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Abstract In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell–cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted integrity among vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The tri-culture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the bi-culture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such tri-culture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior.

BackgroundDespite a unique microbiome in urine, the relationship between nocturnal enuresis and the urobiome remains unclear. This study aimed to compare the presence of specific bacterial species in the urine of children with and without nocturnal enuresis.MethodsWe used 16S ribosomal RNA gene sequencing to analyze the urobiome in urine samples obtained from the two groups of children. The presence of Propionimicrobium lymphophilum was examined using real-time PCR in the urine of 25 children diagnosed with monosymptomatic nocturnal enuresis (MNE), and 17 children without this condition.ResultsChildren with MNE exhibited a significantly higher prevalence of P. lymphophilum: 16 out of 25 (64.0%) compared to 4 out of 17 (23.5%) in the control group. Among children with frequent bedwetting, there was a significantly higher prevalence of P. lymphophilum;15 out of 16 (93.8%) compared to 2 out of 9 (22.2%) in those with infrequent bedwetting. Bacterial culture tests confirmed the anaerobic growth of P. lymphophilum isolates from urine samples of two PCR-positive patients with MNE. These isolates were found to be susceptible to ampicillin.ConclusionThese findings suggest that P. lymphophilum may be associated with chronic urinary tract infections and potentially contribute to the development of MNE in children.

Objective: Herein, we present a case of mosaic trisomy 6 detected by amniocentesis. Case report: Amniocentesis (G-banding) was performed at 17 weeks of gestation; the results were 47,XY,+6[3]/46,XY[12]. Fetal screening ultrasonography showed no morphological abnormalities, and the parents desired to continue the pregnancy. The infant was delivered vaginally at 39 weeks' gestation. The male infant weighed 3002 g at birth with no morphological abnormalities. G-banding karyotype analysis performed on the infant's peripheral blood revealed 46,XY[20]. FISH analysis revealed trisomy signals on chromosome 6 in 1–4 out of 100 cells from the placenta. The single nucleotide polymorphism microarray of the umbilical cord blood revealed no abnormalities. Methylation analysis of umbilical cord blood revealed no abnormalities in PLAGL1. No disorders were observed at one year of age. Conclusion: When amniocentesis reveals chromosomal mosaicism, it is essential to provide a thorough fetal ultrasound examination and careful genetic counseling to support the couples’ decision-making.

In general, the life of a rolling bearing is calculated as the total number of rotations until rolling fatigue occurs on the raceway. However, when rolling bearings are used under light loads and high rotational speeds, they are damaged not by rolling fatigue on the raceways but by cage wear due to lubrication life. In such cases, the conventional method for calculating the rolling bearing life is not applicable. Rolling bearings for traction motors of railway vehicles (hereafter referred to as traction motor bearings) are one example of this and are replaced primarily due to lubrication life. However, there is no practical way to calculate lubrication life and these rolling bearings are replaced empirically. The purpose of this paper is to obtain basic data to create a method for calculating lubrication life. Therefore, traction motor bearings were rotated under conditions like actual operating conditions to reproduce damage due to lubrication life. As a result, damage due to lubrication life could be reproduced, so the next step was to investigate the effect on lubrication life when the operating conditions of traction motor bearings were varied as parameters. The parameters considered were “bearing temperature”, “vibration acceleration”, and “grease mass”. As a result of these verifications, lubrication life decreased exponentially when the bearing temperature was increased. In addition, lubrication life decreased exponentially when vibration acceleration was increased. Furthermore, lubrication life increased logarithmically when the grease mass was increased. The effects of these verified parameters on lubrication life could all be formulated within this paper.

Objectives The condition of air bubbles in the large intestine is an influential factor for good quality of colonoscopy. However, the correlative factors of severity of air bubbles during colonoscopy in the large intestine are not established. Therefore, this study aimed to elucidate the correlative factors influencing the severity of air bubbles in the large intestine.

Abstract In this study, a high-throughput fabrication method called laser-assisted direct roller imprinting (LADRI) was developed to lower the cost of nanoimprinting large-area polymer films and to address problems associated with nanoimprinting, namely, microstructural damage and precision in flatness of entire film. With LADRI, the laser directly heats the microstructured surface of the roller mold, which heats and melts the surface of a polymethyl methacrylate (PMMA) film to replicate the microstructures on the mold rapidly. In this study, the effects of laser power density, scanning speed, size of the microstructures, and contact pressure on the replication speed were investigated experimentally. The replication speed increased as the power and scanning speed increased. However, because the film required heating until it filled the entire depth of the microstructure, an appropriate replication speed was necessary. This result was supported by simulation of the temperature distribution inside the mold and the PMMA using transient heat conduction analyses. To demonstrate the applications of LADRI, two different optical surfaces were replicated: an antireflection (AR) structure with conical structures sized several hundred nanometers and a light-extraction structure with a microlens array (MLA) comprising 10 μm lenses, for display and illumination, respectively. The replication degree of the MLA was governed by the contact pressure. Polymer flow simulation indicated that the heat conduction and flow speeds of the melted PMMA surface were comparable within several tens of micrometers. In addition, the reflectivity of the AR structure decreased from 4 to 0.5%, and the light intensity of the light-extraction structure increased by a factor of 1.47.

Hypertrophic cardiomyopathy (HCM) is a common form of cardiomyopathy in cats, and heart failure occurs as diastolic dysfunction progresses. HCM in cats is broadly classified as non-obstructive and obstructive hypertrophic cardiomyopathy, depending on the presence or absence of outflow tract obstruction. Measurement of the intraventricular pressure differences (IVPD) using color M-mode (CMM) has attracted attention as a reliable diastolic index as it correlates with catheterization, the gold standard for the assessment of diastolic performance. Because IVPD is affected by the size of the heart, the intraventricular pressure gradient (IVPG) index, which is unaffected by heart size, is by calculated by dividing IVPD by LV length. In the present study, CMM IVPG was used to non-invasively assess diastolic impairment in cats with obstructive hypertrophic cardiomyopathy. This study was conducted on 10 control cats and 18 cats in the HCM group. Although no severe left atrial enlargement was observed in the HCM group, the basal IVPG was significantly increased in the HOCM group compared to the control group. Although IVPD typically suggests impaired diastolic function and reduced ventricular compliance, the significant increase observed in the HOCM group compared to controls may suggest an indirect elevation in left atrial pressure, likely secondary to left ventricular outflow tract obstruction. The increase in IVPG in HOCM, as shown in this study, is a pathological effect of left ventricular outflow tract obstruction that cannot be detected by conventional echocardiographic indices, and evaluating IVPG is useful to evaluate cardiac function from a perspective that differs from conventional methods.

