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Subdural hematoma (SDH) is bleeding between the dura mater and the brain surface, often visualized as a crescent-shaped lesion on computed tomography (CT). However, some SDHs can appear as a biconvex hyperdense lesion mimicking an acute epidural hematoma. Encapsulated acute SDH (EASDH), a rare subtype characterized by a fresh hematoma within the subdural fibrous capsule, presents with similar CT findings. Herein, we describe an autopsy case of EASDH and discuss its etiology based on the case findings and available literature. The autopsy revealed a rupture of the bridging arteries as the SDH bleeding source, confirming the development of an acute-on-chronic spontaneous SDH. To our knowledge, this is the first autopsy report of EASDH and the third case of spontaneous SDH due to bridging-artery rupture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Root hair, single-celled tubular structures originating from the epidermis, plays a vital role in the uptake of nutrients from the soil by increasing the root surface area. Therefore, optimizing root hair growth is crucial for plants to survive in fluctuating environments. Root hair length is determined by the action of various plant hormones, among which the roles of auxin and ethylene have been extensively studied. However, evidence for the involvement of cytokinins has remained elusive. We recently reported that the cytokinin-activated B-type response regulators, ARABIDOPSIS RESPONSE REGULATOR 1 (ARR1) and ARR12 directly upregulate the expression of ROOT HAIR DEFECTIVE 6-LIKE 4 ( RSL4 ), which encodes a key transcription factor that controls root hair elongation. However, depending on the nutrient availability, it is unknown whether the ARR1/12-RSL4 pathway controls root hair elongation. This study shows that phosphate deficiency induced the expression of RSL4 and increased the root hair length through ARR1/12, though the transcript and protein levels of ARR1/12 did not change. These results indicate that cytokinins, together with other hormones, regulate root hair growth under phosphate starvation conditions.

Sudden unexpected death in the young (SUDY) is a traumatic occurrence for their family; however, information on the genetic variations associated with the condition is currently lacking. It is important to carry out postmortem genetic analyses in cases of sudden death to provide information for relatives and to allow appropriate genetic counselling and clinical follow-up. This study aimed to investigate the genetic variations associated with the occurrence of SUDY in Japan, using next-generation sequencing (NGS). The study included 18 cases of SUDY (16 males, 2 females; age 15-47 years) who underwent autopsy, including NGS DNA sequencing for molecular analysis. A total of 168 genes were selected from the sequencing panel and filtered, resulting in the identification of 60 variants in cardiac disease-related genes. Many of the cases had several of these genetic variants and some cases had a cardiac phenotype. The identification of genetic variants using NGS provides important information regarding the pathogenicity of sudden death.

Cell size control is one of the prerequisites for plant growth and development. Recently, a GRAS family transcription factor, SCARECROW-LIKE28 (SCL28), was identified as a critical regulator for both mitotic and postmitotic cell-size control. Here, we show that SCL28 is specifically expressed in proliferating cells and exerts its function to delay G2 progression during mitotic cell cycle in Arabidopsis thaliana . Overexpression of SCL28 provokes a significant enlargement of cells in various organs and tissues, such as leaves, flowers and seeds, to different extents depending on the type of cells. The increased cell size is most likely due to a delayed G2 progression and accelerated onset of endoreplication, an atypical cell cycle repeating DNA replication without cytokinesis or mitosis. Unlike DWARF AND LOW-TILLERING , a rice ortholog of SCL28 , SCL28 may not have a role in brassinosteroid (BR) signaling because sensitivity against brassinazole, a BR biosynthesis inhibitor, was not dramatically altered in scl28 mutant and SCL28 -overexpressing plants. Collectively, our findings strengthen a recently proposed model of cell size control by SCL28 and suggest the presence of diversified evolutionary mechanisms for the regulation and action of SCL28.

Although it is well known that hierarchical transcriptional networks are essential for various aspects of plant development and environmental response, little has been investigated about whether and how they also regulate the plant cell cycle. Recent studies on cell cycle regulation in Arabidopsis thaliana identified SCARECROW-LIKE28 (SCL28), a GRAS-type transcription factor, that constitutes a hierarchical transcriptional pathway comprised of MYB3R, SCL28 and SIAMESE-RELATED (SMR). In this pathway, MYB3R family proteins regulate the G2/M-specific transcription of the SCL28 gene, of which products, in turn, positively regulate the transcription of SMR genes encoding a group of plant-specific inhibitor proteins of cyclin-dependent kinases. However, this pathway with a role in cell cycle inhibition is solely demonstrated in A. thaliana , thus leaving open the question of whether and to what extent this pathway is evolutionarily conserved in plants. In this study, we conducted differential display RT-PCR on synchronized Nicotiana tabacum (tobacco) BY-2 cells and identified several M-phase-specific cDNA clones, one of which turned out to be a tobacco ortholog of SCL28 and was designated NtSCL28 . We showed that NtSCL28 is expressed specifically during G2/M and early G1 in the synchronized cultures of BY-2 cells. NtSCL28 contains MYB3R-binding promoter elements, so-called mitosis-specific activator elements, and is upregulated by a hyperactive form of NtmybA2, one of the MYB3R proteins from tobacco. Our study indicated that a part of the hierarchical pathway identified in A. thaliana is equally operating in tobacco cells, suggesting the conservation of this pathway across different families in evolution of angiosperm., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© 2023 Japanese Society for Plant Biotechnology.)

