The etiology of Kawasaki disease (KD) has not yet been completely elucidated. We evaluated the temporal association between respiratory pathogens and KD incidence and the association between respiratory pathogens and treatment responsiveness in patients with KD. This retrospective study was conducted to compare the number of symptomatic children with pathogens detected using multiplex PCR tests with the number of KD cases. Logistic analysis was performed to assess whether the presence of at least one respiratory virus was associated with immunoglobulin non-responsiveness in patients with KD. A statistically significant temporal association was found between the number of KD patients and the number of patients with a positive respiratory pathogen (Pearson correlation coefficient +0.595; p=0.003). The adjusted odds ratio of respiratory pathogen detection for immunoglobulin responsiveness was 1.24 (95% confidence interval 0.38-4.11) (p=0.721). Our study demonstrated a temporal association between the total number of respiratory infections and KD.

For random compositions of independent and identically distributed measurable maps on a Polish space, we study the existence and finitude of absolutely continuous ergodic stationary probability measures (which are, in particular, physical measures) whose basins of attraction cover the whole space almost everywhere. We characterize and hierarchize such random maps in terms of their associated Markov operators, as well as show the difference between classes in the hierarchy by plenty of examples, including additive noise, multiplicative noise, and iterated function systems. We also provide sufficient practical conditions for a random map to belong to these classes. For instance, we establish that any continuous random map on a compact Riemannian manifold with absolutely continuous transition probability has finitely many physical measures whose basins of attraction cover Lebesgue almost all the manifold.

Animal cells adapt to the stiffness of their environment through mechanotransduction, a process in which mechanical signals are converted into biochemical responses, influencing key cellular processes such as growth and differentiation. We identified ubiquitin-conjugating enzymes E2 A and B (UBE2A/B) as mechanosensitive proteins that translocate between the nucleus and cytoplasm depending on force and substrate stiffness. Here, we hypothesized that UBE2A/B nuclear translocation on stiff substrates triggers gene expression via UBE2A/B-mediated ubiquitination of histone H2B lysine 120 (H2BK120). Chromatin immunoprecipitation sequencing (ChIP-seq) revealed distinct DNA fragments bound to monoubiquitinated H2B in cells cultured on soft (0.2 kPa) versus stiff (64 kPa) substrates. We identified 2245 gene regions binding to ubiquitinated histones on stiff substrates and 294 on soft substrates and further integrated RNA-seq and UBE2A/B knockdown data to pinpoint 179 stiff-specific and 18 soft-specific genes. Among these, filamin C (FLNC), leucine zipper protein 1 (LUZP1), and glutamate-rich WD repeat-containing protein 1 (GRWD1) showed higher expression on stiff substrates, with GRWD1 known for its role in cancer progression through cell cycle and gene regulation. These findings highlight how substrate stiffness modulates gene expression via UBE2A/B-mediated H2B ubiquitination.

Intermediate filaments (IFs) in human cells are the products of six distinct gene families, all sharing homology in a core rod domain. These IFs assemble into non-polar polymers, providing cytoplasmic and nuclear mechanical support. Recent research has revealed the active and dynamic properties of IFs and their binding partners. This regulation extends beyond cell mechanics to include migration, mechanotransduction, and tumor growth. Therefore, this comprehensive review aims to catalog all human IF genes and IF-associated proteins (IFAPs), detailing their names, sizes, functions, associated human diseases, relevant literature, and links to resources like UniProt and the Protein Atlas database. These links provide access to additional information such as protein structure, subcellular localization, disease-causing mutations, and pathology. Using this catalog, we will provide an overview of the current understanding of the biological functions of IFs and IFAPs. This overview is crucial for identifying gaps in their characterization and understanding IF-mediated mechanotransduction. Additionally, we will consider potential future research directions.

