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SUMMARYCancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)- negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss increased the sensitivity of HNSCC cancer cells to IFN-β, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain- Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC, and was associated with poor response to pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.

Introduction Recent international statement on chronic thromboembolic pulmonary hypertension proposed the definition of chronic thromboembolic pulmonary disease (CTEPD) and advocated further research regarding its clinical characteristic, natural history, and therapeutic strategy. Exercise pulmonary hypertension (Ex-PH) has been considered a mild degree of pulmonary hypertension (PH) among patients with normal pulmonary hemodynamics at rest. However, the clinical significance of Ex-PH in CTEPD remains unknown. Purpose In the patients with CTEPD, we aimed to verify 1) the prevalence and clinical profiles of Ex-PH, 2) effect of BPA on pulmonary vascular response after exercise in Ex-PH, 3) long-term clinical outcomes of conservative management in non-Ex-PH. Methods We retrospectively reviewed 26 patients with CTEPD (median age 65 years, 38% male), who underwent cardiopulmonary exercise test with right heart catheterization (CPET-RHC). The definitions of CTEPD are the following 1) pulmonary artery occlusion due to organic thrombus confirmed by imaging studies after ≥3 months of anticoagulation, 2) mPAP3.0, and the patients were divided into Ex-PH and non-Ex PH groups. Clinical profiles and long-term outcomes were compared between two groups. The patients in Ex-PH groupunderwent CPET-RHC 6–12 months after balloon pulmonary angioplasty (BPA). In Non-Ex-PH group, serial measurements of echocardiography were performed. Results Overall, 5 and 21 patients were categorized as CTEPD with PH (mPAP 21–24mmHg) and without PH (mPAP≤20mmHg), and 14 and 12 were categorized Ex-PH and non-Ex-PH groups, respectively. Although all 5 patients with CTEPD with PH were classified as Ex-PH group (Figure 1), there was no significant difference in baseline hemodynamics at rest between Ex-PH and non-Ex-PH groups (mPAP: 19.5 [18.4–20.6] vs. 17.7 [16.6–18.9] mmHg, PVR: 2.2 [1.7–2.7] vs. 2.3 [1.9–2.8] wood units, P>0.05, respectively). PQ slope was significantly higher in Ex-PH group (4.6 [3.2–6.0] vs. 1.31 [0.2–2.8], p=0.002). There were no differences in respiratory function test, blood gas analysis, and 6-minute walk distance between two groups. There were no major adverse events such as all-cause mortality and hospitalization for PH in overall cohort. Among Ex-PH group, BPA decreased PQslope (4.8 [3.6–6.4] to 2.3 [1.9–3.0], p0.05) over the 997 [651–1451] days. Conclusion Ex-PH was common in patients with CTEPD, and there were no clinical profiles differentiating Ex-PH from non-Ex-PH, except parameters of CPET-RHC. BPA improved an abnormal pulmonary vascular response to exercise in Ex-PH. The conservative management in non-Ex-PH was feasible. Randomized clinical trials will be needed to further investigate this treatment strategy. Funding Acknowledgement Type of funding sources: None.