Purpose: This study aimed to investigate the safety and efficacy of lenvatinib in real-world settings, including patients excluded from the REFLECT trial, a phase III trial that compared lenvatinib with sorafenib., Patients and Methods: This multicenter, nonrandomized, open-label prospective study was conducted at 10 medical facilities in Japan (jRCTs031190017). Eligible patients had advanced hepatocellular carcinoma (HCC) and were suitable for lenvatinib therapy. The study included patients with high tumor burden (with >50% intrahepatic tumor volume, main portal vein invasion, or bile duct invasion), Child-Pugh B status, and receiving lenvatinib as second-line therapy following atezolizumab plus bevacizumab., Results: From December 2019 to September 2021, 59 patients were analyzed (47 and 12 patients with Child-Pugh A and B, respectively). In patients with Child-Pugh A, the frequency of aspartate aminotransferase elevation was high (72.7%) in the high-burden group. No other significant ad verse events (AE) were observed even in second-line treatment. However, patients with Child-Pugh B had high incidence of grade ≥3 AE (100.0%) and high discontinuation rates caused by AE (33.3%) compared with patients with Child-Pugh A (80.9% and 17.0%, respectively). Median progression-free survival was 6.4 and 2.5 months and median overall survival was 19.7 and 4.1 months in Child-Pugh A and B, respectively. Lenvatinib plasma concentration was higher in patients with Child-Pugh B on days 8 and 15 and correlated with dose modifications and lower relative dose intensity., Conclusions: Lenvatinib is safe and effective for advanced HCC in patients with Child-Pugh A, even with high tumor burden. However, it carries a higher risk of AE and may not provide adequate efficacy for patients with Child-Pugh B status., (©2023 American Association for Cancer Research.)

ACTIN DEPOLYMERIZING FACTOR (ADF) is a conserved protein that regulates the organization and dynamics of actin microfilaments. Eleven ADFs in the Arabidopsis thaliana genome are grouped into four subclasses, and subclass I ADFs, ADF1-4, are all expressed throughout the plant. Previously, we showed that subclass I ADFs function in the regulation of the response against powdery mildew fungus as well as in the regulation of cell size and endoreplication. Here, we report a new role of subclass I ADFs in the regulation of nuclear organization and gene expression. Through microscopic observation of epidermal cells in mature leaves, we found that the size of chromocenters in both adf4 and transgenic lines where expression of subclass I ADFs is downregulated (ADF1-4Ri) was reduced compared with that of wild-type Col-0. Arabidopsis thaliana possesses eight ACTIN (ACT) genes, among which ACT2, -7 and -8 are expressed in vegetative organs. The chromocenter size in act7, but not in the act2/8 double mutant, was enlarged compared with that in Col-0. Microarray analysis revealed that 1,818 genes were differentially expressed in adf4 and ADF1-4Ri. In particular, expression of 22 nucleotide-binding leucine-rich repeat genes, which are involved in effector-triggered plant immunity, was reduced in adf4 and ADF1-4Ri. qRT-PCR confirmed the altered expressions shown with microarray analysis. Overall, these results suggest that ADF regulates various aspects of plant physiology through its role in regulation of nuclear organization and gene expression. The mechanism how ADF and ACT regulate nuclear organization and gene expression is discussed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Maintaining stable and transient quiescence in differentiated and stem cells, respectively, requires repression of the cell cycle. The plant RETINOBLASTOMA-RELATED (RBR) has been implicated in stem cell maintenance, presumably by forming repressor complexes with E2F transcription factors. Surprisingly we find that mutations in all three canonical E2Fs do not hinder the cell cycle, but similarly to RBR silencing, result in hyperplasia. Contrary to the growth arrest that occurs when exit from proliferation to differentiation is inhibited upon RBR silencing, the e2fabc mutant develops enlarged organs with supernumerary stem and differentiated cells as quiescence is compromised. While E2F, RBR and the M-phase regulatory MYB3Rs are part of the DREAM repressor complexes, and recruited to overlapping groups of targets, they regulate distinct sets of genes. Only the loss of E2Fs but not the MYB3Rs interferes with quiescence, which might be due to the ability of E2Fs to control both G1-S and some key G2-M targets. We conclude that collectively the three canonical E2Fs in complex with RBR have central roles in establishing cellular quiescence during organ development, leading to enhanced plant growth., (© 2023. Springer Nature Limited.)

In a few cases, postmortem computed tomography angiography (PMCTA) is effective in postmortem detection of cortical artery rupture causing subdural hematoma (SDH), which is difficult to detect at autopsy. Here, we explore the usefulness and limitations of PMCTA in detecting the sites of cortical arterial rupture for SDH. In 6 of 10 cases, extravascular leakage of contrast material at nine different places enabled PMCTA to identify cortical arterial rupture. PMCTA did not induce destructive arterial artifacts, which often occur during autopsy. We found that, although not in all cases, PMCTA could show the site of cortical arterial rupture causing subdural hematoma in some cases. This technique is beneficial for cases of SDH autopsy, as it can be performed nondestructively and before destructive artifacts from the autopsy occur.

Root hairs are single-celled tubular structures produced from the epidermis, which play an essential role in water and nutrient uptake from the soil. Therefore, root hair formation and elongation are controlled not only by developmental programs but also by environmental factors, enabling plants to survive under fluctuating conditions. Phytohormones are key signals that link environmental cues to developmental programs; indeed, root hair elongation is known to be controlled by auxin and ethylene. Another phytohormone, cytokinin, also affects root hair growth, while whether cytokinin is actively involved in root hair growth and, if so, how it regulates the signaling pathway governing root hair development have remained unknown. In this study, we show that the two-component system of cytokinin, which involves the B-type response regulators ARABIDOPSIS RESPONSE REGULATOR 1 (ARR1) and ARR12, promotes the elongation process of root hairs. They directly up-regulate ROOT HAIR DEFECTIVE 6-LIKE 4 (RSL4) encoding a basic helix-loop-helix (bHLH) transcription factor that plays a central role in root hair growth, whereas the ARR1/12-RSL4 pathway does not crosstalk with auxin or ethylene signaling. These results indicate that cytokinin signaling constitutes another input onto the regulatory module governed by RSL4, making it possible to fine-tune root hair growth in changing environments., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Large vacuoles are a predominant cell organelle throughout the plant body. They maximally account for over 90% of cell volume and generate turgor pressure that acts as a driving force of cell growth, which is essential for plant development. The plant vacuole also acts as a reservoir for sequestering waste products and apoptotic enzymes, thereby enabling plants to rapidly respond to fluctuating environments. Vacuoles undergo dynamic transformation through repeated enlargement, fusion, fragmentation, invagination, and constriction, eventually resulting in the typical 3-dimensional complex structure in each cell type. Previous studies have indicated that such dynamic transformations of plant vacuoles are governed by the plant cytoskeletons, which consist of F-actin and microtubules. However, the molecular mechanism of cytoskeleton-mediated vacuolar modifications remains largely unclear. Here we first review the behavior of cytoskeletons and vacuoles during plant development and in response to environmental stresses, and then introduce candidates that potentially play pivotal roles in the vacuole-cytoskeleton nexus. Finally, we discuss factors hampering the advances in this research field and their possible solutions using the currently available cutting-edge technologies.

