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Sulfur cross-linking reagents play critical roles not only in cross-linking rubber chains but also in controlling network morphology for reinforcement of rubber. Zinc oxide (ZnO) is clearly discovered as the main component for both roles. Especially, the importance of network inhomogeneity, which is significantly governed by the dispersion of ZnO particles, is emphasized for reinforcing rubber materials. Specifically, the formation of network domains and their continuous structures is discussed by combining the mechanical properties of the vulcanizates from the viewpoint of the reinforcement effect of rubber. Two continuous structures of network domains are termed as the network-domain cluster and network-domain network, which are observed by atomic force microscopy. The ZnO particles play a role as template for the formation of the continuous structures of network domains. The findings provide us with a practical hint for producing high-performance rubber materials.

In ferromagnets, electric current generally induces transverse Hall voltage in proportion to magnetization (anomalous Hall effect), and it is frequently used for electrical readout of the up and down spin states. While these properties are usually not expected in antiferromagnets, recent theoretical studies predicted that non-coplanar antiferromagnetic order with finite scalar spin chirality (i.e. solid angle spanned by neighboring spins) can often induce large spontaneous Hall effect even without net magnetization or external magnetic field. This phenomenon, i.e. spontaneous topological Hall effect, can potentially be used for the efficient electrical readout of the antiferromagnetic states, but its experimental verification has long been elusive due to the lack of appropriate materials hosting such exotic magnetism. Here, we report the discovery of all-in-all-out type non-coplanar antiferromagnetic order in triangular lattice compounds CoTa3S6 and CoNb3S6, by performing the detailed magnetic structure analysis based on polarized neutron scattering experiments as well as systematic first-principles calculations. These compounds are reported to host unconventionally large spontaneous Hall effect despite their vanishingly small net magnetization, and our analysis revealed that it can be well explained in terms of topological Hall effect, which originates from the fictitious magnetic field associated with scalar spin chirality in non-coplanar antiferromagnetic orders. The present results indicate that the scalar spin chirality mechanism can offer a promising route to realize giant spontaneous Hall response even in compensated antiferromagnets, and highlight intercalated van der Waals magnets as an unique quasi-two-dimensional material platform to enable various nontrivial manner of electrical reading and possible writing of non-coplanar antiferromagnetic domains., Comment: to appear in Nature Physics

Background Understandings of subtypes of atypical atrioventricular nodal reentrant tachycardia (AVNRT) using variants of slow pathway (SP) are still growing. Inferolateral (inf-lat-) left atrial (LA) SP is a rare variant extending into an inf-lat-LA along the mitral annulus (MA). Purpose To characterize an unknown subtype of atypical fast-slow (F/S-) AVNRT using an inf-lat-LA-SP as a retrograde limb (inf-lat-LA-F/S-AVNRT). Methods This Japanese multicenter retrospective study enrolled 4 patients of inf-lat-LA-F/S-AVNRT that was characterized by the earliest site of atrial activation during tachycardia (EAA) between 3 and 6 o'clock along the MA. The diagnosis was made by an exclusion of AV reentrant tachycardia (AVRT) and atrial tachycardia (AT) according to the standard criteria and was confirmed by successful elimination of tachycardia and the inf-lat-LA-SP. Results Surface ECG during tachycardia revealed long RP appearance except one who had short RP due to a short conduction time across the inf-lat-LA-SP. During tachycardia, far-field LA activation preceding near-field activation of coronary sinus (CS) musculature was visible in the CS recording in 2. Retrograde conduction via the inf-lat-LA-SP with a decremental delay was consistently reproducible with ventricular stimulation in 2, 1 of whom had double atrial response, while it was always masked by the presence of a retrograde conduction via the fast pathway in 1 and a retrograde block at the lower common pathway in 1. An injection of a small dose of ATP transiently interrupted a retrograde conduction over the inf-lat-LA-SP, suggesting its ATP-sensitivity. Exclusion of AVRT was made by no resetting of tachycardia with left ventricular extrastimulus in 2 and VA dissociation during overdrive pacing of tachycardia in remaining 2. Exclusion of AT was made by V-A-V response after ventricular entrainment in 1 and termination without atrial capture by ventricular pacing in 2. Ablation of the right-sided SP was unsuccessful to eliminate the tachycardia, but ablation at or near the EAA by transseptal approach was successful to cure the tachycardia, associated with an elimination of a retrograde conduction over the inf-lat-LA-SP following a development of an accelerated junction rhythm in all. Low-frequency potentials preceding local atrial activation, consistent with a retrograde activation via the inf-lat-LA-SP were detected along the MA medial to the EAA in 1. Conclusions Differential diagnosis of tachycardia with the EAA in the inf-lat-LA and especially long RP appearance should include inf-lat-LA-F/S-AVNRT. Presumed arrhythmogenic substrate of the inf-lat-LA-SP seemed to be consistent with the remnant of embryogenic AV ring tissue in the electropharmacological and locational characteristics. Successful elimination of this AVNRT can be obtained by ablation of the inf-lat-LA-SP, but not of the right-sided SP. Funding Acknowledgement Type of funding sources: None.