BackgroundHeart rate variability (HRV) is believed to possess the potential for disease detection. However, early identification of heart disease remains challenging, as HRV analysis in dogs primarily reflects the advanced stages of the disease.Hypothesis/objectiveThe aim of this study is to compare 24-h HRV with sleep HRV to assess the potential utility of sleep HRV analysis.AnimalsThirty healthy dogs with no echocardiographic abnormalities were included in the study, comprising 23 females and 7 males ranging in age from 2 months to 8 years (mean [standard deviation], 1.4 [1.6]).MethodsThis study employed a cross-sectional study. 24-h HRV and sleep HRV were measured from 48-h Holter recordings. Both linear analysis, a traditional method of heart rate variability analysis, and nonlinear analysis, a novel approach, were conducted. Additionally, circadian rhythm parameters were assessed.ResultsIn frequency analysis of linear analysis, the parasympathetic index nHF was significantly higher during sleep compared to the mean 24-h period (mean sleep HRV [standard deviation] vs. mean 24 h [standard deviation], 95% confidence interval, p value, r-family: 0.24 [0.057] vs. 0.23 [0.045], 0.006–0.031, p = 0.005, r = 0.49). Regarding time domain analysis, the parasympathetic indices SDNN and RMSSD were also significantly higher during sleep (SDNN: 179.7 [66.9] vs. 156.6 [53.2], 14.5–31.7, p

Abstract Global and regional impacts of El Niño-Southern Oscillation (ENSO) are sensitive to the details of the pattern of anomalous ocean warming and cooling, such as the contrasts between the eastern and central Pacific. However, skillful prediction of such ENSO diversity remains a challenge even a few months in advance. Here, we present an experimental forecast with a deep learning model (IGP-UHM AI model v1.0) for the E (eastern Pacific) and C (central Pacific) ENSO diversity indices, specialized on the onset of strong eastern Pacific El Niño events by including a classification output. We find that higher ENSO nonlinearity is associated with better skill, with potential implications for ENSO predictability in a warming climate. When initialized in May 2023, our model predicts the persistence of El Niño conditions in the eastern Pacific into 2024, but with decreasing strength, similar to 2015–2016 but much weaker than 1997–1998. In contrast to the more typical El Niño development in 1997 and 2015, in addition to the ongoing eastern Pacific warming, an eXplainable Artificial Intelligence analysis for 2023 identifies weak warm surface, increased sea level and westerly wind anomalies in the western Pacific as precursors, countered by warm surface and southerly wind anomalies in the northern Atlantic.

Synaptopodin 2-like protein (SYNPO2L) is localized in the sarcomere of cardiomyocytes and is involved in heart morphogenesis. However, the molecular function of SYNPO2L in the heart is not fully understood. We investigated the interaction of SYNPO2L with sarcomeric α-actinin and actin filaments in cultured mouse cardiomyocytes. Immunofluorescence studies showed that SYNPO2L colocalized with α-actinin and actin filaments at the Z-discs of the sarcomere. Recombinant SYNPO2La or SYNPO2Lb caused a bundling of the actin filaments in the absence of α-actinin and enhanced the α-actinin-dependent formation of actin bundles. In addition, high-speed atomic force microscopy revealed that SYNPO2La directly bound to α-actinin via its globular ends. The interaction between α-actinin and SYNPO2La fixed the movements of the two proteins on the actin filaments. These results strongly suggest that SYNPO2L cooperates with α-actinin during actin bundle formation to facilitate sarcomere formation and maintenance.

Smith–Purcell radiation (SPR) can be generated nondestructively, providing valuable applications in light sources and beam monitors. Coherent SPR is expected to enable single-shot measurements of very short bunch lengths on the fs scale. Since the reconstruction of the longitudinal bunch shape from the coherent SPR is based on the reliable SPR spectrum, a more detailed understanding of the properties of the radiation is important in this context. Employing a 100 fs ultrashort electron bunch at the t-ACTS test accelerator, the spectrum, angular distribution, and polarization of the produced coherent SPR were measured in the terahertz frequency region and compared with a model calculation. In addition to the widely known surface current model evaluation, the effect of the geometrical shading effect on induced currents on metal surfaces was evaluated using 3D numerical calculations. The obtained SPR characteristics are also presented. In the evaluation of the grating with a shallow blaze angle, it was found that the shading effect has a non-negligible effect on the generated SPR intensity; the measured angular distribution and polarization results were in good agreement with this result.

A test-Accelerator as Coherent Terahertz Source (t-ACTS) has been under development at Tohoku University, in which an intense coherent terahertz radiation is generated from the short electron bunches. Velocity bunching scheme in a traveling wave accelerating structure is employed to generate the short electron bunches. The in-phase and quadrature (IQ) modulator and demodulator were installed to the low-level RF systems of t-ACTS linac to control and measure the amplitude and phase of RF power. The amplitude and phase of the RF power applied to an RF electron gun cavities and the accelerating structure are controlled to produce the electron bunches with a uniform and small momentum spread suitable for the velocity bunching. By installing the feed-forward control system using IQ modulators for the beam conditioning, we have successfully generated flat RF pulses and improved beam quality, including the energy spectrum of the beam. The details of feed-forward control system of the amplitude and phase using the IQ modulator and the beam experiments are presented in this paper.

Abstract Background mRNA vaccination is an effective, safe, and widespread strategy for protecting pregnant women against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, information on factors such as perinatal outcomes, safety, and coverage of mRNA vaccinations among pregnant women is limited in Japan. Therefore, this study aimed to investigate the perinatal outcomes, coverage, adverse effects, and short-term safety of mRNA vaccination as well as vaccine hesitancy among pregnant women. Methods We conducted a multicenter online survey of postpartum women who delivered their offspring at 15 institutions around Tokyo from October 2021 to March 2022. Postpartum women were divided into vaccinated and unvaccinated groups. Perinatal outcomes, COVID-19 prevalence, and disease severity were compared between the two groups. Adverse reactions in the vaccinated group and the reasons for being unvaccinated were also investigated retrospectively. Results A total of 1,051 eligible postpartum women were included. Of these, 834 (79.4%) had received an mRNA vaccine, while 217 (20.6%) had not, mainly due to concerns about the effect of vaccination on the fetus. Vaccination did not increase the incidence of adverse perinatal outcomes, including fetal morphological abnormalities. The vaccinated group demonstrated low COVID-19 morbidity and severity. In the vaccinated group, the preterm birth rate, cesarean section rate, and COVID-19 incidence were 7.2%, 33.2%, and 3.3%, respectively, compared with the 13.7%, 42.2%, and 7.8% in the unvaccinated group, respectively. Almost no serious adverse reactions were associated with vaccination. Conclusions mRNA vaccines did not demonstrate any adverse effects pertaining to short-term perinatal outcomes and might have prevented SARS-CoV-2 infection or reduced COVID-19 severity. Concerns regarding the safety of the vaccine in relation to the fetus and the mother were the main reasons that prevented pregnant women from being vaccinated. To resolve concerns, it is necessary to conduct further research to confirm not only the short-term safety but also the long-term safety of mRNA vaccines.

Abstract Particles longer than 5 μm and with a length/diameter ratio >3 are defined as fibers. Asbestos or other fibers are still identified in residential environments due to the emission from asbestos‐used building materials. The respiratory system is the primary route of asbestos exposure; under a longer residence time, asbestos‐related adverse health effects are inevitable. Currently, asbestos fibers have been replaced with man‐made vitreous fibers (MMVFs); however, studies have revealed some similar biological effects of MMVFs with asbestos. Therefore, MMVFs‐induced diseases need to be determined by analyzing their deposition characteristics and foci in human respiratory tracts. In this study, we used computational fluid dynamics method to investigate fibers' airflow and deposition patterns in two realistic human respiratory models. Two drag models were used to predict the deposition of uniform 1 μm (asbestos) and 3.66 μm (carbon fiber‐CF) diameter, 15–300 μm long fibers. Two drag models provided comparable results with the experimental data. Comparatively, asbestos deposition was independent of fiber length, while CF deposition increased proportionally to fiber length. The highest level of local deposition was detected in the anterior nasal cavity. The results obtained from this study can extend current knowledge of human vitreous fiber exposure‐related lung diseases.