Social participation prevents social isolation and loneliness among older adults while having numerous positive effects on their health and well-being in rapidly aging societies. We aimed to estimate the effect of retaining more natural teeth on social participation among older adults in Japan. The analysis used longitudinal data from 24,872 participants in the Japan Gerontological Evaluation Study (2010, 2013, and 2016). We employed a longitudinal modified treatment policy approach to determine the effect of several hypothetical scenarios (preventive scenarios and tooth loss scenarios) on frequent social participation (1 = at least once a week/0 = less than once a week) after a 6-y follow-up. The corresponding statistical parameters were estimated using targeted minimum loss-based estimation (TMLE) method. Number of teeth category (edentate/1–9/10–19/≥20) was treated as a time-varying exposure, and the outcome estimates were adjusted for time-varying (income, self-rated health, marital status, instrumental activities of daily living, vision loss, hearing loss, major comorbidities, and number of household members) and time-invariant covariates (age, sex, education, baseline social participation). Less frequent social participation was associated with older age, male sex, lower income, low educational attainment, and poor self-rated health at the baseline. Social participation improved when tooth loss prevention scenarios were emulated. The best preventive scenario (i.e., maintaining ≥20 teeth among each participant) improved social participation by 8% (risk ratio [RR] = 1.08; 95% confidence interval [CI], 1.05–1.11). Emulated tooth loss scenarios gradually decreased social participation. A hypothetical scenario in which all the participants were edentate throughout the follow-up period resulted in a 11% (RR = 0.89; 95% CI, 0.84–0.94) reduction in social participation. Subsequent tooth loss scenarios showed 8% (RR = 0.92; 95% CI, 0.88–0.95), 6% (RR = 0.94; 95% CI, 0.91–0.97), and 4% (RR = 0.96; 95% CI, 0.93–0.98) reductions, respectively. Thus, among Japanese older adults, retaining a higher number of teeth positively affects their social participation, whereas being edentate or having a relatively lower number of teeth negatively affects their social participation.

Study question Does the result of endometrial microbiome metagenomic analysis (EMMA), a next generation sequencing (NGS)-based test of the intrauterine microbiome, have an impact on pregnancy rate after the test? Summary answer After recommend treatment with antimicrobial and probiotic therapy, the group diagnosed as dysbiosis by EMMA achieved pregnancy significantly earlier than the group with Normal result. What is known already Using NGS technology, EMMA testing can determine the composition of the endometrial microbiome by analysing bacterial 16S ribosomal RNA with a focus on the lactobacillus population. Endometrial flora in patients undergoing in vitro fertilization (IVF) is often composed of pathogenic microorganisms which decrease implantation rates, such as the Enterobacteriaceae family, Staphylococcus spp., Escherichia coli and Gram-negative bacteria. Other studies also indicate that Lactobacillus spp. is a major microorganism in the endometrium. Especially, lactobacillus-dominated microbiota (LDM, defined as > 90% Lactobacillus spp.) in the endometrium has been reported to lead to better pregnancy outcomes than non-LDM ( Study design, size, duration This study was a prospective, multicenter cohort study of 527 patients (under 42 years old) with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) at 14 IVF treatment facilities in Japan from June 2019 to August 2021. Defining RIF as three or more failed implantation attempts and RPL as two or more miscarriages, we examined the prognosis of two additional embryo transfers (ETs) after the EMMA test in patients who underwent the test. Participants/materials, setting, methods Endometrial tissue was obtained by aspiration from patients in day 15-25 of their menstrual cycles, and sample tissues were analyzed by NGS for EMMA. Participant centers treated patients according to the therapies specified in the reports, including antibiotic treatments, probiotic treatments, re-analysis, and embryo transfer. Multivariate analysis was performed using a generalized linear model with the endpoint of ongoing pregnancy. For the time-to-event analyses, we used Kaplan-Meier survival analysis to compare time to ongoing pregnancy. Main results and the role of chance The results of the first EMMA were as follows: 229 patients (43.4%) were normal with Lactobacillus spp. >90% (Normal group), 110 patients (20.9%) were abnormal with less than 90% Lactobacillus spp. and predominantly pathogenic bacteria (Abnormal group), and 188 patients (35.7%) were mild with low absolute amounts of bacteria and ultralow biomass indicating almost sterile (Mild + Ultralow group). There were no significant differences in background factors such as age, duration of infertility, number of previous ETs, or history of deliveries among the three groups. Gardnerella was the most pathogenic bacteria detected in patients with Abnormal EMMA results. All patients in the Abnormal group were treated with antimicrobials and probiotics, and those in Mild + Ultralow group were treated with probiotics. Odds ratio for ongoing pregnancy rate was 1.10(95%CI 0.67-1.82, p = 0.699) in Abnormal group and 1.23(95%CI 0.80-1.89, p = 0.342) in Mild + Ultralow group, respectively. After the intervention, ongoing pregnancies were comparable to those in Normal group.Analysis of time to pregnancy using Kaplan-Meier survival curves showed that Abnormal group had a significantly higher rate of ongoing pregnancies during the observation period than the other groups (p = 0.031). Limitations, reasons for caution Since this study was not necessarily limited to euploid embryos transferred after testing, an aging bias cannot be excluded. Since this study was conducted with all patients receiving EMMA, the effectiveness of the test needs to be further validated by comparison to patients without EMMA testing. Wider implications of the findings This study is the first multicenter study to demonstrate that the intervention based on EMMA reports improve pregnancy outcome in the patients with RIF and RPL. We suggest that the EMMA procedure, which aims at establishing an appropriate uterine microbiome, may be important for implantation and pregnancy continuation. Trial registration number UMIN000036917