High-performance computing resources allow us to conduct numerical simulations with a horizontal grid spacing that is sufficiently high to resolve cloud systems on a global scale, and high-resolution models (HRMs) generally provide better simulation performance than low-resolution models (LRMs). In this study, we execute a next-generation model that is capable of simulating global aerosols using version 16 of the Nonhydrostatic Icosahedral Atmospheric Model (NICAM.16). The simulated aerosol distributions are obtained for 3 years with an HRM using a global 14 km grid spacing, an unprecedentedly high horizontal resolution and long integration period. For comparison, a NICAM with a 56 km grid spacing is also run as an LRM, although this horizontal resolution is still high among current global aerosol climate models. The comparison elucidated that the differences in the various variables of meteorological fields, including the wind speed, precipitation, clouds, radiation fluxes and total aerosols, are generally within 10 % of their annual averages, but most of the variables related to aerosols simulated by the HRM are slightly closer to the observations than are those simulated by the LRM. Upon investigating the aerosol components, the differences in the water-insoluble black carbon and sulfate concentrations between the HRM and LRM are large (up to 32 %), even in the annual averages. This finding is attributed to the differences in the aerosol wet deposition flux, which is determined by the conversion rate of cloud to precipitation, and the difference between the HRM and LRM is approximately 20 %. Additionally, the differences in the simulated aerosol concentrations at polluted sites during polluted months between the HRM and LRM are estimated with normalized mean biases of −19 % for black carbon (BC), −5 % for sulfate and −3 % for the aerosol optical thickness (AOT). These findings indicate that the impacts of higher horizontal grid spacings on model performance for secondary products such as sulfate, and complex products such as the AOT, are weaker than those for primary products, such as BC. On a global scale, the subgrid variabilities in the simulated AOT and cloud optical thickness (COT) in the 1∘×1∘ domain using 6-hourly data are estimated to be 28.5 % and 80.0 %, respectively, in the HRM, whereas the corresponding differences are 16.6 % and 22.9 % in the LRM. Over the Arctic, both the HRM and the LRM generally reproduce the observed aerosols, but the largest difference in the surface BC mass concentrations between the HRM and LRM reaches 30 % in spring (the HRM-simulated results are closer to the observations). The vertical distributions of the HRM- and LRM-simulated aerosols are generally close to the measurements, but the differences between the HRM and LRM results are large above a height of approximately 3 km, mainly due to differences in the wet deposition of aerosols. The global annual averages of the effective radiative forcings due to aerosol–radiation and aerosol–cloud interactions (ERFari and ERFaci) attributed to anthropogenic aerosols in the HRM are estimated to be -0.293±0.001 and -0.919±0.004 W m−2, respectively, whereas those in the LRM are -0.239±0.002 and -1.101±0.013 W m−2. The differences in the ERFari between the HRM and LRM are primarily caused by those in the aerosol burden, whereas the differences in the ERFaci are primarily caused by those in the cloud expression and performance, which are attributed to the grid spacing. The analysis of interannual variability revealed that the difference in reproducibility of both sulfate and carbonaceous aerosols at different horizontal resolution is greater than their interannual variability over 3 years, but those of dust and sea salt AOT and possibly clouds were the opposite. Because at least 10 times the computer resources are required for the HRM (14 km grid) compared to the LRM (56 km grid), these findings in this study help modelers decide whether the objectives can be achieved using such higher resolution or not under the limitation of available computational resources.