One of the causes of bleeding in subdural hematoma is cortical artery rupture, which is difficult to detect at autopsy. Therefore, reports of autopsy cases with this condition are limited and hence, the pathogenesis of subdural hematoma remains unclear. Herein, for the detection and morphological analysis of cortical artery ruptures as the bleeding sources of subdural hematoma, we used the tissue-clearing CUBIC (clear, unobstructed, brain/body imaging cocktails and computational analysis) method with light-sheet fluorescence microscopy and reconstructed the two-dimensional and three-dimensional images. Using the CUBIC method, we could clearly visualize and detect cortical artery ruptures that were missed by conventional methods. Indeed, the CUBIC method enables three-dimensional morphological analysis of cortical arteries including the ruptured area, and the creation of cross-sectional two-dimensional images in any direction, which are similar to histopathological images. This highlights the effectiveness of the CUBIC method for subdural hematoma analysis.

Cell size requires strict and flexible control as it significantly impacts plant growth and development. Unveiling the molecular mechanism underlying cell size control would provide fundamental insights into plants' nature as sessile organisms. Recently, a GRAS family transcription factor SCARECROW-LIKE28 (SCL28) was identified as a determinant of cell size in plants; specifically, SCL28 directly induces a subset of SIAMESE-RELATED ( SMR ) family genes encoding plant-specific inhibitors of cyclin-dependent kinases (i.e., SMR1 , SMR2 , SMR6 , SMR8 , SMR9 , SMR13, and SMR14 ), thereby slowing down G2 phase progression to provide the time to increase cell volume. Of the SMR genes regulated by SCL28, genetic analysis has demonstrated that SMR1, SMR2, and SMR13 cooperatively regulate the cell size downstream of SCL28 in roots and leaves, whereas other SMR members' contribution remains unexplored. This study shows that in root meristematic cells, SMR9 redundantly participates in cell size control with SMR1, SMR2, and SMR13. Moreover, our cell cycle analysis provides the first experimental evidence that SMR proteins inhibit the G2 progression of proliferating cells. Overall, these findings illuminate the diverse yet overlapping roles of SMR proteins in cell cycle regulation while reinforcing that SMRs are essential downstream effectors of SCL28 to modulate G2 progression and cell size.

Quality control of special steel is accomplished through visual inspection of its microstructure based on microscopic images. This study proposes an 'automatic-quality-level-estimation system' based on machine learning. Visual inspection of this type is sensory-based, so training data may include variations in judgments and training errors due to individual differences between inspectors, which makes it easy for a drop in generalization performance to occur due to overfitting. To deal with this issue, we here propose the preprocessing of inspection images and a data augmentation technique. Preprocessing reduces variation in images by extracting features that are highly related to the level of quality from inspection images. Data augmentation, meanwhile, suppresses the problem of overfitting when training with a small number of images by taking into account information on variation in judgment values obtained from on-site experience. While the correct-answer rate for judging the quality level by an inspector was about 90%, the proposed method achieved a correct-answer rate of 92.5%, which indicates that the method shows promise for practical applications., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society of Microscopy.)

The RNA polymerase II-associated factor 1 complex (PAF1C) is a protein complex that consists of LEO1, RTF1, PAF1, CDC73, and CTR9, and has been shown to be involved in RNA polymerase II-mediated transcriptional and chromatin regulation. Although it has been shown to regulate a variety of biological processes, the precise role of the PAF1C during germ line development has not been clarified. In this study, we found that reduction in the function of the PAF1C components, LEO-1, RTFO-1, PAFO-1, CDC-73, and CTR-9, in Caenorhabditis elegans affects oogenesis. Defects in oogenesis were also confirmed using an oocyte maturation marker, OMA-1::GFP. While four to five OMA-1::GFP-positive oocytes were observed in wild-type animals, their numbers were significantly decreased in pafo-1 mutant and leo-1(RNAi), pafo-1(RNAi), and cdc-73(RNAi) animals. Expression of a functional PAFO-1::mCherry transgene in the germline significantly rescued the oogenesis-defective phenotype of the pafo-1 mutants, suggesting that expression of the PAF1C in germ cells is required for oogenesis. Notably, overexpression of OMA-1::GFP partially rescued the oogenesis defect in the pafo-1 mutants. Based on our findings, we propose that the PAF1C promotes oogenesis in a cell-autonomous manner by positively regulating the expression of genes involved in oocyte maturation., (© 2022 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

How cell size and number are determined during organ development remains a fundamental question in cell biology. Here, we identified a GRAS family transcription factor, called SCARECROW-LIKE28 (SCL28), with a critical role in determining cell size in Arabidopsis. SCL28 is part of a transcriptional regulatory network downstream of the central MYB3Rs that regulate G2 to M phase cell cycle transition. We show that SCL28 forms a dimer with the AP2-type transcription factor, AtSMOS1, which defines the specificity for promoter binding and directly activates transcription of a specific set of SIAMESE-RELATED (SMR) family genes, encoding plant-specific inhibitors of cyclin-dependent kinases and thus inhibiting cell cycle progression at G2 and promoting the onset of endoreplication. Through this dose-dependent regulation of SMR transcription, SCL28 quantitatively sets the balance between cell size and number without dramatically changing final organ size. We propose that this hierarchical transcriptional network constitutes a cell cycle regulatory mechanism that allows to adjust cell size and number to attain robust organ growth., (© 2022. The Author(s).)