Study question Abnormal cleavage (AC) has been confirmed at early development. We performed an NGS analysis on AC-derived blastocysts to investigate ploidy of the resulting embryos. Summary answer Group in which AC occurred during second division showed significantly higher rates for embryos appropriate for transfer than group where AC occurred during first division. What is known already Early division is important in embryogenesis and serves as an indicator of subsequent embryonic development. The occurrence of AC during early development can be identified with the advent of the time-lapse incubator, which in turn has led to difficulties in determining whether such AC-derived blastocysts can be used embryo transfer. In this study, we performed NGS analysis on AC-derived blastocysts to investigate the ploidy of the resulting embryos. Study design, size, duration The subjects comprised women from whom oocytes were collected for NGS analysis from January 2019 to November 2021. Retrospective analysis was performed using a time-lapse system (EmbryoScope+). Embryos were categorized into two groups: those with abnormal divisions observed during the first and second divisions and those in which normal divisions were observed in the same cycle. Participants/materials, setting, methods The group with AC observed was designated the AC group and the other with normal divisions as the Normal Cleavage (NC) group. Within the AC group, the subgroup with AC observed during first division was designated as the First (AC-F) group and the subgroup with AC observed during second division as the Second (AC-S) group for comparing the acquisition rates for euploidy embryos and embryos appropriate for transfer. Main results and the role of chance The AC group (17.3%) showed a significantly lower rate of good blastocyst formation than did the NC group (53.4%) (P < 0.01). The cutoff point for mosaicism was defined as > 20% of abnormal cells. Percentage 80, abnormal (aneuploidy); and 20-80, mosaic. Using a cutoff of 50% to differentiate ‘‘low’’ mosaics from ‘‘high’’ mosaics. There was no difference between the two groups in the acquisition rates for euploidy embryos (30.8-35.1%) and the embryos appropriate for transfer, including low-mosaic ones (44.3-46.1%). There also was no difference in the acquisition rates for euploidy embryos (24.0-37.0%) between the AC-F and AC-S groups. However, the AC-S group (59.3%) showed significantly higher acquisition rates than the AC-F group (32.0%) for the embryos appropriate for transfer, including low-mosaic ones (P < 0.05). Limitations, reasons for caution PGT-A is still under clinical research in Japan. Wider implications of the findings The group in which AC occurred during second division showed significantly higher acquisition rates for the embryos appropriate for transfer than the group in which AC occurred during first division. This indicates that the most important factor for identifying euploidy embryos is going through the two-cell phase during first division. Trial registration number not applicable

Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour affecting mainly elderly patients and is more common in the West than in Asia. It is associated with Merkel cell polyomavirus (MCPyV), immunosuppression, and ultraviolet light. In this study, we retrospectively investigated the first series of MCC from Taiwan and identified 19 cases from three tertiary centres. All patients were males with a median age of 67.5. Twelve (63%) cases occurred in the extremities, with one unique case presenting initially as nodal metastasis of unknown primary. Immunohistochemically, the great majority of tumours expressed CK20 (89%), synaptophysin (89%), and INSM1 (84%), with none positive for TTF1. Eleven (58%) cases were positive for MCPyV by immunohistochemistry (clone CM2B4). All patients were treated with excision, including four with additional radiotherapy and one with radiotherapy and chemotherapy. Nodal status and treatment modalities significantly affected survival. The median survival time of MCPyV-positive cases was much longer than the negative cases (median 40 vs. 10 months). In summary, we presented the first report on the clinicopathological features of MCC in Taiwan, with 58% cases associated with MCPyV. The prognosis of patients with MCPyV-positive tumours was better than those negative for MCPyV.