Abstract Background High levels of public awareness regarding the hazards of asbestos, rights to health, and benefits of an asbestos-free country can increase advocacy and political commitment to a total ban on asbestos. We aimed to investigate asbestos awareness and associated sociodemographic characteristics among the adult population of St. Kitts and Nevis. Methods In this cross-sectional study, 1009 participants completed an online questionnaire with questions about sociodemographic data and asbestos awareness. We applied multiple regression models to estimate associations between sociodemographic factors, levels of asbestos knowledge, and attitudes toward asbestos management. Results We found that 70% of residents of St. Kitts and Nevis considered asbestos exposure to be a general public concern and believed the government should prevent it. Of all participants, 54% were in favor of completely banning the use and importation of all asbestos products and materials; those with higher levels of asbestos knowledge were more likely to favor a total ban. Higher proportions and odds of favoring a total asbestos ban were also observed in participants aged ≥ 30 years, women, those with higher education, and those living in St. Kitts (vs. Nevis). Conclusions These findings support implementing policies to regulate and outright ban the use of asbestos products and materials in St. Kitts and Nevis. This data can be used to develop tailored campaigns to improve asbestos knowledge among sociodemographic groups with lower asbestos awareness, such as in the wider Caribbean and other under-resourced countries.

Abstract Achondrogenesis type II (ACG2) is a lethal skeletal disorder caused by pathogenic variants in COL2A1. We present a fetus with cystic hygroma and severe shortening of the limbs at 14 weeks of gestation. We performed postnatal genetic analysis of the parents and fetus to diagnose the disease. A novel missense variant of COL2A1 [NM_001844.5: c.2987G>A, (p. Gly996Asp)] was identified, which led to the ACG2 diagnosis.

Abstract The emergence of hepatitis C virus (HCV) with resistance-associated substitution (RAS), produced by mutations in the HCV genome, is a major problem in direct acting antivirals (DAA) treatment. This study aimed to clarify the mutational spectrum in HCV-RNA and the substitution pattern for the emergence of RASs in patients with chronic HCV infection. HCV-RNA from two HCV replicon cell lines and the serum HCV-RNA of four non-liver transplant and four post-liver transplant patients with unsuccessful DAA treatment were analyzed using high-accuracy single-molecule real-time long-read sequencing. Transition substitutions, especially A>G and U>C, occurred prominently under DAAs in both non-transplant and post-transplant patients, with a mutational bias identical to that occurring in HCV replicon cell lines during 10-year culturing. These mutational biases were reproduced in natural courses after DAA treatment. RASs emerged via both transition and transversion substitutions. NS3-D168 and NS5A-L31 RASs resulted from transversion mutations, while NS5A-Y93 RASs was caused by transition substitutions. The fidelity of the RNA-dependent RNA polymerase, HCV-NS5B, produces mutational bias in the HCV genome, characterized by dominant transition mutations, notably A>G and U>C substitutions. However, RASs are acquired by both transition and transversion substitutions, and the RASs-positive HCV clones are selected and proliferated under DAA treatment pressure.

Myocardial infarction (MI) is a serious cardiovascular disease as the leading cause of death globally. Hence, reconstruction of the cardiac tissue comes at the forefront of strategies adopted to restore heart functions following MI. In this investigation, we studied the capacity of rat adipose-derived mesenchymal stem cells (r-AdMSCs) and decellularized porcine pericardium (DPP) to restore heart functions in MI animals. MI was induced in four different groups, three of which were treated either using DPP (MI-DPP group), stem cells (MI-SC group), or both (MI-SC/DPP group). Cardiac functions of these groups and the Sham group were evaluated using echocardiography, the intraventricular pressure gradient (IVPG) on weeks 2 and 4, and intraventricular hemodynamics on week 4. On day 31, the animals were euthanized for histological analysis. Echocardiographic, IVPG and hemodynamic findings indicated that the three treatment strategies shared effectively in the regeneration process. However, the MI-SC/DPP group had a unique synergistic ability to restore heart functions superior to the other treatment protocols. Histology showed that the MI-SC/DPP group presented the lowest (p < 0.05) degeneration score and fibrosis % compared to the other groups. Conclusively, stem cell-seeded DPP is a promising platform for the delivery of stem cells and restoration of heart functions post-MI.

Abstract Although checkpoint inhibitors (CPIs) have changed the paradigm of cancer therapy, low response rates and serious systemic adverse events remain challenging. In situ vaccine (ISV), intratumoral injection of immunomodulators that stimulate innate immunity at the tumor site, allows for the development of vaccines in patients themselves. K3-SPG, a second-generation nanoparticulate Toll-like receptor 9 (TLR9) ligand consisting of K-type CpG oligodeoxynucleotide (ODN) wrapped with SPG (schizophyllan), integrates the best of conventional CpG ODNs, making it an ideal cancer immunotherapy adjuvant. Focusing on clinical feasibility for pancreaticobiliary and gastrointestinal cancers, we investigated the antitumor activity of K3-SPG-ISV in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). K3-SPG-ISV suppressed tumor growth more potently than K3-ISV or K3-SPG intravenous injections, prolonged survival, and enhanced the antitumor effect of CPIs. Notably, in PDAC model, K3-SPG-ISV alone induced systemic antitumor effect and immunological memory. ISV combination of K3-SPG and agonistic CD40 antibody further enhanced the antitumor effect. Our results imply that K3-SPG-based ISV can be applied as monotherapy or combined with CPIs to improve their response rate or, conversely, with CPI-free local immunotherapy to avoid CPI-related adverse events. In either strategy, the potency of K3-SPG-based ISV would provide the rationale for its clinical application to puncturable pancreaticobiliary and gastrointestinal malignancies.

Abstract Background Over the past few decades, economic, political, and social changes have directly and indirectly affected the health of the Mongolian population. To date, no comprehensive analysis has been conducted on the burden of diseases in this country. Thus, we aimed to describe the leading causes of death and disabling conditions and their trends between 1990 and 2019 in the Mongolian population. Methods We used the data from the Global Burden of Disease (GBD) 2019 study. In the current study, we examined life expectancy at birth, healthy life expectancy, the 20 leading causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted-life-years (DALYs), and the contribution of major risk factors to DALYs in Mongolia. Findings The life expectancy at birth in Mongolia has gradually increased since 1995 and reached 63.8 years for men and 72.7 for women in 2019. The highest increase in the age-standardised death rate between 1990 and 2019 occurred in alcohol use disorders (628.6%; 95% UI 10.0–1109.6) among men, and in liver cancer (129.1%; UI 65.3–222.4) among women. Ischaemic heart disease and stroke showed the highest rates of death, YLLs, and DALYs among both men and women. In 2019, the highest age-standardised rates of DALYs were attributable to high systolic blood pressure and dietary risks. Interpretation Although Mongolia saw substantial improvements across many communicable diseases, maternal and neonatal disorders, and under-5 mortality between 1990 and 2019, non-communicable diseases remained leading causes of mortality. The mortality from the most preventable causes such as injury, alcohol use, and dietary risks remain substantially high, suggesting that individual and social efforts are needed to tackle these diseases. Our analyses will support the development of policy priorities and action plans in multiple sectors to improve the overall health of the Mongolian population. Funding Bill & Melinda Gates Foundation.

