protein-protein interactions.

/pdf/creating-new-fluorescent-probes-for-cell-biology-4l24l7b55e.pdf

Creating new fluorescent probes for cell biology.

The transient receptor potential (TRP) superfamily consists of a large number of cation channels that are mostly permeable to both monovalent and divalent cations. The 28 mammalian TRP channels can be subdivided into six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels are expressed in almost every tissue and cell type and play an important role in the regulation of various cell functions. Currently, significant scientific effort is being devoted to understanding the physiology of TRP channels and their relationship to human diseases. At this point, only a few channelopathies in which defects in TRP genes are the direct cause of cellular dysfunction have been identified. In addition, mapping of TRP genes to susceptible chromosome regions (e.g., translocations, breakpoint intervals, increased frequency of polymorphisms) has been considered suggestive of the involvement of these channels in hereditary diseases. Moreover, strong indications of the involvement of TRP channels in several diseases come from correlations between levels of channel expression and disease symptoms. Finally, TRP channels are involved in some systemic diseases due to their role as targets for irritants, inflammation products, and xenobiotic toxins. The analysis of transgenic models allows further extrapolations of TRP channel deficiency to human physiology and disease. In this review, we provide an overview of the impact of TRP channels on the pathogenesis of several diseases and identify several TRPs for which a causal pathogenic role might be anticipated.

/pdf/transient-receptor-potential-cation-channels-in-disease-26ridjewn0.pdf

Transient Receptor Potential Cation Channels in Disease

Green fluorescent protein (GFP) from the jellyfish Aequorea victoria and its homologs from diverse marine animals are widely used as universal genetically encoded fluorescent labels. Many laboratories have focused their efforts on identification and development of fluorescent proteins with novel characteristics and enhanced properties, resulting in a powerful toolkit for visualization of structural organization and dynamic processes in living cells and organisms. The diversity of currently available fluorescent proteins covers nearly the entire visible spectrum, providing numerous alternative possibilities for multicolor labeling and studies of protein interactions. Photoactivatable fluorescent proteins enable tracking of photolabeled molecules and cells in space and time and can also be used for super-resolution imaging. Genetically encoded sensors make it possible to monitor the activity of enzymes and the concentrations of various analytes. Fast-maturing fluorescent proteins, cell clocks, and timers further expand the options for real time studies in living tissues. Here we focus on the structure, evolution, and function of GFP-like proteins and their numerous applications for in vivo imaging, with particular attention to recent techniques.

Fluorescent Proteins and Their Applications in Imaging Living Cells and Tissues

Since the advent of the green fluorescent protein, the subcellular localization, mobility, transport routes and binding interactions of proteins can be studied in living cells. Live cell imaging, in combination with photobleaching, energy transfer or fluorescence correlation spectroscopy are providing unprecedented insights into the movement of proteins and their interactions with cellular components. Remarkably, these powerful techniques are accessible to non-specialists using commercially available microscope systems.

/pdf/studying-protein-dynamics-in-living-cells-2jib9fauyq.pdf

Studying protein dynamics in living cells.

Acute graft-versus-host disease (aGVHD) is one of the potentially fatal complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with steroids is the standard therapy for aGVHD [1]. Based on the response to steroid therapy, aGVHD is divided into steroid-sensitive (SS) and steroid-refractory (SR) categories. There has been great discussion about SR-aGVHD because its prognosis is extremely poor [2, 3]. In contrast, little attention has been given to SS-aGVHD due to its good prognosis. However, some patients with SS-aGVHD demonstrated transient recurrence of aGVHD, and its clinical implications have not been well elucidated. This study aimed to clarify the clinical characteristics of transient recurrence of SS-aGVHD. We retrospectively reviewed 223 consecutive patients who underwent allo-HSCT between January 2007 and December 2016 at The University of Tokyo Hospital. The clinical data of patients with aGVHD who received systemic methylprednisolone (mPSL) therapy (≥1 mg per recipient’s body weight) were collected. Diagnosis of aGVHD was based on clinical symptoms and pathological examination [4]. The severity of aGVHD was graded according to symptoms affecting the skin, liver, and gut [5]. SR-aGVHD was defined as aGVHD that progressed within 5 days after treatment, remained unchanged within 7 days, or responded incompletely within 14 days [6]. Furthermore, any patient who received secondary treatment including antithymocyte globulin or steroid pulse therapy was regarded as having SR-aGVHD. SS-aGVHD was defined as aGVHD that did not fulfill the criteria of SR-aGVHD. SSaGVHD was divided into non-recurrence and transientrecurrence groups. Transient recurrence was defined as recurrence of aGVHD during steroid taper, which demonstrated rapid recovery after increasing the steroid dose. Severe infections were defined as those requiring hospitalization. Statistical analyses were performed with EZR (modified R software) version 1.32 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [7]. Survival analysis was performed using the Kaplan–Meier method, and the log-rank test was used for comparison between the two groups. The Mann–Whitney U-test and Fisher’s exact test were used to evaluate the risk factors associated with transient recurrence of aGVHD. The level of significance was defined as two-tailed (p < 0.05). This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethical Review Board of our institute. Sixty-seven patients were diagnosed with aGVHD, and 41 (61%) patients received systemic steroid administration. Among them, 16 patients with SR-aGVHD were excluded and 25 patients were classified as SS-aGVHD. In SSaGVHD patients, 11 (44%) patients showed transient recurrence of aGVHD with a median of 42 (8–237) days after diagnosis of aGVHD. There were no significant differences in the patients’ baseline characteristics between the transient-recurrence and non-recurrence groups, including age, gender, underlying diseases, and disease status at transplantation (Table 1a). Similarly, there were no significant differences in transplantation setting, including donor source, proportion of sibling donor, donor–recipient HLA match, ABO match, sex match, conditioning regimen, and prophylaxis of aGVHD (Table 1a). As risk factors associated with transient recurrence of SS-aGVHD, we evaluated the initial dose and reduction speed of mPSL. However, there were no significant differences in the initial dose of mPSL and duration from the start of administration of mPSL to the time when the dose was reduced to half (Table 1a). When compared with the non-recurrence group, * Mineo Kurokawa kurokawa-tky@umin.ac.jp