A Japanese man in his 30s died suddenly. Postmortem computed tomography and autopsy revealed a pulmonary embolism from an organizing thrombus in the inferior vena cava as the cause of death. Genomic analysis of congenital thrombophilia-related genes (i.e., SERPINC1, PROC, PROS1, F2, F5, PLG, and MTHFR) revealed a heterozygous variant of PROS1 (p.A139V), which has been reported in patients with congenital protein S deficiency. After a genetic conference that included forensic pathologists, molecular scientists, genetic researchers, genetic clinicians, and clinical physicians, the results of the genetic analysis were explained to the family. Biochemical analyses of protein S (PS) activity and total PS antigen levels were performed with samples from the deceased's family and genetic analysis was not performed until clinical symptoms appear. Herein we demonstrate the importance of genetic background in cases of a sudden death due to pulmonary embolism., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Caenorhabditis elegans encodes three class I histone deacetylases (HDACs), HDA-1, HDA-2, and HDA-3. Although HDA-1 is known to be involved in embryogenesis, the regulatory roles of HDA-2 and HDA-3 in embryonic development remain unexplored., Objective: To elucidate the functional roles of the three class I HDACs in C. elegans embryonic development., Methods: The roles of Class I HDACs, HDA-1, HDA-2, and HDA-3 in Caenorhabditis elegans during embryogenesis were investigated through the analysis of embryonic lethality via gene knockdown or deletion mutants. Additionally, the size of these knockdown and mutant eggs was observed using a differential interference contrast microscope. Finally, expression pattern and tissue-specific role of hda-2 and transcriptome of the hda-2 mutant were analyzed., Results: Here, we report that HDA-1 and HDA-2, but not HDA-3, play essential roles in Caenorhabditis elegans embryonic development. Our observations of the fertilized egg size variance demonstrated that HDA-2 is involved in regulating the size of fertilized eggs. Combined analysis of expression patterns and sheath cell-specific rescue experiments indicated that the transgenerational role of HDA-2 is involved in the viability of embryonic development and fertilized egg size regulation. Furthermore, transcriptome analysis of hda-2 mutant embryos implies that HDA-2 is involved in epigenetic regulation of embryonic biological processes by downregulating and upregulating the gene expression., Conclusion: Our finding suggests that HDA-2 regulates the embryonic development in Caenorhabditis elegans by controling a specific subset of genes, and this function might be mediated by transgenerational epigenetic effect., (© 2021. The Author(s) under exclusive licence to The Genetics Society of Korea.)

SARS-CoV-2 is the causative agent of a new type of coronavirus infection, COVID-19, which has rapidly spread worldwide. The overall genome sequence homology between SARS-CoV-2 and SARS-CoV is 79%. However, the homology of the ORF8 protein between these two coronaviruses is low, at ~26%. Previously, it has been suggested that infection by the ORF8-deleted variant of SARS-CoV-2 results in less severe symptoms than in the case of wild-type SARS-CoV-2. Although we found that ORF8 is involved in the proteasome autoimmunity system, the precise role of ORF8 in infection and pathology has not been fully clarified. In this study, we determined a new network of ORF8-interacting proteins by performing in silico analysis of the binding proteins against the previously described 47 ORF8-binding proteins. We used as a dataset 431 human protein candidates from Uniprot that physically interacted with 47 ORF8-binding proteins, as identified using STRING. Homology and phylogenetic profile analyses of the protein dataset were performed on 446 eukaryotic species whose genome sequences were available in KEGG OC. Based on the phylogenetic profile results, clustering analysis was performed using Ward's method. Our phylogenetic profiling showed that the interactors of the ORF8-interacting proteins were clustered into three classes that were conserved across chordates (Class 1: 152 proteins), metazoans (Class 2: 163 proteins), and eukaryotes (Class 3: 114 proteins). Following the KEGG pathway analysis, classification of cellular localization, tissue-specific expression analysis, and a literature study on each class of the phylogenetic profiling cluster tree, we predicted that the following: protein members in Class 1 could contribute to COVID-19 pathogenesis via complement and coagulation cascades and could promote sarcoidosis; the members of Class 1 and 2, together, may contribute to the downregulation of Interferon-β; and Class 3 proteins are associated with endoplasmic reticulum stress and the degradation of human leukocyte antigen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takatsuka, Fahmi, Hamanishi, Sakuratani, Kubota and Ito.)

Background: The blood concentration of cyclosporine (CyA) is frequently elevated following the transfusion of red blood cell concentrate (RCC) to patients after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to identify the variable factors affecting changes in the blood concentration of CyA before and after transfusion of RCC., Methods: We enrolled 105 patients (age, 5-66 years) who received both CyA and transfusion after HSCT. The ratio of the measurement after transfusion to the measurement before transfusion was calculated for the hematocrit and blood concentration/dose ratio of CyA (termed the HCT ratio and the CyA ratio, respectively)., Results: The blood concentration/dose ratio of CyA was increased after transfusion compared with before transfusion (P < 0.001). The HCT ratio was significantly correlated with the CyA ratio (P = 0.23, P < 0.001). The HCT ratio, concomitant medication that could elevate CyA concentration after RCC transfusion, and difference in the alkaline phosphatase level between before and after transfusion (ΔALP) were explanatory variables associated with the variation in the CyA ratio. There was no correlation between the CyA concentration after transfusion and the change in the estimated glomerular filtration rate., Conclusions: A change in the blood concentration/dose ratio of CyA was found to be associated with a change in the HCT, concomitant medication that could elevate CyA concentration after RCC transfusion, and ALP levels. If the HCT level rises significantly after RCC transfusion, clinicians and pharmacists should pay attention to changes in the blood CyA concentration., (© 2022. The Author(s).)