Background. Although HBV infection is a serious health issue worldwide, the landscape of HBV genome dynamics in the host has not yet been clarified. This study aimed to determine the continuous genome sequence of each HBV clone using a single-molecule real-time sequencing platform, and clarify the dynamics of structural abnormalities during persistent HBV infection without antiviral therapy. Patients and Methods. Twenty-five serum specimens were collected from 10 untreated HBV-infected patients. Continuous whole-genome sequencing of each clone was performed using a PacBio Sequel sequencer; the relationship between genomic variations and clinical information was analyzed. The diversity and phylogeny of the viral clones with structural variations were also analyzed. Results. The whole-genome sequences of 797,352 HBV clones were determined. The deletion was the most common structural abnormality and concentrated in the preS/S and C regions. Hepatitis B e antibody (anti-HBe)-negative samples or samples with high alanine aminotransferase levels have significantly diverse deletions than anti-HBe-positive samples or samples with low alanine aminotransferase levels. Phylogenetic analysis demonstrated that various defective and full-length clones evolve independently and form diverse viral populations. Conclusions. Single-molecule real-time long-read sequencing revealed the dynamics of genomic quasispecies during the natural course of chronic HBV infections. Defective viral clones are prone to emerge under the condition of active hepatitis, and several types of defective variants can evolve independently of the viral clones with the full-length genome.

Climate-related phenomena in Peru have been slowly but continuously changing in recent years beyond historical variability. These include sea surface temperature increases, irregular precipitation patterns and reduction of glacier-covered areas. In addition, climate scenarios show amplification in rainfall variability related to the warmer conditions associated with El Niño events. Extreme weather can affect human health, increase shocks and stresses to the health systems, and cause large economic losses. In this article, we study the characteristics of El Niño events in Peru, its health and economic impacts and we discuss government preparedness for this kind of event, identify gaps in response, and provide evidence to inform adequate planning for future events and mitigating impacts on highly vulnerable regions and populations. This is the first case study to review the impact of a Coastal El Niño event on Peru's economy, public health, and governance. The 2017 event was the third strongest El Niño event according to literature, in terms of precipitation and river flooding and caused important economic losses and health impacts. At a national level, these findings expose a need for careful consideration of the potential limitations of policies linked to disaster prevention and preparedness when dealing with El Niño events. El Niño-related policies should be based on local-level risk analysis and efficient preparedness measures in the face of emergencies.

Background: Combination therapy with anti-programmed death-ligand 1 monoclonal antibody atezolizumab plus anti-vascular endothelial growth factor agent bevacizumab (Atezo/Bev) was approved in 2020 as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Atezo/Bev therapy is relatively well tolerated; however, factors that can predict its response have not yet been reported. Thus, we aimed to investigate whether the pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict the therapeutic response in patients with HCC treated with Atezo/Bev therapy. Methods: We analyzed the course of 40 patients with HCC who received Atezo/Bev therapy at our hospital and attempted to identify pretreatment factors that could predict response by comparing those who achieved disease control with those who did not. Results: The pretreatment NLR value in patients who achieved disease control was significantly lower than that in patients with disease progression (2.47 vs. 4.48, p = 0.013). Using the optimal NLR cut-off value for predicting response (3.21) determined by receiver operating characteristic curve analysis, patients with NLR ≤ 3.21 had significantly better progression-free survival than those with NLR > 3.21 (p < 0.0001), although there were no significant differences in liver function or tumor-related background factors between the two groups. Conclusions: The pretreatment NLR value may be a useful predictor of response to Atezo/Bev therapy for HCC.

Introduction Mesothelioma is a key asbestos-related disease (ARD) but can be difficult to diagnose. Countries presumably ban asbestos to reduce future ARD burdens, but it is unknown if countries ban asbestos as a consequence of ARD burdens. We assessed if and to what extent mesothelioma burden has an impact on a country banning asbestos and obtaining targets for preventative strategies.Methods We analysed the status of asbestos ban and mesothelioma burden during 1990–2019 in 198 countries. We assessed mesothelioma burden by age-adjusted mortality rates (MRs) estimated by the Global Burden of Disease Study (GBD) and mesothelioma identification by the WHO mortality database. For GBD-estimated mesothelioma MR, the pre-ban period in the asbestos-banned countries was compared with the 1990–2019 period in the not-banned countries. For mesothelioma identification, the 1990–2019 period was applied to both banned and not-banned countries.Results The association of mesothelioma MR with ban status increased as the ban year approached. Logistic regression analyses showed that the odds of a country banning asbestos increased 14.1-fold (95% CI 5.3 to 37.9) for mesothelioma identification combined with a 26% (12% to 42%) increase per unit increase of mesothelioma MR (one death per million per year) during the period 1–5 year before ban (model p

BackgroundThe intraventricular pressure difference (IVPD) and intraventricular pressure gradients (IVPG), estimated from color M-mode echocardiography (CMME) of the transmitral flow, have been introduced as novel indices for the evaluation of heart functions. Until now, no study demonstrated the feasibility of the CMME approach to measure IVPD and IVPG in any farm animals. The aim of this study was to assess the feasibility and repeatability of CMME-derived IVPD and IVPG variables in goats and explore the effect of sedation on the measured variables.Materials and methodsSixteen male Shiba goats were included in this study and underwent conventional echocardiography. Eight goats were used in the repeatability of IVPD/IVPG variables. Another eight goats were used to evaluate the effect of sedation by xylazine on IVPD/IVPG measurements. CMME between the base and the apex of the left ventricle was carried out. The IVPD and IVPG were analyzed using in-house code software. The IVPD and IVPG were expressed as total, basal, mid-to-apical, mid, and apical segments. Data analysis including the imaging quality score (IQS), repeatability, variability, intraclass correlation coefficient (ICC), as well as the effect size of sedation on the measured variables was calculated.ResultsIVPD and IVPG variables from CMME were feasible in all goats. Low to moderate variability of IVPD and IVPG variables was observed (CV 95% 0.8).ConclusionWe reported, for the first time, IVPD and IVPG measurements by CMME in goats. The assessment of IVPD and IVPG by CMME is feasible in goats which can be evaluated in further cardiovascular or pharmacological studies in this species.

The assessment of diastolic function has received great interest in order to comprehend its crucial role in the pathophysiology of heart failure and for the early identification of cardiac events. Silent changes in the intraventricular flow (IVF) dynamics occur before the deterioration of the cardiac wall, although they cannot be detected using conventional echocardiography. Collective information on left ventricular (LV) pressures throughout the cardiac cycle has great value when dealing with patients with altered hemodynamics. Accurate pressure measurement inside the ventricle can be obtained by invasive methods to determine the LV diastolic pressures, which reflect the myocardial relaxation and compliance. However, catheterization is only feasible in the laboratory setting and is not suitable for clinical use due to its disadvantages. In contrast, echocardiography is simple, safe, and accessible. Color M-mode echocardiography (CMME) is an advanced cardiac evaluation technique that can measure the intraventricular pressure differences (IVPDs) and intraventricular pressure gradients (IVPGs) based on the Doppler shift of the IVF. Recently, the assessment of IVPD and IVPG has gained growing interest in the cardiovascular literature in both animal and human studies as a non-invasive method for the early diagnosis of cardiac dysfunctions, especially diastolic ones. The usability of IVPD and IVPG has been reported in various surgically induced heart failure or pharmacologically altered cardiac functions in rats, dogs, cats, and goats. This report aims to give an overview of the current studies of CMME-derived IVPD and IVPG in animal studies and its feasibility for clinical application in veterinary practice and to provide the prospects of the technique’s ability to improve our understanding.