Supplemental Digital Content is available in the text., Extracorporeal life support (ECLS) can result in complications due to increased left ventricular (LV) afterload. The percutaneous ventricular assist device (PVAD) and intra-aortic balloon pump (IABP) are both considered to be effective means of LV unloading. This study describes the efficacy of LV unloading and related outcomes with PVAD or IABP during ECLS. From January 2010 to April 2018, all cardiogenic shock patients who underwent ECLS plus simultaneous PVAD or IABP were analyzed. Forty-nine patients received ECLS + PVAD, while 91 received ECLS + IABP. At 48 hours, mean pulmonary artery pressure was significantly reduced in both groups [34 mm Hg to 22, p < 0.01; 32 mm Hg to 21, p < 0.01; ECLS + PVAD and ECLS + IABP group, respectively]. The two groups had similar 30 day survival rates [19 patients (39%) vs. 35 (39%), p = 0.56]. The ECLS + PVAD group had higher incidences of bleeding at the insertion site [11 (22%) vs. 0, p < 0.01] and major hemolysis [9 (18%) vs. 0, p < 0.01]. Both groups had improvement in LV end-diastolic dimension (61 ± 12 mm to 54 ± 12, p = 0.03; 60 ± 12 mm to 47 ± 10, p < 0.01), and LV ejection fraction (16 ± 7% to 22 ± 10, p < 0.01; 22 ± 12% to 29 ± 15, p = 0.01). Both ECLS + PVAD and ECLS + IABP effectively reduced pulmonary artery pressure and improved LV function. Bleeding at the PVAD or IABP insertion site occurred more frequently in the ECLS + PVAD group than the ECLS + IABP group (p < 0.01). Nine patients (18%) in the ECLS + PVAD group experienced major hemolysis, while there was no hemolysis in the ECLS + IABP group (p < 0.01). Careful considerations are required before selecting an additional support to ECLS.

The Prede sky radiometer measures direct solar irradiance and the angular distribution of diffuse radiances at the ultraviolet, visible, and near-infrared wavelengths. These data are utilized for the remote sensing of aerosols, water vapor, ozone, and clouds, but the calibration constant, which is the sensor output current of the extraterrestrial solar irradiance at the mean distance between Earth and the Sun, is needed. The aerosol channels, which are the weak gas absorption wavelengths of 340, 380, 400, 500, 675, 870, and 1020 nm, can be calibrated by an on-site self-calibration method, the Improved Langley method. This on-site self-calibration method is useful for the continuous long-term observation of aerosol properties. However, the continuous long-term observation of precipitable water vapor (PWV) by the sky radiometer remains challenging because calibrating the water vapor absorption channel of 940 nm generally relies on the standard Langley (SL) method at limited observation sites (e.g., the Mauna Loa Observatory) and the transfer of the calibration constant by a side-by-side comparison with the reference sky radiometer calibrated by the SL method. In this study, we developed the SKYMAP algorithm, a new on-site method of self-calibrating the water vapor channel of the sky radiometer using diffuse radiances normalized by direct solar irradiance (normalized radiances). Because the sky radiometer measures direct solar irradiance and diffuse radiance using the same sensor, the normalization cancels the calibration constant included in the measurements. The SKYMAP algorithm consists of three steps. First, aerosol optical and microphysical properties are retrieved using direct solar irradiances and normalized radiances at aerosol channels. The aerosol optical properties at the water vapor channel are interpolated from those at aerosol channels. Second, PWV is retrieved using the angular distribution of the normalized radiances at the water vapor channel. Third, the calibration constant at the water vapor channel is estimated from the transmittance of PWV and aerosol optical properties. Intensive sensitivity tests of the SKYMAP algorithm using simulated data of the sky radiometer showed that the calibration constant is retrieved reasonably well for PWV cm, which indicates that the SKYMAP algorithm can calibrate the water vapor channel on-site in dry conditions. Next, the SKYMAP algorithm was applied to actual measurements under the clear-sky and low-PWV ( cm) conditions at two sites, Tsukuba and Chiba, Japan, and the annual mean calibration constants at the two sites were determined. The SKYMAP-derived calibration constants were 10.1 % and 3.2 % lower, respectively, than those determined by a side-by-side comparison with the reference sky radiometer. After determining the calibration constant, we obtained PWV from the direct solar irradiances in both the dry and wet seasons. The retrieved PWV values corresponded well to those derived from a global-navigation-satellite-system–global-positioning-system receiver, a microwave radiometer, and an AERONET (Aerosol Robotic Network) sun–sky radiometer at both sites. The correlation coefficients were greater than 0.96. We calculated the bias errors and the root mean square errors by comparing PWV between the DSRAD (direct solar irradiance) algorithm and other instruments. The magnitude of the bias error and the root mean square error were and  cm for PWV cm, respectively. However, our method tended to underestimate PWV in the wet conditions, and the magnitude of the bias error and the root mean square error became large, and  cm for PWV>3 cm, respectively. This problem was mainly due to the overestimation of the aerosol optical thickness before the retrieval of PWV. These results show that the SKYMAP algorithm enables us to observe PWV over the long term, based on its unique on-site self-calibration method.