We aimed to evaluate the efficacy and safety of propranolol gel at various concentrations with infantile hemangiomas after proliferative phases. We designed a single-center, randomized, double-blind, dose-dependent trial with placebo control and randomized patients to receive propranolol gel at 0, 1, or 5%, twice daily for 24 weeks. The primary efficacy endpoint was the percentage change in redness of the tumors. Safety endpoints were skin characteristics changes and systemic symptoms. We made two comparisons to evaluate the superiority of 1 and 5% propranolol gels against placebo for primary endpoint analysis and used the t-test to compare parents' satisfaction with these treatments. Initially, 19 patients were enrolled, but 8 were excluded from the analysis. We were underpowered to answer the question of efficacy. In the per-protocol set, we found similar results for the redness percentage change among the patients on placebo, 1 and 5% gel. However, the difference in redness before and after treatment suggested a slight decreasing trend of lesion's redness as the propranolol concentration increased. The difference in parents' satisfaction between the placebo and 5% propranolol gel groups was significant (p = 0.08). We observed no serious adverse events. We did not find an obvious dose-dependent effect for the propranolol gel treatment against infantile hemangiomas after the proliferative phase. However, external applications twice daily were less burdensome for parents and led to good compliances. It had a favorable safety profile in Japanese pediatric patients with infantile hemangiomas.

Observing chromosomes is a time-consuming and labor-intensive process, and chromosomes have been analyzed manually for many years. In the last decade, automated acquisition systems for microscopic images have advanced dramatically due to advances in their controlling computer systems, and nowadays, it is possible to automatically acquire sets of tiling-images consisting of large number, more than 1000, of images from large areas of specimens. However, there has been no simple and inexpensive system to efficiently select images containing mitotic cells among these images. In this paper, a classification system of chromosomal images by deep learning artificial intelligence (AI) that can be easily handled by non-data scientists was applied. With this system, models suitable for our own samples could be easily built on a Macintosh computer with Create ML. As examples, models constructed by learning using chromosome images derived from various plant species were able to classify images containing mitotic cells among samples from plant species not used for learning in addition to samples from the species used. The system also worked for cells in tissue sections and tetrads. Since this system is inexpensive and can be easily trained via deep learning using scientists' own samples, it can be used not only for chromosomal image analysis but also for analysis of other biology-related images., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: Achieving a deep response with induction therapy has a major impact on outcomes following autologous stem cell transplantation. Although longer and intensified induction therapy may provide better disease control, longer exposure to lenalidomide negatively affects stem cell yield. We examined the feasibility of 6 cycles of lenalidomide-based triplet induction therapy before stem cell collection in transplant-eligible multiple myeloma patients., Methods: In this prospective study, patients received a combination of bortezomib, lenalidomide, and dexamethasone for 6 cycles. For patients who did not achieve a deep response after 3 cycles, bortezomib was substituted with carfilzomib for the last 2 cycles (5th and 6th courses)., Results: Although only half of the patients achieved a deep response after 3 cycles, all but 1 patient achieved a very good partial response ( n  = 4) or complete response ( n  = 5) after completing 6 cycles. Among 9 patients who received cyclophosphamide-based stem cell mobilization, 1 patient required a second mobilization that was successfully performed using plerixafor. After autologous transplantation, 7 patients showed complete response, including 5 with minimal residual disease-negative status., Conclusion: This study demonstrates that 6 cycles of lenalidomide-based induction therapy before stem cell collection are a feasible and promising approach for transplant-eligible newly diagnosed multiple myeloma patients.The study is registered at UMIN Clinical Trials Registry as UMIN000026936. Trial registration: UMIN Japan identifier: UMIN000026936.

Acute subdural hematoma (SDH) occurs following severe head trauma with brain contusion or rupture of bridging veins. Conversely, SDH caused by rupture of a cortical artery without trauma or with minor trauma is also possible. Although over 180 cases of the latter SDH have been reported, they were predominantly diagnosed only during surgery, and therefore, no adequate histological evaluation has been performed. Therefore, essential etiology of this SDH type has remained unclear. In addition, the scarcity of autopsy cases may be attributed to arterial rupture being missed if the microscopic findings are too minimal to detect during autopsy. Here, we describe two autopsy cases of SDH of cortical artery origin. Extravasation on postmortem computed tomography angiography and arterial leakage on macroscopic observation during autopsy facilitated detection of the ruptured artery and allowed detailed histological evaluation of the ruptured artery and adjacent dura mater. The etiology of arterial rupture is briefly described on the basis of histopathological findings in this study and the available literature., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The DNA of all organisms is constantly damaged by physiological processes and environmental conditions. Upon persistent damage, plant growth and cell proliferation are reduced. Based on previous findings that RBR1, the only Arabidopsis homolog of the mammalian tumor suppressor gene retinoblastoma, plays a key role in the DNA damage response in plants, we unravel here the network of RBR1 interactors under DNA stress conditions. This led to the identification of homologs of every DREAM component in Arabidopsis, including previously not recognized homologs of LIN52. Interestingly, we also discovered NAC044, a mediator of DNA damage response in plants and close homolog of the major DNA damage regulator SOG1, to directly interact with RBR1 and the DREAM component LIN37B. Consistently, not only mutants in NAC044 but also the double mutant of the two LIN37 homologs and mutants for the DREAM component E2FB showed reduced sensitivities to DNA-damaging conditions. Our work indicates the existence of multiple DREAM complexes that work in conjunction with NAC044 to mediate growth arrest after DNA damage., (© 2021 Lang et al.)

Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure "chromatin". Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

Rett syndrome (OMIM #312750) is a developmental neurological disorder that is caused by a mutation in methyl-CpG-binding protein 2 (MeCP2). MeCP2 localizes to the nucleus, binds to methylated DNA, and regulates gene expression during neuronal development. MeCP2 assembles multiple protein complexes and its functions are controlled by interactions with its binding partners. Therefore, functional analysis of MeCP2 binding proteins is important. Previously, we proposed nine MeCP2-binding candidates in the cerebral cortex. In this study, we characterized and examined the function of the MeCP2 binding protein zinc finger protein 483 (ZNF483) to determine the significance of the MeCP2-ZNF483 interaction in neuronal development. Phylogenetic profiling revealed that the ZNF483 protein is broadly conserved in metazoans. In contrast, MeCP2 was obtained during evolution to chordates. To investigate ZNF483 functions, ZNF483-knockout P19 cell lines were established using the CRISPR-Cas9 system. These cell lines showed decreased cell proliferation, altered aggregate formation, decreased neuronal marker NeuN expression, and altered MeCP2 phosphorylation patterns. Notably, cytosolic localization of MeCP2 was enhanced by ZNF483-overexpression. Taken together, we propose that ZNF483 might be involved in the promotion of neuronal differentiation by regulating the subcellular localization of MeCP2 in P19 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

MYB3R family transcription factors play a central role in the regulation of G2/M-specific gene transcription in Arabidopsis thaliana . Among the members of this family, MYB3R3 and MYB3R5 are structurally closely related and are involved in the transcriptional repression of target genes in both proliferating and quiescent cells. This type of MYB3R repressor is widespread in plants; however, apart from the studies on MYB3Rs in Arabidopsis thaliana , little information about them is available. Here we isolated tobacco cDNA clones encoding two closely related MYB3R proteins designated as NtmybC1 and NtmybC2 and determined the nucleotide sequences of the entire coding regions. Phylogenetic analysis suggested that NtmybC1 and NtmybC2 can be grouped into a conserved subfamily of plant MYB3Rs that also contains MYB3R3 and MYB3R5. When transiently expressed in protoplasts prepared from tobacco BY-2 cells, NtmybC1 and NtmybC2 repressed the activity of target promoters and blocked promoter activation mediated by NtmybA2, a MYB3R activator from tobacco. Unlike MYB3R3 and MYB3R5 , NtmybC1 and NtmybC2 showed cell cycle-regulated transcript accumulation. In synchronized cultures of BY-2 cells, mRNAs for both NtmybC1 and NtmybC2 were preferentially expressed during the G2 and M phases, coinciding with the expression of NtmybA2 and G2/M-specific target genes. These results not only broadly confirm our fundamental view that this type of MYB3R protein acts as transcriptional repressor of G2/M-specific genes but also suggest a possible divergence of MYB3R repressors in terms of the mechanisms of their action and regulation., (© 2021 Japanese Society for Plant Biotechnology.)

When transplacental therapy is conducted, the maternal serum concentrations of digoxin and flecainide may fluctuate throughout third trimester. Therefore, TDM may be effective in improving the efficacy and safety of treatment., Competing Interests: None declared., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Under environmental stress, plants are believed to actively repress their growth to save resource and alter its allocation to acquire tolerance against the stress. Although a lot of studies have uncovered precise mechanisms for responding to stress and acquiring tolerance, the mechanisms for regulating growth repression under stress are not as well understood. It is especially unclear which particular genes related to cell cycle control are involved in active growth repression. Here, we showed that decreased growth in plants exposed to moderate salt stress is mediated by MYB3R transcription factors that have been known to positively and negatively regulate the transcription of G2/M-specific genes. Our genome-wide gene expression analysis revealed occurrences of general downregulation of G2/M-specific genes in Arabidopsis under salt stress. Importantly, this downregulation is significantly and universally mitigated by the loss of MYB3R repressors by mutations. Accordingly, the growth performance of Arabidopsis plants under salt stress is significantly recovered in mutants lacking MYB3R repressors. This growth recovery involves improved cell proliferation that is possibly due to prolonging and accelerating cell proliferation, which were partly suggested by enlarged root meristem and increased number of cells positive for CYCB1;1-GUS. Our ploidy analysis further suggested that cell cycle progression at the G2 phase was delayed under salt stress, and this delay was recovered by loss of MYB3R repressors. Under salt stress, the changes in expression of MYB3R activators and repressors at both the mRNA and protein levels were not significant. This observation suggests novel mechanisms underlying MYB3R-mediated growth repression under salt stress that are different from the mechanisms operating under other stress conditions such as DNA damage and high temperature.

This chapter describes a method used to analyze the behavior of histone modifications in S phase in Arabidopsis using a whole-mount immunostaining technique. Previous studies have demonstrated that dramatic changes in local chromatin structure are required for the initiation and progression of DNA replication, and that histone modifications play an essential role in the determination of chromatin structure in S phase. Since euchromatic and heterochromatic regions are replicated in distinct S-phase stages, it is important to identify histone modifications at each stage. Here, we introduce a protocol for whole-mount immunostaining combined with 5-ethynyl-2'-deoxyuridine (EdU) staining, which enables the visualization of spatial patterns in histone modifications in the early and late S-phase nuclei of Arabidopsis roots.

Precise control of cytoskeleton dynamics and its tight coordination with chromosomal events are key to cell division. This is exemplified by formation of the spindle and execution of cytokinesis after nuclear division. Here, we reveal that the central cell cycle regulator CYCLIN DEPENDENT KINASE A;1 (CDKA;1), the Arabidopsis homologue of Cdk1 and Cdk2, partially in conjunction with CYCLIN B3;1 (CYCB3;1), is a key regulator of the microtubule cytoskeleton in meiosis. For full CDKA;1 activity, the function of three redundantly acting CDK-activating kinases (CAKs), CDKD;1, CDKD;2, and CDKD;3, is necessary. Progressive loss of these genes in combination with a weak loss-of-function mutant in CDKA;1 allowed a fine-grained dissection of the requirement of cell-cycle kinase activity for meiosis. Notably, a moderate reduction of CDKA;1 activity converts the simultaneous cytokinesis in Arabidopsis, i.e., one cytokinesis separating all four meiotic products concurrently into two successive cytokineses with cell wall formation after the first and second meiotic division, as found in many monocotyledonous species., (© 2020 Sofroni et al.)