Abstract Objective We aimed to simplify our fetal RHD genotyping protocol by changing the method to attach Illumina’s sequencing adaptors to PCR products from the ligation-based method to a PCR-based method, and to improve its reliability and robustness by introducing unique molecular indexes, which allow us to count the numbers of DNA fragments used as PCR templates and to minimize the effects of PCR and sequencing errors. Results Both of the newly established protocols reduced time and cost compared with our conventional protocol. Removal of PCR duplicates using UMIs reduced the frequencies of erroneously mapped sequences reads likely generated by PCR and sequencing errors. The modified protocols will help us facilitate implementing fetal RHD genotyping for East Asian populations into clinical practice.

Abstract Purpose Although non‐invasive prenatal testing (NIPT) based on cell‐free DNA (cfDNA) in maternal plasma has been prevailing worldwide, low levels of fetal DNA fraction may lead to false‐negative results. Since fetal cells in maternal blood provide a pure source of fetal genomic DNA, we aimed to establish a workflow to isolate and sequence fetal nucleated red blood cells (fNRBCs) individually as a target for NIPT. Methods Using male‐bearing pregnancy cases, we isolated fNRBCs individually from maternal blood by FACS, and obtained their genomic sequence data through PCR screening with a Y‐chromosome marker and whole‐genome amplification (WGA)‐based whole‐genome sequencing. Results The PCR and WGA efficiencies of fNRBC candidates were consistently lower than those of control cells. Sequencing data analyses revealed that although the majority of the fNRBC candidates were confirmed to be of fetal origin, many of the WGA‐based genomic libraries from fNRBCs were considered to have been amplified from a portion of genomic DNA. Conclusions We established a workflow to isolate and sequence fNRBCs individually. However, our results demonstrated that, to make cell‐based NIPT targeting fNRBCs feasible, cell isolation procedures need to be further refined such that the nuclei of fNRBCs are kept intact.

Congestive heart failure (CHF), the leading cause of death, is deemed a grave sequel of myocardial infarction (MI). The employment of left ventricular end-diastolic pressure (LVEDP), as a primary indication of CHF, becomes restricted owing to the potential impairment of heart function and caused injury to the aortic valve during its measurement. Echocardiography is the standard technique to detect cardiac dysfunction. However, it exhibits a low capacity to predict the progression of CHF post chronic MI. Being extremely sensitive, noninvasive, and preload-independent, intraventricular pressure gradient (IVPG) was lately introduced to evaluate cardiac function, specifically during cardiomyopathy. Yet, the utility of its use to assess the CHF progression after chronic MI was not investigated. Herein, in the current research, we aimed to study the efficacy of a novel echocardiographic-derived index as IVPG in the assessment of cardiac function in a chronic MI rat model with CHF. Fifty healthy male rats were involved, and MI was surgically induced in 35 of them. Six months post-surgery, all animals were examined using transthoracic conventional and color M-mode echocardiography (CMME) for IVPG. Animals were euthanized the following day after hemodynamics recording. Gross pathological and histological evaluations were performed. J-tree cluster analysis was conducted relying on ten echocardiographic parameters suggestive of CHF. Animals were merged into two main clusters: CHF+ (MI/HF + group, n = 22) and CHF– (n = 28) that was joined from Sham (n = 15), and MI/HF– (n = 13) groups. MI/HF+ group showed the most severe echocardiographic, hemodynamic, anatomic, and histologic alterations. There was no significant change in the total IVPG among various groups. However, the basal IVPG was significantly increased in MI/HF+ group compared to the other groups. The remaining IVPG measures were considerably increased in the MI/HF+ group than in the Sham one. The segmental IVPG measures were significantly correlated with the anatomical, histological, echocardiographic, and hemodynamic findings except for the heart rate. Moreover, they were significant predictors of CHF following a long-standing MI. Conclusively, IVPG obtained from CMME is a substantially promising noninvasive tool with a high ability to detect and predict the progression of CHF following chronic MI compared to conventional echocardiography.

Helical gears are commonly used in the gear units of railway vehicles in Japan, and the bearing types used for the gear units are tapered roller bearings. In this gear unit bearing arrangements, it is important to appropriately adjust the combined clearance, called the endplay, of the two bearings supporting the pinion to prevent the damage such as seizure. Our previous research has shown that the smaller the endplay value at gear unit assembly (Initial endplay value) and the lower the ambient temperature, the greater the decrease in endplay value during rotation and the greater the risk of seizure. One of method to prevent seizure is to increase the initial endplay value, but this means an increase in the internal clearance of the bearings, which may reduce the fatigue life of the bearings or cause damage to their cages due to increased vibration. In order to prevent seizure without reducing bearing life, therefore, this study has examined the use of cylindrical roller bearings with ribs that allow a certain degree of axial displacement of inner rings and outer rings, and has compared its performance with that of a conventional structure using tapered roller bearings through various rotating tests. As a result, it is found that the temperature rise immediately after the start of rotation and torque of pinion shaft are lower for the cylindrical roller bearings with ribs than for the tapered roller bearings during the rotation test using the actual gear unit. Further, the results of rotating tests under the radial and axial loads for the pinion bearings alone showed that the torque of cylindrical roller bearings with ribs tended to be lower than that of tapered roller bearings under a large range of flow rate and temperature of lubricants.

BackgroundNovel non-invasive evaluation of the intraventricular pressure differences and gradients (IVPD and IVPG) by color M-mode echocardiography (CMME) is a promising method in diastolic function evaluation. Patent ductus arteriosus (PDA) is a congenital heart defect which is associated with increased preload. The present work provides a clinical trial for the assessment of IVPD and IVPG changes in dogs before and after surgical occlusion of PDA.Materials and MethodsA total of 12 client-owned dogs were enrolled in this study. PDA was confirmed using echocardiography, and all dogs underwent PDA occlusion. Conventional echocardiography and CMME were conducted on each patient on the operation day (Pre-PDA) and 48 h after its occlusion (Post-PDA). The total IVPD and total IVPG, as well as segmental intraventricular pressure (basal, mid-to-apical, mid, and apical) were measured from Euler's equation using specific software (MATLAB). Data were analyzed for variability and for the difference between pre- and post-PDA. The effect of PDA occlusion on the measured variables was calculated using biserial ranked correlation (rc).ResultsThere was a significant reduction in end-diastolic volume, fraction shortening, stroke volume, and mitral inflow velocities (early and late) after PDA closure. CMME was feasible in all dogs, and the CMME indices showed moderate variability, except for the apical segment of IVPD and IVPG. After PDA closure, in comparison with the pre-PDA occlusion, there was a significant reduction in total IVPD (2.285 ± 0.374 vs. 1.748 ± 0.436 mmHg; P = 0.014), basal IVPD (1.177 ± 0.538 vs. 0.696 ± 0.144 mmHg; P = 0.012), total IVPG (1.141 ± 0.246 vs. 0.933 ± 0.208 mmHg; P = 0.032), and basal IVPG (0.578 ± 0.199 vs. 0.377 ± 0.113 mmHg; P = 0.001); meanwhile, mid, mid-to-apical, and apical segments of both IVPD and IVPG showed non-significant difference. The magnitude of PDA occlusion on the measured variables was clinically relevant and associated with a large effect size on total and basal IVPD and IVPG (rc > 0.6).ConclusionThe current clinical study revealed matched response of IVPD and IVPG to the reduced preload rather than left ventricular relaxation. This result is an initial step in the clinical utility of CMME-derived IVPD and IVPG measurements in the diastolic function evaluation in dogs with PDA that warrants further clinical studies.