Retrospective analysis on transient recurrence of steroid-sensitive acute graft-versus-host disease.

Thrombocytopenia is a frequent complication in chronic lymphocytic leukemia (CLL). Differentiating autoimmune thrombocytopenia from thrombocytopenia due to bone marrow infiltration is necessary for appropriate treatment, but sometimes difficult. Here we report a 60-year-old male patient with CLL who had achieved complete response after treatment with fludarabine, cyclophosphamide, and rituximab two years prior to presentation. He was admitted with severe thrombocytopenia that was unresponsive to intravenous immunoglobulin. Imaging studies revealed systemic enlarged lymph nodes and bone marrow aspiration was hypercellular with > 95% lymphocytes and scant megakaryocytes. Acalabrutinib 200 mg/day was administered for the treatment of CLL exacerbation. A gradual decrease in CLL cells and recovery of megakaryocytes in bone marrow were observed, but platelet counts remained low. Systemic administration of prednisolone 0.5 mg/kg, in addition to acalabrutinib, was started, considering the contribution of autoimmune thrombocytopenia; platelet recovery was rapid and sustained for more than a year. Even if bone marrow examination suggested thrombocytopenia due to direct leukemic infiltration, it is difficult to exclude the possibility of concomitant immunogenic thrombocytopenia. We conclude that for CLL patients with severe thrombocytopenia, repeating bone marrow examination and concurrent immunosuppressive therapies and treatment of the underlying CLL may be beneficial.

Acalabrutinib and steroid for autoimmune thrombocytopenia due to relapsed chronic lymphocytic leukemia with severe bone marrow infiltration

A 71-year-old female with type B3 thymoma developed severe aplastic anemia. Anti-thymocyte globulin was administered with glucocorticoids and cyclosporin A as the treatment for aplastic anemia. Computed tomography scan revealed that thymoma apparently shrank and remained without regrowth for at least 7 months. As previously reported, glucocorticoid has therapeutic effects on thymoma especially with abundant lymphocytes. Anti-thymocyte globulin also depletes peripheral lymphocytes, but its efficacy in the treatment of thymoma is unknown. Anti-thymocyte globulin and glucocorticoids may have cooperated with each other in reducing thymoma in our case. More cases should be accumulated to elucidate the effects of anti-thymocyte globulin on thymoma.

A case of thymoma showing significant tumor reduction after anti-thymocyte globulin

Idiopathic hypereosinophilic syndrome (iHES) is a condition wherein persistent hypereosinophilia associated with end-organ damage occurs without any known causes. Due to the rarity of the disease, insufficient knowledge has been accumulated. We therefore conducted a retrospective, multicentre, nationwide survey on iHES in Japan. A total of 57 patients were identified. For 43 patients who received any treatment, all cases were first treated with corticosteroids. An eosinophil percentage of less than 30% in the bone marrow and the absence of oedema were identified as factors associated with steroid dependency. The 5-year overall survival was 88.2%, and five patients died during follow-up; factors associated with worse overall survival were age >50, haemoglobin <12 g/dL, activated partial thromboplastin time >34 s, the presence of dyspnoea, the presence of thrombotic tendency and the presence of renal failure. Given the rarity of fatalities in our cohort, time-to-next-treatment (TTNT) was further analysed; the presence of renal failure, splenomegaly and lung abnormalities were associated with worse TTNT. Our nationwide study not only demonstrated clinical characteristics and the outcome of patients with iHES but also for the first time revealed clinical factors associated with steroid dependency and duration of first-line corticosteroid efficacy.

Prognostic factors of idiopathic hypereosinophilic syndrome: A nationwide survey in Japan.

Protein kinase G (PKG)-mediated tonic inhibition of vascular transient receptor potential (TRP) channel TRPC6

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