Aspergillus empyema is treated with either systemic administration of antifungal drugs or surgery, but the mortality rate is very high. Here, we report a case of Aspergillus empyema successfully treated using combined intrathoracic and intravenous administration of voriconazole (VRCZ). Treatment success was achieved by monitoring VRCZ plasma trough concentration. The patient was a 71-year-old Japanese woman diagnosed with Aspergillus empyema whom we started on intravenous administration of VRCZ. Although penetration of VRCZ into the pleural effusion was confirmed, the level was below 1 μg/mL, which is the minimum inhibitory concentration for Aspergillus fumigatus determined by antifungal susceptibility testing in pleural effusion culture. Therefore, we initiated combination therapy with intrathoracic and intravenous administration of VRCZ. VRCZ 200 mg was first dissolved in 50-100 mL of saline and administered into the thoracic cavity via a chest tube. The chest tube was clamped for 5-6 h, and then VRCZ solution was excreted though the chest tube. When a single dose of the VRCZ was administered into the intrathoracic space, the plasma concentration before intravenous administration increased from 1.45 μg/mL on day 27 to 1.53 μg/mL on day 28. Although intravenous administration was continued, the VRCZ plasma trough concentration decreased to 1.36 μg/mL on day 29. We therefore decided on an intrathoracic administration schedule of 2-3 times a week. Intrathoracic administration was performed 14 times in total until fenestration surgery on day 64. Our case suggests that combined intrathoracic and intravenous administration of VRCZ may be a valid treatment option for Aspergillus empyema., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background Elevated blood concentration of tacrolimus is frequently observed following transfusion of red blood cell concentrate in patients after allogeneic hematopoietic stem cell transplantation. Objective The aim of this retrospective study was to clarify the effects of transfusion of red blood cell concentrate on the blood concentration of tacrolimus. Setting Chiba University Hospital in Japan. Method Fifty-two patients (aged 0-65 years) receiving both tacrolimus and transfusion after allogeneic hematopoietic stem cell transplantation were enrolled. The ratio of measurement after transfusion to measurement before transfusion was calculated for hematocrit and blood concentration/dose ratio of tacrolimus (termed the hematocrit ratio and the tacrolimus ratio, respectively). Main outcome measure Change in blood concentration/dose ratio of tacrolimus and variable factors associated with variation in tacrolimus ratio. Results The blood concentration/dose ratio of tacrolimus was increased after transfusion compared with before transfusion (p < 0.001). A statistically significant correlation was seen between the hematocrit ratio and tacrolimus ratio (r = 0.32, p < 0.001). Hematocrit ratio, age or body surface area, and difference in aspartate aminotransferase level before and after transfusion were associated with the variation in tacrolimus ratio. There was no correlation between tacrolimus ratio and change in serum creatinine or potassium level in the short term. Conclusion Change in the blood concentration/dose ratio of tacrolimus was associated with change in the hematocrit ratio after transfusion, and more attention is required for children or patients with small body surface area. Dose adjustment of tacrolimus is required if the blood concentration of tacrolimus is much higher than the target concentration.

Background: Although continuous hemodiafiltration (CHDF) is often performed in critically ill patients during sepsis treatment, the pharmacokinetics of vancomycin (VCM) during CHDF with a polymethylmethacrylate hemofilter (PMMA-CHDF) have not been revealed. In this study, the authors aimed to describe the population pharmacokinetics of VCM in critically ill patients undergoing PMMA-CHDF and clarify its hemofilter clearance (CLhemofilter)., Methods: This single-center, retrospective study enrolled patients who underwent intravenous VCM therapy during PMMA-CHDF at the intensive care unit of Chiba University Hospital between 2008 and 2016. A population analysis was performed, and CLhemofilter was assessed., Results: Twenty-five patients were enrolled. Median body weight (BW) and Sequential Organ Failure Assessment (SOFA) score were 63 kg and 15, respectively. Mean conditions for CHDF were 107.5 ± 18.3 mL/min for blood flow rate and 26.3 ± 6.3 mL/kg/h for effluent flow rate. The mean parameter estimates were distribution volume of the central compartment (V1), 59.1 L; clearance of the central compartment (CL1), 1.35 L/h; distribution volume of the peripheral compartment (V2), 56.1 L; and clearance of the peripheral compartment (CL2), 3.65 L/h. BW and SOFA score were significantly associated with V1 (P < 0.05) and CL1 (P < 0.05), respectively, and were thus selected as covariates in the final model. The estimated dosage of VCM to achieve a target area under the concentration-time curve/minimum inhibitory concentration ≥400 was 27.1 mg/kg for loading and 9.7 mg/kg every 24 hours for maintenance; these dosages were affected by BW and SOFA score. Mean CLhemofilter obtained from 8 patients was 1.35 L/h, which was similar to CL1., Conclusions: The authors clarified the pharmacokinetics and CLhemofilter of VCM in PMMA-CHDF patients. The PK of VCM in patients undergoing CHDF appeared to vary not only with the CHDF setting and BW but also with SOFA score.

Purpose: To clarify an early postmortem change, we investigated the volume changes of the spleen and kidney on postmortem CT compared with antemortem CT in the same patients., Materials and Methods: We retrospectively evaluated the volumes of 56 spleens (56 cases) and 50 kidneys (25 cases) using antemortem and postmortem CT, which were performed within 168 min after death. We divided the cases of spleen analysis into a hemorrhagic group (n = 12) and a non-hemorrhagic group (n = 44)., Results: The volumes of the organs before and after death were 101.0 ± 70.9 (cm 3 , mean ± standard deviation) and 81.1 ± 57.8 in spleens, 120.3 ± 49.2 and 109.2 ± 39.2 in kidneys, respectively. Both spleens and kidneys shrank after death (p < 0.05). The volumes of spleens before and after death were 111 ± 66.5 and 67.5 ± 27.7 in the hemorrhagic group, and 98.2 ± 72.5 and 84.9 ± 63.3 in the non-hemorrhagic group, respectively. The median value of the ratio of postmortem splenic volume to antemortem volume in the hemorrhagic group (65.0%) was smaller than the one in the non-hemorrhagic group (90.5%) (p < 0.05)., Conclusion: We demonstrated that spleens and kidneys significantly reduced in size after death. The rate of shrinkage of spleens in the hemorrhagic group significantly became larger than the one in the non-hemorrhagic group.