Cylindrical roller bearings used in traction motors for railway vehicles are used at high rotational speeds and under light loads. Under these operating conditions, the life due to cage wear is much shorter than the life due to raceway fatigue. Therefore, bearing life can be extended by reducing cage wear. The authors thought that to reduce cage wear, it is necessary to establish a dynamic analysis method for the contact between the roller and the cage, and to identify the wear mode of the cage. If cage wear follows Archard’s equation, then cage wear is proportional to the impulse caused by the contact between the rollers and the cage. Therefore, in this paper, a simple model consisting only of a roller and a cage was constructed, and the impulse was obtained via dynamic analysis. The impulses calculated by the dynamic analysis were in good agreement with those measured. In addition, the experiments showed that cage wear is proportional to the impulse and revealed the wear mode of the cage. These allow the method proposed in this paper to be used to predict cage wear and to determine bearing specifications to reduce cage wear.

Abstract Gravity determines shape of body tissue and affects the functions of life, both in plants and animals. The cellular response to gravity is an active process of mechanotransduction. Although plants and animals share some common mechanisms of gravity sensing in spite of their distant phylogenetic origin, each species has its own mechanism to sense and respond to gravity. In this review, we discuss current understanding regarding the mechanisms of cellular gravity sensing in plants and animals. Understanding gravisensing also contributes to life on Earth, e.g., understanding osteoporosis and muscle atrophy. Furthermore, in the current age of Mars exploration, understanding cellular responses to gravity will form the foundation of living in space.

When rolling bearings are used under light loads and high rotational speeds, their life may be determined by cage wear rather than raceway flaking. Under these operating conditions, the life and reliability of the bearings can be improved by reducing cage wear. To reduce cage wear, it is necessary to measure and analyze the contact forces acting on the cage due to the interactions between the roller and the cage pocket. In this paper, a measurement system capable of measuring “the contact forces between the roller and the cage pocket” and “the cage center displacement” at the same time has been constructed. Measurements have been conducted using this system for a cylindrical roller bearing at various rotational speeds. As a result of measuring the contact forces, it has been found that “the force to accelerate the cage” is generated continuously in the load zone of the bearing, while “the force to decelerate the cage” is generated intermittently in the non-load zone of the bearing. Since the contact forces are not constant during one rotation of the cage, the impulses due to the interactions have been calculated to evaluate not only the contact force but also the contact time. Results indicate that the impulses per rotation of the cage caused by each force show a tendency to decrease up to 2000 min-1 of rotational speed and not to almost change at higher speeds. In addition, it has been found that the cage center displacement measured becomes a constant velocity circular motion when the rotational speed exceeds 2000 min-1. These findings suggest that the contact between the roller and the cage can be easily modeled when the rotational speed exceeds 2000 min-1. The analysis based on this model created is in general agreement with the impulses obtained from the measurement results.

BackgroundUremic cardiomyopathy (UC), the main cause of death in progressive chronic kidney disease (CKD), is characterized by diastolic dysfunction. Intraventricular pressure gradients (IVPG) derived from color m-mode echocardiography (CMME) and two-dimensional speckle tracking echocardiography (2DSTE) were established as novel echocardiographic approaches for non-invasive and repeatable assessment of cardiac function. Previously, salvianolic acid B (Sal B) showed the potential to alleviate concentric LV hypertrophy in the pressure overload model. The purpose of this study was to evaluate the changes in cardiac function in UC and assess the efficacy of Sal B therapy using IVPG and 2DSTE techniques.Materials and MethodsTwenty-four rats underwent subtotal nephrectomy to produce progressive renal failure and were allocated equally into UC (n = 12) and Sal B-UC (n = 12) groups and monitored for 8 weeks. A sham-operated group was also included in this study (n = 12). Sal B was injected from weeks 4 to 8 in the Sal B-UC group. Conventional echocardiography, 2DSTE, and CMME were performed every 2 weeks post-operation, concomitantly with an evaluation of renal function. Histopathological and immunohistochemistry analyses were carried out to confirm the echocardiography findings.ResultsRenal failure and myocardial dysfunction were confirmed in the UC group from weeks 2 through 8. Eccentric and concentric hypertrophy was observed in the UC group, while the Sal B-UC group showed only eccentric hypertrophy. IVPG analysis did not reveal any significant differences between the groups. Edema, inflammation, fibrosis, and immunohistochemical expression of CD3 infiltration were higher in the UC group compared with sham and Sal B-UC groups.Conclusion2DSTE and IVPG explored the pathophysiology during the development of UC and indicated the incidence of myocardial dysfunction before ventricular morphological changes without intracardiac flow changes. This study confirmed increased ventricular stiffness and fibrosis in UC rats which was potentially treated by Sal B via decreasing edema, inflammation, and fibrosis.

The purpose of this paper is to understand the load state of pinion bearings used for a gear unit in an electric railway vehicle. For this purpose, a system capable of measuring the rolling element load distribution of the pinion bearing in an actual gear unit was constructed, and the measurement was conducted under the same conditions as in an actual railway vehicle. Generally, tapered roller bearings are used for pinion bearings in a face-to-face arrangement, which has an axial clearance (endplay value). Therefore, the effect of the endplay value on the rolling element load distribution was investigated by changing the endplay value at specified values, larger values, and smaller values. As a result of measuring the rolling element load, it was found that the rolling element load tended to increase as the transmission torque of the gear unit increased. In addition, large rolling element loads occurred only when the endplay value was smaller than the specified value. The reason for this is that the axial thermal expansion of the pinion shaft exceeded the endplay value, and the bearing became pressurized. The bearing loads (radial and axial loads) were determined from the measured rolling element loads, and it was found that under conditions where the endplay value was smaller than the specified value, the axial load was significantly higher, which could cause a reduction in bearing life and wear of the bearing. Finally, the load distribution factor of the bearing was determined for each condition. It was observed that the load distribution factor decreased as the endplay value increased, and that for the same endplay value, the load factor tended to be smaller for the conditions with lower torque. It was also found that the load distribution of the rolling elements does not change significantly except under conditions where the endplay value is smaller than the specified value.

