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Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors., Competing Interests: Competing interests statement:The authors declare no competing interest.

The transcription and transportation of mRNA are coupled processes; however, the mechanisms linking these processes remain unclear. Additionally, the significance of this connection in cancer drug development is poorly understood. To address these issues, we investigated the role of CDK12 kinase, which regulates RNA transcription through the phosphorylation of RNA polymerase II (Pol II) and has a repeated serine-arginine dipeptide (RS domain) involved in mRNA transport. Despite the anticipated uniqueness of CDK12 function, the mechanism by which CDK12 bridges and manages mRNA transcription and transport has not been fully analyzed. Our study revealed that CDK12 interacts with NXF1, a key molecule involved in the export of mRNA from the nucleus to the cytosol. Although CDK12 does not phosphorylate NXF1, we found that NXF1 unexpectedly stabilized the CDK12 protein, suggesting that NXF1 mRNA export activity indirectly affects mRNA transcriptional activity by modifying the protein level of CDK12. Furthermore, CDK12 recruited other essential RNA transporters, specifically the exon junction complex (EJC) and THO complexes, into the CDK12-NXF1 axis through its kinase activity. These observations provide insights into the mechanisms linking mRNA transcription and transport through the formation of a novel CDK12-NXF1 complex that involves EJC and THO. Importantly, the expression level of NXF1 influences sensitivity to CDK12 inhibitors, which are emerging as novel anti-cancer drug candidates. This highlights the importance of considering the relationship between mRNA transcription and transport when targeting RNA transcription in cancer therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daisuke Morishita reports a relationship with Chordia Therapeutics Inc. that includes: employment and equity or stocks. Shunsuke Ebara reports a relationship with Chordia Therapeutics Inc. that includes: employment and equity or stocks. Misaki Yoshida reports a relationship with Chordia Therapeutics Inc. that includes: employment. Hiroko Yamakawa reports a relationship with Chordia Therapeutics Inc. that includes: employment and equity or stocks. Kenichiro Shimokawa reports a relationship with Chordia Therapeutics Inc. that includes: employment and equity or stocks. If there are other authors, they 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 © 2024. Published by Elsevier Inc.)

Background: Imagination represents a pivotal capability of human intelligence. To develop human-like artificial intelligence, uncovering the computational architecture pertinent to imaginative capabilities through reverse engineering the brain's computational functions is essential. The existing Structure-Constrained Interface Decomposition (SCID) method, leverages the anatomical structure of the brain to extract computational architecture. However, its efficacy is limited to narrow brain regions, making it unsuitable for realizing the function of imagination, which involves diverse brain areas such as the neocortex, basal ganglia, thalamus, and hippocampus., Objective: In this study, we proposed the Function-Oriented SCID method, an advancement over the existing SCID method, comprising four steps designed for reverse engineering broader brain areas. This method was applied to the brain's imaginative capabilities to design a hypothetical computational architecture. The implementation began with defining the human imaginative ability that we aspire to simulate. Subsequently, six critical requirements necessary for actualizing the defined imagination were identified. Constraints were established considering the unique representational capacity and the singularity of the neocortex's modes, a distributed memory structure responsible for executing imaginative functions. In line with these constraints, we developed five distinct functions to fulfill the requirements. We allocated specific components for each function, followed by an architectural proposal aligning each component with a corresponding brain organ., Results: In the proposed architecture, the distributed memory component, associated with the neocortex, realizes the representation and execution function; the imaginary zone maker component, associated with the claustrum, accomplishes the dynamic-zone partitioning function; the routing conductor component, linked with the complex of thalamus and basal ganglia, performs the manipulation function; the mode memory component, related to the specific agranular neocortical area executes the mode maintenance function; and the recorder component, affiliated with the hippocampal formation, handles the history management function. Thus, we have provided a fundamental cognitive architecture of the brain that comprehensively covers the brain's imaginative capacities., 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 © 2024 Yamakawa, Fukawa, Yairi and Matsuo.)