What Is Known and Objective: Determination of phenobarbital (PB) dosing during continuous haemodiafiltration (CHDF) requires evaluation of both the patient's own clearance and CHDF clearance., Case Description: Systemic clearance of PB in a 9-year-old female patient with Dravet syndrome, who was undergoing CHDF, was calculated by the Sawchuk-Zaske method, and clearance by CHDF was calculated as the difference between PB levels in influx and efflux, adjusted for the blood purification conditions. Dosage adjustment produced seizure control., What Is New and Conclusion: Adjusting PB dose by evaluating the patient's own PB clearance as well as that by CHDF resulted in accurate control of PB level and a reduction in the occurrence of seizures., (© 2019 John Wiley & Sons Ltd.)

Yearly, several reports of unknown boats and corpses brought by the Tsushima Current are found ashore Japanese coast. Niigata prefecture had the highest number of the drifting ashore corpses in Japan with 45.7% (16/35) in 2017. Corpses from North Korea, confirmed by documents and photos were autopsied and in 3/16 was possible to recover worms full of eggs, morphologically identified as ascarids. Further molecular analysis of ITS1, 5.8S rDNA and ITS2 sequences confirmed all specimens were Ascaris lumbricoides. The contamination level by Ascaris lumbricoides eggs in the coast, the health impact and consequences of the epidemiological bridging produced by this forced migration in public health should be investigated. Moreover, control of helminthiases might be a necessary task in North Korea., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This report describes the autopsy case of a 4-year-old boy who died from hepatic hemorrhage and rupture caused by peliosis hepatis with X-linked myotubular myopathy. Peliosis hepatis is characterized by multiple blood-filled cavities of various sizes in the liver, which occurs in chronic wasting disease or with the use of specific drugs. X-linked myotubular myopathy is one of the most serious types of congenital myopathies, in which an affected male infant typically presents with severe hypotonia and respiratory distress immediately after birth. Although each disorder is rare, 12 cases of pediatric peliosis hepatis associated with X-linked myotubular myopathy have been reported, including our case. Peliosis hepatis should be considered as a cause of hepatic hemorrhage despite its low incidence, and it requires adequate gross and histological investigation for correct diagnosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Measurement of heart weight is important when investigating cause of death, but there is presently no satisfactory method of heart weight estimation by postmortem computed tomography (PMCT)., Method: We investigated 33 consecutive cases that underwent both PMCT and autopsy between February 2008 and June 2014. Heart and left ventricular (LV) weights were calculated by PMCT morphometry. We used a simple method to estimate LV weight: We assumed that LV was an ellipsoid and multiplied its volume on PMCT with myocardial specific gravity. We then compared the various heart and LV weights using linear regression. The calculated and estimated LV weights on PMCT were also compared., Results: It was not possible to predict heart weight at autopsy from PMCT (R 2  = 0.53). However, heart weight at autopsy could be accurately predicted from LV weight calculated by PMCT (R 2  = 0.77). In addition, there was a strong correlation between the estimated and calculated LV weights by PMCT (R 2  = 0.92). Heart weight at autopsy could also be accurately predicted using the PMCT-estimated LV weight (R 2  = 0.72)., Conclusion: Heart weight at autopsy could be accurately predicted using a simple method in which LV volume was assumed to be an ellipsoid on PMCT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cell elongation, which plays an important role in root penetration into the soil, responds to a variety of environmental factors. A previous study demonstrated that abscisic acid, a phytohormone involved in stress responses, inhibits root growth by delaying the onset of cell elongation. In contrast, we recently reported that cytokinins promote elongation of root cells by enhancing actin bundling. However, the control of root cell elongation through the interaction between abscisic acid and cytokinin signaling has not yet been uncovered. Here, we show that abscisic acid-induced delay in cell elongation requires inhibition of cytokinin signaling; further, stress is signaled to cell elongation by the pathway mediated by B-type ARABIDOPSIS RESPONSE REGULATOR 2 (ARR2), which retards root growth.

Root growth is controlled by mechanisms underlying cell division and cell elongation, which respond to various internal and external factors. In Arabidopsis ( Arabidopsis thaliana ), cells produced in the proximal meristem (PM) elongate and differentiate in the transition zone (TZ) and the elongation/differentiation zone (EDZ). Previous studies have demonstrated that endoreplication is involved in root cell elongation; however, the manner by which cells increase in length by more than 2-fold remains unknown. Here, we show that epidermal and cortical cells in Arabidopsis roots undergo two modes of rapid cell elongation: the first rapid cell elongation occurs at the border of the proximal meristem and the TZ, and the second mode occurs during the transition from the TZ to the EDZ. Our previous study showed that cytokinin signaling promotes endoreplication, which triggers the first rapid cell elongation. Our cytological and genetic data revealed that the second rapid cell elongation involves dynamic actin reorganization independent of endoreplication. Cytokinins promote actin bundling and the resultant second rapid cell elongation through activating the signaling pathway involving the cytokinin receptors ARABIDOPSIS HISTIDINE KINASE3 (AHK3) and AHK4 and the B-type transcription factor ARABIDOPSIS RESPONSE REGULATOR2. Our results suggest that cytokinins promote the two modes of rapid cell elongation by controlling distinct cellular events: endoreplication and actin reorganization., (© 2018 American Society of Plant Biologists. All rights reserved.)