BACKGROUND Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, the current treatment strategies for AF have limited efficacy. Thus, a better understanding of the mechanisms underlying AF is important for future therapeutic strategy. A previous study (Exome-Wide Association Study (ExWAS)) identified a rare variant, rs202011870 (MAF=0.00036, GenomAD), which is highly associated with AF (OR=3.617, P

The mass of the W boson, a mediator of the weak force between elementary particles, is tightly constrained by the symmetries of the standard model of particle physics. The Higgs boson was the last missing component of the model. After observation of the Higgs boson, a measurement of the W boson mass provides a stringent test of the model. We measure the W boson mass, MW, using data corresponding to 8.8 inverse femtobarns of integrated luminosity collected in proton-antiproton collisions at a 1.96 tera-electron volt center-of-mass energy with the CDF II detector at the Fermilab Tevatron collider. A sample of approximately 4 million W boson candidates is used to obtain MW ¼ 80;433:5 T 6:4stat T 6:9syst ¼ 80;433:5 T 9:4 MeV=c2, the precision of which exceeds that of all previous measurements combined (stat, statistical uncertainty; syst, systematic uncertainty; MeV, mega-electron volts; c, speed of light in a vacuum). This measurement is in significant tension with the standard model expectation. © 2022 American Association for the Advancement of Science. All rights reserved.

In this study, we proposed a new non-contact cardiac motion measurement for the purpose of treating cardiac mechanical activity (physical contraction / expansion mode) as clinical information. The proposed method is a hybrid method that combines passive stereo and active stereo, and simultaneously realized three-dimensional reconstruction of the chest shape and measurement of minute changes in the chest by cardiac motion. As a result of the experiment using the prototype system, it was clarified that the respiratory motion and the cardiac motion appearing in the chest can be extracted separately by the proposed method. In addition, based on the extracted signal of cardiac motion, it was clarified that the cardiac mechanical activity can be visualized by expressing the minute displacement on the chest surface due to cardiac motion as a color change.

Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

Bearing behaviour of steel pipe piles and helical piles has been investigated in the past. However, their performance, considering similar pile tip diameter in dense ground condition is not well understood. Based on the above, the present study was focused on the model study of closed-ended steel pipe piles and single helix piles having similar tip diameters under dense ground conditions. Test results showed that steel pipe piles require 332% and 417% higher installation force than helical piles having equivalent tip diameters DPS = DH = 43mm and 60mm respectively. However, the installation effort of screw pile in terms of power consumption was on average 29% higher than steel pipe pile. Also, helical piles exhibit 27% less ultimate bearing capacity than steel pipe piles having equivalent tip diameters. It was also observed that the installation force required to install the steel pipe pile is quite close to the ultimate bearing capacity of pile.

Supplemental material, sj-pdf-1-jdr-10.1177_00220345211005782 for Dental Pain and Worsened Socioeconomic Conditions Due to the COVID-19 Pandemic by Y. Matsuyama, J. Aida, K. Takeuchi, S. Koyama and T. Tabuchi in Journal of Dental Research

At the Fermilab Tevatron proton-antiproton (pp¯) collider, high-mass electron-neutrino (eν) pairs are produced predominantly in the process pp¯→W(→eν)+X. The asymmetry of the electron and positron yield as a function of their pseudorapidity constrain the slope of the ratio of the u- to d-quark parton distributions versus the fraction of the proton momentum carried by the quarks. This paper reports on the measurement of the electron-charge asymmetry using the full data set recorded by the Collider Detector at Fermilab in 2001-2011 and corresponding to 9.1 fb-1 of integrated luminosity. The measurement significantly improves the precision of the Tevatron constraints on the parton-distribution functions of the proton. Numerical tables of the measurement are provided. © 2021 authors. Published by the American Physical Society.