It remains difficult for mobile robots to continue accurate self-localization when they are suddenly teleported to a location that is different from their beliefs during navigation. Incorporating insights from neuroscience into developing a spatial cognition model for mobile robots may make it possible to acquire the ability to respond appropriately to changing situations, similar to living organisms. Recent neuroscience research has shown that during teleportation in rat navigation, neural populations of place cells in the cornu ammonis-3 region of the hippocampus, which are sparse representations of each other, switch discretely. In this study, we construct a spatial cognition model using brain reference architecture-driven development, a method for developing brain-inspired software that is functionally and structurally consistent with the brain. The spatial cognition model was realized by integrating the recurrent state-space model, a world model, with Monte Carlo localization to infer allocentric self-positions within the framework of neuro-symbol emergence in the robotics toolkit. The spatial cognition model, which models the cornu ammonis-1 and -3 regions with each latent variable, demonstrated improved self-localization performance of mobile robots during teleportation in a simulation environment. Moreover, it was confirmed that sparse neural activity could be obtained for the latent variables corresponding to cornu ammonis-3. These results suggest that spatial cognition models incorporating neuroscience insights can contribute to improving the self-localization technology for mobile robots. The project website is https://nakashimatakeshi.github.io/HF-IGL/., Competing Interests: HY was employed by The Whole Brain Architecture Initiative. The remaining 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 © 2024 Nakashima, Otake, Taniguchi, Maeyama, El Hafi, Taniguchi and Yamakawa.)

We report a case of a 69-year-old woman with pleural mesothelioma presenting in the posterior mediastinum with a maximum diameter of 25 cm. She had a chronic cough and a pleural effusion was noted on chest X-ray. The examination of the effusion showed high hyaluronic acid levels, and mesothelioma was suspected. A chest computed tomography scan showed a huge mediastinal mass, which caused rapid progression of respiratory failure and compression of the heart. Sufficient tissue samples could not be obtained before death. The patient died approximately 1 month after the initial visit, and a pathological autopsy was performed. The diagnosis of malignant pleural mesothelioma was made. Malignant pleural mesothelioma with a huge posterior mediastinal mass such as in this case is considerably rare; however, it is a rapidly progressing form of the disease and is reported here as an important differential diagnosis for mediastinal tumours., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: Nintedanib is generally safe and well tolerated and can improve prognosis in patients with various interstitial lung diseases (ILDs). Appropriate management of adverse events of nintedanib is important to ensure its long-term persistent use. Weight loss is a routinely assessed adverse event in clinical practice. This study aimed to elucidate whether body weight change in the first year of nintedanib therapy can indicate prognosis and predict tolerability in patients with ILD., Methods: We analysed 245 consecutive ILD patients treated with nintedanib. We calculated the slope of body weight change using baseline weight and that recorded closest after the first year and then categorized percent change in body weight at this time. Significant weight loss was defined as that ≥5%., Results: Subjects included 67 patients with idiopathic pulmonary fibrosis (IPF) and 76 with non-IPF progressive fibrosing-ILD including fibrotic hypersensitivity pneumonitis (n = 16), unclassifiable (n = 35), connective tissue disease-ILD (n = 21), and nonspecific interstitial pneumonia (n = 4). Older age, low body weight at initial examination, significant weight loss, and lower %FVC were significant predictors of discontinuation of nintedanib. Patients with weight loss ≥5% over the first year showed worse survival than those with weight loss <5% regardless of whether IPF existed or BMI indicated obesity., Conclusions: Careful monitoring of body weight change might suggest useful information for predicting long-term use of nintedanib and mortality risk in ILD patients treated with nintedanib. Appropriate body weight management is needed to prevent adverse events of nintedanib itself., Competing Interests: Declaration of competing interest H.Y. and S.S. received honoraria from Nippon Boehringer Ingelheim Co., Ltd. The other authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal accumulation of surfactants in the alveoli. Most cases are classified as autoimmune PAP (APAP) because they are associated with autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). However, GM-CSF autoantibody levels are unlikely to correlate with the disease severity or prognosis of APAP., Methods: We collected clinical records and measured 38 serum cytokine concentrations for consecutive patients with APAP. After exclusion of 21 cytokines because of undetectable levels, 17 cytokine levels were compared between low and high disease severity scores (DSSs). We also compared whole lung lavage (WLL)-free survival with cut-off values defined by receiver operating characteristic (ROC) curves of cytokine levels and WLL administration at 11 months., Results: Nineteen patients with APAP were enrolled in the study. Five were classified as DSS 1 or 2, while the others were classified as DSS 4 or 5. Comparison between DSS 1-2 and 4-5 revealed that the concentrations of IP-10 and GRO increased in the latter groups (p < 0.05). Fifteen patients underwent WLL. Comparison between those who underwent WLL within 11 months and the others showed that IP-10 and TNF-α were tended to be elevated in the former group (p = 0.082 and 0.057, respectively). The cut-off values of IP-10, 308.8 pg/mL and TNF-α, 19.1 pg/mL, defined by the ROC curves, significantly separated WLL-free survivals with log-rank analyses (p = 0.005)., Conclusions: The concentrations of IP-10 and GRO may reflect the DSSs of APAP. A combination of IP-10 and TNF-α levels could be a biomarker to predict WLL-free survival., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real-world utility in the therapeutic decision-making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents., Methods: We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC-based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing., Results: In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed-effects analysis showed that declines in the slopes of %FVC and %DL CO in patients with TBLC-based UIP "Score ≥ 2" were significantly steeper than those of patients with "Score ≤ 1." During follow-up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure., Conclusions: TBLC-based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti-inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Pleuroparenchymal fibroelastosis (PPFE) is characterized by fibrosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lobes. As PPFE appears to occur in patients with heterogeneous etiologies, the disease course is thus also heterogenous, with some patients showing rapid progression while others have slow progression. Therefore, it is very difficult to predict prognosis with PPFE. Needless to say, this problematic matter has influenced the treatment strategy of PPFE patients. In fact, until now no evidence has been shown for use in creating an appropriate management algorithm for PPFE. We speculate that "uncoordinated breathing" is the most important reason for dyspnea in PPFE patients. Because monitoring of physique and not just pulmonary function and radiological evaluation is also very important, particularly in PPFE patients, this review focused on the characteristics of PPFE through an overview of previous studies in this field, and we proposed an algorithm as precision medicine based on the current evidence. Multiple views by the pulmonologist are needed to standardize a clinical algorithm that is necessary to correctly assess PPFE patients under the premise of maintenance of physique by providing appropriate nutritional care and pulmonary rehabilitation.