We present the development of neutron-tagging techniques in Super-Kamiokande IV using a neural network analysis. The detection efficiency of neutron capture on hydrogen is estimated to be 26%, with a mis-tag rate of 0.016 per neutrino event. The uncertainty of the tagging efficiency is estimated to be 9.0%. Measurement of the tagging efficiency with data from an Americium-Beryllium calibration agrees with this value within 10%. The tagging procedure was performed on 3,244.4 days of SK-IV atmospheric neutrino data, identifying 18,091 neutrons in 26,473 neutrino events. The fitted neutron capture lifetime was measured as 218±9 μs. We present the development of neutron-tagging techniques in Super-Kamiokande IV using a neural network analysis. The detection efficiency of neutron capture on hydrogen is estimated to be 26%, with a mis-tag rate of 0.016 per neutrino event. The uncertainty of the tagging efficiency is estimated to be 9.0%. Measurement of the tagging efficiency with data from an Americium-Beryllium calibration agrees with this value within 10%. The tagging procedure was performed on 3,244.4 days of SK-IV atmospheric neutrino data, identifying 18,091 neutrons in 26,473 neutrino events. The fitted neutron capture lifetime was measured as 218 \pm 9 \mu s.

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein–protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence.

Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GDNF Family Receptor α1 - GFRα1) are well known to mediate spermatogonial stem cell (SSC) proliferation and survival in the mammalian testes. In nonmammalian species, Gdnf and Gfrα1 orthologs have been found but their functions remain poorly investigated in the testis. Considering this background, this study aimed to understand the roles of Gdnf-Gfrα1 signaling pathway in the zebrafish testis by combining in vivo, in silico and ex vivo approaches. Our analysis showed that zebrafish exhibited two paralogs of Gndf (gdnfa and gdnfb) and its receptor, Gfrα1 (gfrα1a and gfrα1b), in agreement with the teleost-specific third round (3R) of whole genome duplication. Expression analysis further revealed that gdnfa and gfrα1a were the most expressed copies in the zebrafish adult testes. Subsequently, we demonstrated that gdnfa is expressed in the germ cells, while Gfrα1a was detected in early spermatogonia (mainly in types Aund and Adiff) and Sertoli cells. Functional ex vivo analysis showed that Gdnf promoted the creation of new available niches by stimulating proliferation of both type Aund spermatogonia and their surrounding Sertoli cells, but without changing pou5f3 mRNA levels. Strikingly, Gdnf also inhibited late spermatogonial differentiation as shown by the decrease of type B spermatogonia and down-regulation of dazl in the co-treatment with Fsh. Altogether, our data revealed for the first time that a germ cell-derived factor is associated with maintaining germ cell stemness through the creation of new available niches, supporting development of differentiating spermatogonial cysts and inhibiting late spermatogonial differentiation in autocrine and paracrine manners.

Despite the significant increase in the generation of SARS-CoV-2 contaminated domestic and hospital wastewater, little is known about the ecotoxicological effects of the virus or its structural components in freshwater vertebrates. In this context, this study evaluated the deleterious effects caused by SARS-CoV-2 Spike protein on the health of Danio rerio, zebrafish. We demonstrated, for the first time, that zebrafish injected with fragment 16 to 165 (rSpike), which corresponds to the N-terminal portion of the protein, presented mortalities and adverse effects on liver, kidney, ovary and brain tissues. The conserved genetic homology between zebrafish and humans might be one of the reasons for the intense toxic effects followed inflammatory reaction from the immune system of zebrafish to rSpike which provoked damage to organs in a similar pattern as happen in severe cases of COVID-19 in humans, and, resulted in 78,6% of survival rate in female adults during the first seven days. The application of spike protein in zebrafish was highly toxic that is suitable for future studies to gather valuable information about ecotoxicological impacts, as well as vaccine responses and therapeutic approaches in human medicine. Therefore, besides representing an important tool to assess the harmful effects of SARS-CoV-2 in the aquatic environment, we present the zebrafish as an animal model for translational COVID-19 research., Graphical abstract Unlabelled Image