Background High plasma B-Type natriuretic peptide (BNP) level is associated with cardiac events or stroke in patients with atrial fibrillation (AF). However, it is still unknown whether BNP predicts worse clinical outcomes after catheter ablation ofAF. Purpose We aimed to see if plasma BNP level is associated with major adverse cardiac and cerebrovascular events (MACCE) after catheter ablation of AF. Methods We retrospectively analyzed 1,853 participants (73.1% men, mean age 63.3±10.3 years, 60.7% paroxysmal AF) who received first catheter ablation of AF with pre-ablation plasma BNP level measurement and completed follow-up more than 3 months after the procedure from AF Frontier Ablation Registry, a multicenter cohort study in Japan. We evaluated an association between plasma BNP level before catheter ablation and first MACCE in cox-regression hazard models adjusted for known risk factors. MACCE were defined as stroke/transient ischemic attack (TIA), cardiovascular events or all-cause death. Results The mean plasma BNP level was 120.2±3.7 pg/mL. During a mean follow-up period of 21.9 months, 57 patients (3.1%) suffered MACCE (ischemic stroke 8 [14.0%], hemorrhagic stroke 5 [8.8%], TIA 5 [8.8%], hospitalization for heart failure 11 [19.2%], acute coronary syndrome 9 [15.8%], hospitalization for other cardiovascular events 8 [14.0%] and all-cause death 11 [19.2%]). Plasma BNP level of patients with MACCE were significantly higher than those without MACCE (291.7±47.0 vs 114.7±3.42 pg/mL, P Conclusions Elevation of plasma BNP level was independently related to the increased risk of MACCE after catheter ablation ofAF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Meiers Squibb

Background The genetic bases of cardiac conduction-system disease (CCSD) range from ion channelopathies to mutations in many other genes. Genome-wide association studies have shown common variants in SCN10A influence cardiac conduction. However, it has not yet to be determined whether vulnerability to CCSD is associated with rare coding sequence variation in the SCN10A gene. Purpose We sought to determine the clinical impact of rare variants in SCN10A in patients with CCSD and classified the variants according to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Methods We performed screening for rare variants (minor allele frequency ≤0.001) in SCN10A in CCSD patients with an onset at a young age under 65 or those who had a family history of pacemaker implantation (PMI) (n=40; 18 female; mean age, 41±18 years). We transiently expressed engineered variants in ND 7/23 cells, and conducted whole-cell voltage clamp experiments to clarify the functional properties of the Nav1.8 current. Results We identified nine rare variants in SCN10A in 7 patients. Two patients were carriers of two rare variants in SCN10A and 5 were carriers of one rare variant in SCN10A. Four patients were affected with sinus node dysfunction, 1 were atrioventricular block, and 2 were both dysfunctions. We performed electrophysiological study for 8 of 9 rare variants. It demonstrated that 2 rare variants showed gain-of-function, and 3 rare variants showed loss-of-function. We finally determined 5 likely pathogenic variants in SCN10A in 5 patients (12.5%) according to the ACMG standards and guidelines. All 5 patients underwent a pacemaker implantation at an average age of 43±16. Conclusions These results demonstrate that SCN10A variants play a pivotal role in enhanced susceptibility of CCSD. We suggest the importance for screening SCN10A variants in clinical settings. Funding Acknowledgement Type of funding source: None