Background/Aims: Numerous patients with ulcerative colitis (UC) become mentally unstable after experiencing a long-standing, physically painful life, and their long-term prognosis is poorer than that of those who are mentally stable. The current study aimed to evaluate serum biomarkers for predicting mental instability, which is challenging to objectively quantify. Methods: In total, 29 refractory UC patients newly treated with filgotinib underwent measurements of blood parameters associated with depression and a quantitative assessment of quality of life using the Inflammatory Bowel Disease Questionnaire (IBDQ) before and after treatment initiation with a 12-week interval. The data collected were examined in relation to each other. Results: The induction of remission treatment with filgotinib resulted in a clinical response rate of 89.7% and a clinical remission rate of 86.2%, with all eight extraintestinal manifestations resolved. No adverse events were observed. The serum zinc, high-density lipoprotein cholesterol, mature brain-derived neurotrophic factor (BDNF) concentrations, and the IBDQ psychiatric subscores increased significantly after treatment (p < 0.05). Among these parameters, the mature-BDNF concentration and the IBDQ psychiatric subscore had the strongest positive correlation (R = 0.29, p = 0.08). Based on the logistic regression analysis, the mature-BDNF concentration (cutoff value: 20.5 ng/mL) had a sensitivity of 68.2%, specificity of 64.7%, and area under the curve of 0.67 for predicting psychiatric remission (subscore > 42.5) (p = 0.04). Conclusions: While it is not easy to objectively predict the degree of psychiatric instability in patients with refractory UC, serum mature-BDNF levels can be a useful biomarker.

Cell contact inhibition progresses through three stages: (i) increasing cell density leads to reduced movement while mitosis continues; (ii) a rapid shift to epithelial morphology; and (iii) ongoing division with decreased cell size. This transition involves reorganizing the actin cytoskeleton from stress fibers to a cortical network, stabilizing cell shape, and strengthening cell-cell connections. However, the signaling pathways regulating the final stage remain unclear. We identified histidine triad nucleotide-binding protein 1 (HINT1), also known as protein kinase C inhibitor 1 (PKCI-1), as essential for monolayer maturation. At low density, HINT1 is located in the nucleus, binding to open chromatin. As density increases, exportin-1 relocates HINT1 to the cytoplasm, where it inhibits PKC and remodels the actin cytoskeleton. While monolayer formation can occur without HINT1, its presence is necessary for fully confining cells and achieving a mature monolayer. Additionally, MARCKS phosphorylation decreases in high-density cells, and loss of HINT1 leads to increased cell area, similar to hypertrophic conditions in patients with low HINT1 levels.

Infusion-related reaction (IRR) is a common adverse event induced by rituximab. Although first-generation histamine 1 receptor antagonists (H1RAs) are commonly used to prevent IRR, evidence on IRR suppression by the second-generation H1RA bepotastine is scarce. In this study, we assessed the inhibitory effects of bepotastine on rituximab-induced IRR and compared them with those of the first-generation H1RA diphenhydramine. We retrospectively evaluated IRR incidence in patients with B-cell non-Hodgkin lymphoma who received their first dose of rituximab. The incidence of any grade IRR was 9.8

Purpose Infusion-related reaction (IRR) is a common adverse event induced by rituximab. Although first-generation histamine 1 receptor antagonists (H1RAs) are commonly used for the prevention of IRR, evidence is scarce on the incidence of IRR suppression with the second-generation H1RA bepotastine. This study assessed inhibitory effects of bepotastine on rituximab-induced IRR and compared them with those of first-generation H1RA diphenhydramine. Methods We retrospectively evaluated IRR incidence in patients with B-cell non-Hodgkin’s lymphoma who received their first dose of rituximab. Results The incidence of IRR was 9.8% in the bepotastine group (n = 92), which was significantly lower than the 30.2% incidence rate in the diphenhydramine group (n = 96; p < 0.001). The median IRR onset time after rituximab administration in the bepotastine group was 60 min, which was significantly shorter than the 120 min of the diphenhydramine group (p = 0.002). Multivariable logistic regression analysis revealed that the risk of IRR incidence was higher in patients with B symptoms (odds ratio [OR] = 2.96, 95% confidence interval [CI]: 1.20–7.27) and bulky disease (OR = 9.12, 95% CI: 2.53–32.9). Bepotastine use as premedication was an independent factor reducing the risk of IRR incidence (OR = 0.19, 95% CI: 0.08–0.47). Conclusion Bepotastine more effectively reduced the incidence of rituximab-induced IRR than diphenhydramine, particularly delayed-type reactions.