Abstract Background There is a global commitment to eliminating tuberculosis (TB). It is critical to detect and treat cases of latent TB infection (LTBI), the reservoir of new TB cases. Our study assesses trends in publication of LTBI-related research. Methods We used the keywords (“latent tuberculosis” OR “LTBI” OR “latent TB”) to search the Web of Science for LTBI-related articles published 1995–2018, then classified the results into three research areas: laboratory sciences, clinical research, and public health. We calculated the proportions of LTBI-related articles in each area to three areas combined, the average rates of LTBI-related to all scientific and TB-related articles, and the average annual percent changes (AAPC) in rates for all countries and for the top 13 countries individually and combined publishing LTBI research. Results The proportion of LTBI-related articles increased over time in all research areas, with the highest AAPC in laboratory (38.2%/yr), followed by public health (22.9%/yr) and clinical (15.1%/yr). South Africa (rate ratio [RR] = 8.28, 95% CI 5.68 to 12.08) and India (RR = 2.53, 95% CI 1.74 to 3.69) had higher RRs of overall TB-related articles to all articles, but did not outperform the average of the top 13 countries in the RRs of LTBI-related articles to TB-related articles. Italy (RR = 1.95, 95% CI 1.45 to 2.63), Canada (RR = 1.73, 95% CI 1.28 to 2.34), and Spain (RR = 1.53, 95% CI 1.13 to 2.07) had higher RRs of LTBI-related articles to TB-related articles. Conclusions High TB burden countries (TB incidence > 100 per 100,000 population) published more overall TB-related research, whereas low TB burden countries showed greater focus on LTBI. Given the potential benefits, high TB burden countries should consider increasing their emphasis on LTBI-related research.

Abstract Background Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%–5% of non‐small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK‐positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib. Method Next‐generation sequencing (NGS) and Sanger sequencing were performed on a liver biopsy tissue obtained from a clinical case. Ba/F3 cells in which mutant EML4‐ALK were overexpressed were prepared, and cell viability assay and immunoblotting were performed to check the sensitivity of five independent ALK inhibitors. Results I1171S + G1269A double mutation was identified by NGS and Sanger sequencing on a liver biopsy tissue from a patient who relapsed on lorlatinib treatment. Ceritinib and brigatinib—but not other ALK inhibitors—were active against the compound mutations in the cell line model. Conclusions With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib. Key points ALK compound mutation was found in a clinical sample that was resistant to lorlatinib after sequential ALK‐tyrosine kinase inhibitor (TKI) treatment. Ceritinib and brigatinib are potential overcoming drugs against ALK I1171S + G1269A double mutation.

The long-term prognosis and genetic mechanism of pregnancy after intrauterine mosaic aneuploid blastocyst transfer remain unknown. We report the case of two babies after the aforementioned procedure and chromosomal analysis of their cord blood and chorionic villi. Case Report 1. A 41-year-old primipara, with two previous spontaneous abortions, was pregnant after intrauterine transfer of a blastocyst carrying 40% mosaicism of long-arm monosomy of chromosome 5. The amniocentesis results were 46,XX. A cesarean section was performed at 39 weeks. The female infant was 3,315 g at birth. Case Report 2. A 44-year-old primipara, with two spontaneous abortions, was pregnant after intrauterine transfer of a blastocyst carrying 40% mosaicism of long-arm monosomy of chromosome 9 and monosomy of chromosome 14. After genetic counselling, she decided not to undergo amniocentesis. No abnormalities were found by ultrasound. A cesarean section was performed at 38 weeks. The male infant was 3,340 g at birth. Chromosome analyses of postnatal cord blood and chorionic villi were performed using SNP arrays. The cord blood and chorionic villi showed no chromosomal structural abnormalities or mosaicism. For both, no disorders were observed at 10 months of age. We experienced the birth of babies after intrauterine transfer of mosaic aneuploid blastocysts.

Malignant mesothelioma is an aggressive cancer with poor prognosis, predominantly caused by human occupational exposure to asbestos. The global incidence of mesothelioma is predicted to increase as a consequence of continued exposure to asbestos from a variety of sources, including construction material produced in the past in developed countries, as well as those currently being produced in developing countries. Mesothelioma typically develops after a long latency period and consequently it is often diagnosed in the clinic at an advanced stage, at which point standard care of treatment, such as chemo- and radio-therapy, are largely ineffective. Much of our current understanding of mesothelioma biology, particularly in relation to disease pathogenesis, diagnosis and treatment, can be attributed to decades of preclinical basic science research. Given the postulated rising incidence in mesothelioma cases and the limitations of current diagnostic and treatment options, continued preclinical research into mesothelioma is urgently needed. The ever-evolving landscape of preclinical models and laboratory technology available to researchers have made it possible to study human disease with greater precision and at an accelerated rate. In this review article we provide an overview of the various resources that can be exploited to facilitate an enhanced understanding of mesothelioma biology and their applications to research aimed to improve the diagnosis and treatment of mesothelioma. These resources include cell lines, animal models, mesothelioma-specific biobanks and modern laboratory techniques/technologies. Given that different preclinical models and laboratory technologies have varying limitations and applications, they must be selected carefully with respect to the intended objectives of the experiments. This review therefore aims to provide a comprehensive overview of the various preclinical models and technologies with respect to their advantages and limitations. Finally, we will detail about a highly valuable preclinical laboratory resource to curate high quality mesothelioma biospecimens for research; the biobank. Collectively, these resources are essential to the continued advancement of precision medicine to curtail the increasing health burden caused by malignant mesothelioma.

Gravity affects the function and maintenance of organs, such as bones, muscles, and the heart. Several studies have used DNA microarrays to identify genes with altered expressions in response to gravity. However, it is technically challenging to combine the results from various microarray datasets because of their different data structures. We hypothesized that it is possible to identify common changes in gene expression from the DNA microarray datasets obtained under various conditions and methods. In this study, we grouped homologous genes to perform a meta-analysis of multiple vascular endothelial cell and skeletal muscle datasets. According to the t-distributed stochastic neighbor embedding (t-SNE) analysis, the changes in the gene expression pattern in vascular endothelial cells formed specific clusters. We also identified candidate genes in endothelial cells that responded to gravity. Further, we exposed human umbilical vein endothelial cells (HUVEC) to simulated microgravity (SMG) using a clinostat and measured the expression levels of the candidate genes. Gene expression analysis using qRT-PCR revealed that the expression level of the prostaglandin (PG) transporter gene SLCO2A1 decreased in response to microgravity, consistent with the meta-analysis of microarray datasets. Furthermore, the direction of gravity affected the expression level of SLCO2A1, buttressing the finding that its expression was affected by gravity. These results suggest that a meta-analysis of DNA microarray datasets may help identify new target genes previously overlooked in individual microarray analyses.

Early studies of weather, seasonality, and environmental influences on COVID-19 have yielded inconsistent and confusing results. To provide policy-makers and the public with meaningful and actionable environmentally-informed COVID-19 risk estimates, the research community must meet robust methodological and communication standards.

Reactive oxygen species (ROS) plays a role in intracellular signal transduction under physiological conditions while also playing an essential role in diseases such as hypertension, ischemic heart disease, and diabetes, as well as in the process of aging. The influence of ROS has some influence on the frequent occurrence of cardiovascular diseases (CVD) in diabetic patients. In this review, we considered the pathophysiological relationship between diabetes and CVD from the perspective of ROS. In addition, considering organ damage due to ROS elevation during ischemia–reperfusion, we discussed heart and lung injuries. Furthermore, we have focused on the transient receptor potential (TRP) channels and L-type calcium channels as molecular targets for ROS in ROS-induced tissue damages and have discussed about the pathophysiological mechanism of the injury.