Background Recent observational studies have suggested that catheter ablation for atrial fibrillation (AF) is significantly associated with reduced risk for stroke, cardiovascular events and all-cause death. However, little is known whether late recurrence of AF after catheter ablation is associated with worse clinical outcomes. Purpose We aimed to clarify whether late recurrence of AF after catheter ablation is associated with major adverse cardiac and cerebrovascular events (MACCE). Methods We retrospectively investigated 2,737 participants (74.4% men, mean age 63.4±10.3 years, 62.7% paroxysmal AF) who received first catheter ablation for AF and completed follow-up more than 3 months after the procedure from AF Frontier Ablation Registry, a multicenter cohort study in Japan. We evaluated an association between late recurrence of AF after catheter ablation and first MACCE in cox-regression hazard models adjusted for known risk factors. MACCE were defined as stroke/transient ischemic attack (TIA), cardiovascular events or all-cause death. Late recurrence was defined as AF relapse more than 3 months after the procedure. Results During a mean follow-up period of 25.2 months, 2,070 patients (75.6%) were free from AF after catheter ablation and 122 patients (4.5%) had MACCE (ischemic stroke 18 [14.8%], hemorrhagic stroke 16 [13.1%], TIA 7 [5.7%], hospitalization for heart failure 19 [15.6%], acute coronary syndrome 19 [15.6%], hospitalization for other cardiovascular events 24 [20%] and all-cause death 19 [15.6%]). The MACCE occurred significantly more frequently in the recurrence group than in non-recurrence group (7.5% vs. 3.5%; hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.28–2.65; P=0.001) (Figure). Multivariate analysis revealed that baseline age (HR 1.05; 95% CI 1.03–1.08; P Conclusion In the Japanese multicenter cohort of AF ablation, late recurrence of AF was independently associated with increased MACCE, suggesting the significance of sinus rhythm maintenance by catheter ablation. Kaplan-Meier curves for MACCE Funding Acknowledgement Type of funding source: None

Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Here we develop a method to generate heart organoids from mouse embryonic stem cell-derived embryoid bodies. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. The heart organoids exhibit ultrastructural, histochemical and gene expression characteristics of considerable similarity to those of developmental hearts in vivo. Our results demonstrate that this method not only provides a biomimetic model of the developing heart-like structure with simplified differentiation protocol, but also represents a promising research tool with a broad range of applications, including drug testing., Our understanding of the development of the heart has been limited by a lack of in vitro cellular models. Here, the authors treat mouse embryonic stem cell-derived embryoid bodies with laminin-entactin (to mimic the developing microenvironment) and FGF4 to form heart organoids, with atrial and ventricular-like parts.

Atom switches embedded in read-only memories (ROMs) and field programmable gate arrays (FPGAs) were investigated in terms of single event effects (SEEs). In this study, their radiation tolerance against single event upset (SEU) was demonstrated with an LET of up to 68.9 MeV/(mg/cm2), irrespective of the voltage conditions or logic states of the cells.

Glypican-5 (GPC5) is a heparan sulfate proteoglycan (HSPG) localized to the plasma membrane. We previously reported that in the human mesenchymal stem cell line UE6E7T3, GPC5 is overexpressed in association with transformation and promotes cell proliferation by acting as a co-receptor for Sonic hedgehog signaling. In this study, we found using an immunofluorescence microscopy that in transformed cells (U3DT), GPC5 localized not only at primary cilia on the cell surface, but also at the leading edge of migrating cells, at the intercellular bridge and blebs during cytokinesis, and in extracellular vesicles. In each subcellular region, GPC5 colocalized with the small GTPase Rab11. These observations suggest that the colocalization of GPC5 with Rab11 is crucial for its function, and that its activity in each subcellular compartment promotes proliferation of U3DT cells. Our findings indicate that GPC5 plays active and essential roles in regulation of U3DT cell proliferation, and provides several insights into the functions of GPC5 that could be elucidated by future studies.

Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock, multiorgan failure, and high mortality. Although STSS is mainly caused by Streptococcus pyogenes, group G streptococcus identified as S. dysgalactiae subsp. equisimilis (SDSE) causing STSS has also been reported; however, no study has analyzed >100 isolates of SDSE causing STSS. Therefore, we characterized the emm genotype of 173 SDSE isolates obtained from STSS patients in Japan during 2014–2016 and performed antimicrobial susceptibility testing using the broth microdilution method and emm gene typing. The predominant emm genotype was found to be stG6792, followed by stG485, stG245, stG10, stG6, and stG2078. These six genotypes constituted more than 75% of the STSS isolates. The proportion of each emm genotype in STSS isolates correlated with that in invasive isolates previously reported. We found that 16.2% of the isolates showed clindamycin resistance. The proportion of clindamycin-resistant SDSE isolates was significantly higher than that of S. pyogenes isolates. Thus, while treating STSS caused by SDSE, it is necessary to consider the possibility of clindamycin resistance and to ensure judicious use of the drug.