Background: To evaluate the effect of the type and codetection of respiratory viruses on admission requirements among children with respiratory infections in the post-COVID-19 pandemic era. Methods: In this retrospective study, we analyzed patients with acute respiratory symptoms using FilmArray (R) Respiratory Panel between December 2020 and March 2024. The viruses were classified into eight groups: adenovirus, seasonal coronavirus, human metapneumovirus, human rhinovirus/enterovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and severe acute respiratory virus coronavirus-2. The impact of the detected viral groups and viral codetection on hospitalization rates were examined using multivariable regression analysis in three pediatric age groups (< 2 years, 2-4 years, and 5-17 years). Results: A total of 4684 tests were performed, of which 3555 (75.9 %) tested positive for at least one respiratory virus and negative for atypical bacteria. Of these, 946 (26.6 %) were hospitalized. Multivariable regression analyses showed that respiratory syncytial virus (RSV) infection was associated with hospitalization requirement among young children (adjusted odds ratios (aOR) 2.46 [1.65-3.67], p < 0.001 in < 2 years, and 1.34 [1.02-2.30], p = 0.042 in 2-4 years). Influenza (aOR 0.23 [0.07-0.83], p = 0.025) and SARSCoV-2 (aOR 0.39 [0.22-0.69], p = 0.001) were negatively correlated with hospitalization among children younger than 2 years. Viral codetection was not significantly associated with hospitalization in any pediatric age group. Conclusion: RSV infection was associated with a higher risk of hospitalization in children younger than 5 years than other respiratory viruses. These results highlight the importance of preventive measures against RSV infections, including maternal vaccination and childhood immunization.

Mechanotransduction leads to a variety of biological responses including gene expression, changes in cell shape, migration, tissue development, and immune responses. Dysregulation of mechanotransduction is implicated in the progression of various diseases such as cardiovascular diseases and cancer. The actin cytoskeleton plays a crucial role in transmitting mechanical stimuli. Actin filaments, essential for cell motility and shape changes, respond to mechanical cues by remodeling, influencing gene expression via the linker of nucleoskeleton and cytoskeleton complex and mechanosensitive transcription factors. This study employs the dithiobis(succinimidyl propionate) (DSP)-micrococcal nuclease (MNase) proteogenomics method to explore the relationship between cellular mechanosensing, chromatin architecture, and the identification of proteins involved in mechanosensitive nucleocytoplasmic shuttling, revealing how actin polymerization affects chromatin and gene expression. We found that depolymerization of actin filaments by latrunculin B (Lat B) for 30 min is sufficient to alter open chromatin and identified core-binding factor subunit beta as mechanosensitive nucleocytoplasmic shuttling protein.

Contact inhibition (CI) represents a crucial tumor-suppressive mechanism responsible for controlling the unbridled growth of cells, thus preventing the formation of cancerous tissues. CI can be further categorized into two distinct yet interrelated components: CI of locomotion (CIL) and CI of proliferation (CIP). These two components of CI have historically been viewed as separate processes, but emerging research suggests that they may be regulated by both distinct and shared pathways. Specifically, recent studies have indicated that both CIP and CIL utilize mechanotransduction pathways, a process that involves cells sensing and responding to mechanical forces. This review article describes the role of mechanotransduction in CI, shedding light on how mechanical forces regulate CIL and CIP. Emphasis is placed on filamin A (FLNA)-mediated mechanotransduction, elucidating how FLNA senses mechanical forces and translates them into crucial biochemical signals that regulate cell locomotion and proliferation. In addition to FLNA, trans-acting factors (TAFs), which are proteins or regulatory RNAs capable of directly or indirectly binding to specific DNA sequences in distant genes to regulate gene expression, emerge as sensitive players in both the mechanotransduction and signaling pathways of CI. This article presents methods for identifying these TAF proteins and profiling the associated changes in chromatin structure, offering valuable insights into CI and other biological functions mediated by mechanotransduction. Finally, it addresses unanswered research questions in these fields and delineates their possible future directions.

Prolonged positive polymerase chain reaction (PCR) results, irrespective of the transmission risk, can lead to prolonged restrictions on daily activities and infection precaution interventions. Studies evaluating the duration of PCR positivity for multiple pathogens in a single patient cohort are scarce. This study aimed to evaluate and compare the durations of PCR positivity for multiple respiratory viruses among children and adolescents. This retrospective study was conducted between April 2018 and March 2024 using a multiplex PCR respiratory panel for symptomatic children and adolescents who had at least two tests within 90 days of study period, with the first PCR test positive. The rate and likelihood of persistent PCR positivity were evaluated for multiple respiratory viruses. For 1325 positive results, repeat tests were conducted within 90 days. The persistent PCR positivity rate at repeat testing decreased over time (60.6%, Days 1-15 and 21.7%, Days 76-90, after the first test). In multivariate logistic regression analysis, an increased likelihood of persistent PCR positivity was observed for rhinovirus/enterovirus and adenovirus, whereas decreased likelihood of persistent positivity was seen in influenza and seasonal coronaviruses, compared with parainfluenza viruses. Persistent PCR positivity is common for multiple respiratory viruses in symptomatic children.