Background: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny., Case Presentation: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal., Conclusions: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind., (© 2024. The Author(s).)

Sweetpotato ( Ipomoea batatas ) includes diverse cultivars with flesh textures ranging from dry to moist. Moist-fleshed cultivars often contain starch with a lower gelatinization temperature (GT). To elucidate the genetic determinants of flesh texture and starch GT, we conducted a QTL analysis using F 1 progenies obtained from a cross between dry-fleshed and moist-fleshed cultivars, 'Benikomachi' (BK) and 'Amahazuki' (AH), by using an updated polyploid QTL-seq pipeline. Flesh texture was assessed based on the wet area ratio (WAR) observed on the cut surface of steamed tubers, as progenies with dry and moist flesh exhibited low and high WAR values, respectively, demonstrating a strong correlation. Three QTLs were found to regulate the WAR. Notably, two AH-derived alleles at 4.30 Mb on Itr&#95;chr05 and 21.01 Mb on Itr&#95;chr07, along with a BK-derived allele at 2.89 Mb on Itr&#95;chr15, were associated with increased WAR. Starch GT, which displayed no correlation with either flesh texture or WAR, was distinctly influenced by two QTLs: a GT-increasing BK-derived allele at 1.74 Mb on Itr&#95;chr05 and a GT-decreasing AH-derived allele at 30.16 Mb on Itr&#95;chr12. Consequently, we developed DNA markers linked to WAR, offering a promising avenue for the targeted breeding of sweetpotato with the desired flesh textures., (Copyright © 2024 by JAPANESE SOCIETY OF BREEDING.)

DNA markers serve as essential tools in breeding selection and genetic analysis. However, developing DNA markers can be time-consuming and labor-intensive due to the need to identify polymorphisms between cultivars/lines and to design suitable primers. To address these challenges, we have developed DNAMarkMaker, a tool designed to automate the process of primer design for Amplification Refractory Mutation System (ARMS) and Cleaved Amplified Polymorphic Sequences (CAPS) markers, utilizing resequencing data. One key feature of DNAMarkMaker is its user-friendly graphical user interface (GUI), ensuring its accessibility and ease of use, even for researchers not well-versed in bioinformatics. We confirmed DNAMarkMaker's applicability by developing DNA markers for rice, potato, and turnip-each representing distinct genome structures: homozygous diploid, heterozygous autotetraploid, and heterozygous diploid, respectively. DNAMarkMaker will contribute to the rapid and efficient development of DNA markers, accelerating breeding and genetic analysis in various crops., (Copyright © 2024 by JAPANESE SOCIETY OF BREEDING.)