The method presented in this article are related to the research article entitled as “Role of the TRPM4 channel in mitochondrial function, calcium release, and ROS generation in oxidative stress'' [1]. TRPM4, a non-selective monovalent cation channel, is not only involved in the generation of the action potential in cardiomyocytes, but also thought to be a key molecule in the development of the ischemia–reperfusion injury of the brain and the heart [2–5]. However, existing pharmacological inhibitors for the TRPM4 channel have problems of non-specificity [6]. This article describes methods used for targeted genomic deletion in the rat cardiomyocyte H9c2 using the CRISPR-Cas9 genome editing system in order to suppress TRPM4 protein expression. Confocal microscopy, flow cytometry, Sanger sequencing, and western blotting are performed to confirm vector transfection and the subsequent knockout of the TRPM4 protein. • These data provide information on the comprehensive analyses for knocking out the rat TRPM4 channel using CRISPR/Cas9. The analyses include confocal microscopy, flow cytometry, Sanger sequencing, and western blotting. • This dataset will benefit biological and medical researchers studying the function of TRPM4-expressing cells including neurons, cardiomyocytes, and vascular endothelial cells. It is also useful to study the involvement of the TRPM4 channel in pathological processes such as cardiac arrhythmia and ischemia–reperfusion injury. • The dataset can be used to guide the experiment of knocking out the TRPM4 gene and its subsequent application to the study of disease process caused by the gene.

BackgroundThe diagnosis of malignant pleural mesothelioma (MPM) can be difficult, in part due to the difficulty in distinguishing between MPM and reactive mesothelial hyperplasia (RMH). The tumor suppressor gene, CDKN2A, is frequently silenced by epigenetic mechanisms in many cancers; in the case of MPM it is mostly silenced via genomic deletion. Co-deletion of the CDKN2A and methylthioadenosine phosphorylase (MTAP) genes has been researched extensively and discovered to be a highly specific characteristic of MPM. Most studies have used FISH to detect the deletion of CDKN2A and IHC for MTAP as a surrogate for this. In this study, we aim to investigate and validate droplet digital PCR (ddPCR) as an emerging alternative and efficient testing method in diagnosing MPM, by particularly emphasizing on the loss of MTAP and CDKN2A.MethodsThis study included 75 formalin fixed paraffin embedded (FFPE) MPM tissue, and 12 normal pleural tissue and 10 RMH as control. Additionally, primary MPM cell lines and normal pleural samples were used as biomarker detection controls, as established in our previous publication. All FFPE specimens were processed to isolate the DNA, that was subsequently used for ddPCR detection of CDKN2A and MTAP. FFPE samples were also analyzed by fluorescence in situ hybridization (FISH) for CDKN2A and MTAP deletion, and for MTAP IHC expression. Concordance of IHC and ddPCR with FISH were studied in these samples.Results95% and 82% of cases showed co-deletion of both MTAP and CDKN2A when determined by FISH and ddPCR respectively. ddPCR has a sensitivity of 72% and specificity of 100% in detecting CDKN2A homozygous loss in MPM. ddPCR also has a concordance rate of 92% with FISH in detecting homozygous loss of CDKN2A. MTAP IHC was 68% sensitive and 100% specific for detecting CDKN2A homozygous loss in MPM when these losses were determined by ddPCR.ConclusionOur study confirms that MTAP is often co-deleted with CDKN2A in MPM. Our in-house designed ddPCR assays for MTAP and CDKN2A are useful in differentiating MPM from RMH, and is highly concordant with FISH that is currently used in diagnosing MPM. ddPCR detection of these genetic losses can potentially be utilized as an alternative method in the diagnosis of MPM and for the future development of a less-invasive MPM-specific detection technique on MPM tumor tissue DNA.

Abstract Background Monozygotic twins with 45,X/46,XY mosaicism, discordant for phenotypic sex, are extremely rare. Methods This report describes the clinical findings of a rare case of 45,X/46,XY mosaicism in monozygotic twins with different external genitalia. Single nucleotide polymorphism (SNP) array analysis, performed by collecting DNA from each umbilical cord, showed identical SNPs in the autosomal chromosomes of both fetuses. Results Chorionic villus sampling of a 37‐year‐old primigravida carrying monozygotic twins revealed a 45,X/46,XY karyotype. Autopsy of the aborted fetuses revealed a penis and testes on one fetus and a vagina, uterus, and ovaries in the other fetus––which also had severe cystic hygroma. Cell counting using fluorescence in situ hybridization with XY probes (XY‐FISH) showed 20% and 80% abundance of 45,X cells in the internal genitalia, liver, heart, lung, adrenal gland, bone marrow, and spine of the male and female fetuses, respectively. Conclusion These results indicated that the fetuses were genetically monozygotic twins and their different degrees of mosaicism may have resulted in different genital phenotypes.

In recent years, >100 cases of coronary artery stenotic lesions due to Kawasaki disease were treated with coronary artery bypass grafting (CABG). Surgical indications include stenosis of >75%, myocardial infarction history, electrocardiographic changes, and ischemia, as detected by myocardial scintigraphy and electrocardiography, due to drugs or exercise. Some centers have reported good patency rates, even in infants. The advantages of CABG in younger patients are minimal loss of left ventricular function, early elimination of post-operative ischemia risk, and improved quality of life. However, the disadvantage of performing CABG in younger patients is the small coronary artery diameter and the thin vessel wall, which can lead to post-operative occlusion, especially when performed by inexperienced surgeons. The optimal timing of CABG varies by institution and case, which depends on the presence or absence of complications, such as left ventricular dysfunction or valve regurgitation, and surgeon's experience. Importantly, unlike adult surgery, childhood CABG needs to be kept open for the very longest possible period of time to determine the optimal conditions for surgery. We report two pediatric cases of giant coronary artery aneurysms diagnosed in infancy. During school age, the patients had a mild decline of left ventricular ejection function. In one case, there were no clinical symptoms because of the development of collateral vessels and limitation of exercise. Both patients underwent surgery with good results. The gastric gastroepiploic artery could be anastomosed owing to the development of collateral blood vessels, although it was obstructed. At 1 year after surgery, both patients had a good post-operative course without complications of anastomotic stenosis or myocardial damage due to aneurysm resection. If conditions are favorable, bypass surgery can be postponed to several years until the coronary arteries are sufficiently large to warrant a delay in coronary artery stenosis in cases of infantile Kawasaki disease.

A gear case used at a bogie of a rolling stock is an important part to pack a small gear and a large gear that pass the driving force from a main mortar to a wheel. An axle, to which the small gear and the large gear connect, is housed in a gear case through an axle bearing for rotation. The defect of the axle bearings can affect the running safety of rolling stock. In this context we investigate a sensor using a hanging rubber, which can detect of damage of axle bearing in gear case. The hanging rubber is used as a fixing device, which attaches the gear case firmly to the bogie frame. By using hanging rubber for sensor, it can be easily installed for bogie. In addition, the loss of the sensor installed on the bogie and the risk of impact with flying object can be reduce. The sensor using the hanging rubber is incorporated with a piezoelectric elements. The piezoelectric elements can convert mechanical energy to electric energy, and vice versa. The defection of axle bearing in gear case can be detect by the electric signal generated from piezoelectric elements. The rotation test by rotation testing machine of gear system with sensor using hanging rubber is carried out. As the result of rotation test with damaged and normal small gears, it is confirmed that the damage can be detected by amplitude of electric voltage from piezoelectric element when the rotation speed is higher than 50km/h. In case of the rotation speed is lower than 50km/h, the damage can be detected by the frequency analysis of time wave.