輸血開始時の電子認証は重大な過誤の回避に有用である.さらに輸血開始5分後,15分後,輸血終了時もタイムリーに電子認証を実施することにより,副反応の入力により患者観察の証明が可能となる.しかし輸血記録監査を実施すると各認証機会における認証実施率は十分ではなかった.そこで電子認証阻害要因を検討するため全看護スタッフを対象にアンケート調査を実施した.その結果,携帯端末の不足という物理的要因,輸血に関する知識不足という知識的要因,輸血実施方法の特殊性というシステム・環境的要因,急変時対応といった優先順位的要因といった要因の存在が判明し,部署によりその頻度は大きく異なっていた.阻害要因の解析により携帯端末の追加,新システム導入といった対応をとることができた.今後も臨床輸血看護師を中心とした輸血医療チームによる監査・指導といった活動を継続し,部署に合わせた対応をとっていく必要がある.

BACKGROUND:Stage 4 neuroblastoma (NBL), a solid tumor of childhood, has a poor prognosis. Despite intensive molecular genetic studies, no targetable gene abnormalities have been identified. Stage 4S NBL has a characteristic of spontaneous regression, and elucidation of the mechanistic differences between stages 4 and 4S may improve treatment. Conventional NBL studies have mainly focused on the detection of abnormalities in individual genes and have rarely examined abnormalities in gene networks. While the gene coexpression network is expected to contribute to the detection of network abnormalities, the fragility of the network due to data noise and the extraction of arbitrary topological structures for the high-dimensional network are issues. RESULTS:The present paper concerns the classification method of stages 4 and 4S NBL patients using highly accurate gene coexpression network analysis based on RNA-sequencing data of transcription factors (TFs). In particular, after applying a noise reduction method RECODE, generalized topological overlapping measure (GTOM), which weighs the connections of nodes in the network structure, succeeded in extracting a cluster of TFs that showed high classification performance for stages 4 and 4S. In addition, we investigated how these clusters correspond to clinical information and to TFs which control the normal adrenal tissue and NBL characters. CONCLUSIONS:A clustering method is presented for finding intermediate-scale clusters of TFs that give considerable separation performance for distinguishing between stages 4 and 4S. It is suggested that this method is useful as a way to extract factors that contribute to the separation of groups from multiple pieces of information such as gene expression levels.

Liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD), and one of the most important risk factors for NAFLD is type 2 diabetes (T2DM). The Fibrosis-4 (FIB-4) index, a noninvasive liver fibrosis score, has been found to be useful for estimating liver fibrosis. Because individuals with non-obese NAFLD were recently reported to be metabolically unhealthy and have a higher risk of T2DM than individuals with obese NAFLD, we hypothesized that the clinical factors related to a high FIB-4 index would differ between non-obese and obese Japanese T2DM patients. Accordingly, we examined the relationship between clinical factors and the FIB-4 index in non-obese and obese Japanese patients with T2DM. We divided 265 patients into two groups by BMI level - a non-obese group (n = 149) and an obese group (n = 116) - and examined the correlation between the FIB-4 index and clinical parameters. Single regression analysis revealed that a high FIB-4 index was correlated with a reduction in the estimated glomerular filtration rate and hypertension in the non-obese group. Importantly, multiple regression analysis showed that only a reduction in the estimated glomerular filtration rate was significantly associated with a high FIB-4 index in the non-obese group. These results demonstrated that non-obese T2DM patients with a high FIB-4 index might be at risk of kidney dysfunction. Our findings may enable the more appropriate treatment of T2DM patients based on BMI level.

Hereditary stomatocytosis (HSt) is a type of congenital hemolytic anemia caused by abnormally increased cation permeability of erythrocyte membranes. Dehydrated HSt (DHSt) is the most common subtype of HSt and is diagnosed based on clinical and laboratory findings related to erythrocytes. PIEZO1 and KCNN4 have been recognized as causative genes, and many related variants have been reported. We analyzed the genomic background of 23 patients from 20 Japanese families suspected of having DHSt using a target capture sequence and identified pathogenic/likely pathogenic variants of PIEZO1 or KCNN4 in 12 families.

The contact inhibition of proliferation (CIP) denotes the cell density-dependent inhibition of growth, and the loss of CIP represents a hallmark of cancer. However, the mechanism by which CIP regulates gene expression remains poorly understood. Chromatin is a highly complex structure consisting of DNA, histones, and trans-acting factors (TAFs). The binding of TAF proteins to specific chromosomal loci regulates gene expression. Therefore, profiling chromatin is crucial for gaining insight into the gene expression mechanism of CIP. In this study, using modified proteomics of TAFs bound to DNA, we identified a protein that shuttles between the nucleus and cytosol in a cell density-dependent manner. We identified TIPARP, PTGES3, CBFB, and SMAD4 as cell density-dependent nucleocytoplasmic shuttling proteins. In low-density cells, these proteins predominantly reside in the nucleus; however, upon reaching high density, they relocate to the cytosol. Given their established roles in gene regulation, our findings propose their involvement as CIP-dependent TAFs. We also identified and characterized potential open chromatin regions sensitive to changes in cell density. These findings provide insights into the modulation of chromatin structure by CIP.

Mechanotransduction and contact inhibition (CI) control gene expression to regulate proliferation, differentiation, and even tumorigenesis of cells. However, their downstream trans-acting factors (TAFs) are not well known due to a lack of a high-throughput method to quantitatively detect them. Here, we developed a method to identify TAFs on the cis- acting sequences that reside in open chromatin or DNaseI-hypersensitive sites (DHSs) and to detect nucleocytoplasmic shuttling TAFs using computational and experimental screening. The DHS-proteomics revealed over 1000 potential mechanosensing TAFs and UBE2A/B (Ubiquitin-conjugating enzyme E2 A) was experimentally identified as a force-and CI-dependent nucleocytoplasmic shuttling TAF. We found that translocation of YAP/ TAZ and UBE2A/B are distinctively regulated by inhibition of myosin contraction, actinpolymerization, and CI depending on cell types. Next-generation sequence analysis revealed many downstream genes including YAP are transcriptionally regulated by ubiquitination of histone by UBE2A/B. Our results suggested a YAP-independent mechanotransduction and CI pathway mediated by UBE2A/B.

BACKGROUND/AIMS:Although the World Health Organization declared the end of the public health emergency of international concern focusing on COVID-19 in May 2023, this bothersome virus continues to mutate, and the possibility of the emergence of mutant strains with high infectivity and severe disease rates has not disappeared. Thus, medical evidence must be accumulated, which is indispensable for protecting both patients under immunosuppressive treatments and the healthy population. This study examined SARS-CoV-2 vaccination responses in Japanese patients with autoimmune hepatitis (AIH) compared with healthy controls.METHODS:This observational study registered 22 patients with histologically diagnosed AIH and 809 healthy controls in our hospital. Their Elecsys anti-SARS-CoV-2 spike antibody concentrations before and after vaccination were evaluated.RESULTS:In this study, 72.7% and 18.2% of patients with AIH received steroids and azathioprine, respectively. Significant negative correlations were found between age and anti-SARS-CoV-2 spike antibody concentration in both groups; however, no sex differences were found. Although anti-SARS-CoV-2 spike antibody concentration was drastically augmented after the second vaccination (p < 0.05) in the AIH group, these levels were significantly lower than those in the controls (p < 0.05). In the age- and sex-matched analysis, the population ratio with a minimum response (≤100 binding antibody units (BAU/mL) was higher among patients with AIH than among controls 26 weeks after the second vaccination (44% vs. 7%, p < 0.05).CONCLUSIONS:The anti-SARS-CoV-2 spike antibody concentration in AIH patients was significantly lower than that in controls after the second vaccination. Continued and widespread vaccination, particularly for patients requiring medical immunomodulation, is recommended.

Microtubules (MTs) are essential for many cellular processes including establishment of cell shape and polarity, chromosome segregation, vesicle transport, and nuclear positioning. Human cells express 22 tubulin isoforms that have both overlapping and distinctive functions. Tubulins reversely polymerize to form cylindrical MTs, while MT-associated proteins (MAPs), posttranslational modifications (PTMs), and mechanical forces regulate their functions. To help both tubulin researchers and medicinal chemists, this review article lists 489 MAPs, 43 known enzymes that mediate PTMs, and 306 drugs that influence the functions of MTs and MAPs and discusses recent microtubule research. Readers are able to sort the list based on name, size, functions, related human diseases, and date of discovery. The list also contains links to Uniprot and Protein Atlas databases to access further details such as protein structure, associated proteins, subcellular localization, expression levels in cells and tissues, mutations, and pathology. Because the microtubule cytoskeleton is involved in many pathological processes such as tumorigenesis, invasion, and developmental diseases, small molecules that target on MT and MAPs hold potential to treat these diseases and are also listed.