Background There is an ongoing controversy regarding the necessity of single-photon emission computed tomography (SPECT) for patients with ischemic heart diseases after the publication of the results of the ISCHEMIA trial. Purpose We aimed to evaluate the association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan. Methods From the data of 2780 patients with stable angina who were enrolled prospectively between January 2006 and March 2008 in Japan and had undergone physician-referred non-invasive imaging tests, 1205 patients managed with SPECT were stratified by 10% myocardial ischemia. Major adverse cardiac events (MACEs), including death, myocardial infarction, hospitalization for heart failure, and late revascularization, were followed-up for 1 year. Results Patients with ≥10% myocardial ischemia (n=173) were older than patients with Conclusion The presence of ≥10% myocardial ischemia was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease. Funding Acknowledgement Type of funding sources: None. Study flowchartOutcomes

STUDY QUESTION After controlled ovarian stimulation (COS) and IUI, is it clinically feasible to recover in vivo conceived and matured human blastocysts by uterine lavage from fertile women for preimplantation genetic testing for aneuploidy (PGT-A) and compare their PGT-A and Gardner scale morphology scores with paired blastocysts from IVF control cycles? SUMMARY ANSWER In a consecutive series of 134 COS cycles using gonadotrophin stimulation followed by IUI, uterine lavage recovered 136 embryos in 42% (56/134) of study cycles, with comparable in vivo and in vitro euploidy rates but better morphology in in vivo embryos. WHAT IS KNOWN ALREADY In vivo developed embryos studied in animal models possess different characteristics compared to in vitro developed embryos of similar species. Such comparative studies between in vivo and in vitro human embryos have not been reported owing to lack of a reliable method to recover human embryos. STUDY DESIGN, SIZE, DURATION We performed a single-site, prospective controlled trial in women (n = 81) to evaluate the safety, efficacy and feasibility of a novel uterine lavage catheter and fluid recovery device. All lavages were performed in a private facility with a specialized fertility unit, from August 2017 to June 2018. Subjects were followed for 30 days post-lavage to monitor for clinical outcomes and delayed complications. In 20 lavage subjects, a single IVF cycle (control group) with the same ovarian stimulation protocol was performed for a comparison of in vivo to in vitro blastocysts. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Women were stimulated with gonadotrophins for COS. The ovulation trigger was given when there were at least two dominant follicles ≥18 mm, followed by IUI of sperm. Uterine lavage occurred 4–6 days after the IUI. A subset of 20 women had a lavage cycle procedure followed by an IVF cycle (control IVF group). Recovered embryos were characterized morphologically, underwent trophectoderm (TE) biopsy, vitrified and stored in liquid nitrogen. Biopsies were analyzed using the next-generation sequencing technique. After lavage, GnRH antagonist injections were administered to induce menstruation. MAIN RESULTS AND THE ROLE OF CHANCE A total of 134 lavage cycles were performed in 81 women. Uterine lavage recovered 136 embryos in 56 (42%) cycles. At the time of cryopreservation, there were 40 (30%) multi-cell embryos and 96 (70%) blastocysts. Blastocysts were of good quality, with 74% (70/95) being Gardener grade 3BB or higher grade. Lavage blastocysts had significantly higher morphology scores than the control IVF embryos as determined by chi-square analysis (P LIMITATIONS, REASON FOR CAUTION The first objective was to evaluate the feasibility of uterine lavage following ovarian stimulation to recover blastocysts for analysis, and that goal was achieved. However, the uterine lavage system was not completely optimized in our earlier experience to levels that were achieved late in the clinical study and will be expected in clinical service. The frequency of chromosome abnormalities of in vivo and IVF control embryos was similar, but this was a small-size study. However, compared to larger historical datasets of in vitro embryos, the in vivo genetic results are within the range of high-quality in vitro embryos. WIDER IMPLICATIONS OF THE FINDINGS Uterine lavage offers a nonsurgical, minimally invasive strategy for recovery of embryos from fertile women who do not want or need IVF and who desire PGT, fertility preservation of embryos or reciprocal IVF for lesbian couples. From a research and potential clinical perspective, this technique provides a novel platform for the use of in vivo conceived human embryos as the ultimate benchmark standard for future and current ART methods. STUDY FUNDING/COMPETING INTEREST(S) Previvo Genetics, Inc., is the sole sponsor for the Punta Mita, Mexico, clinical study. S.M. performs consulting for CooperGenomics. J.E.B. and S.A.C. are co-inventors on issued patents and patents owned by Previvo and ownshares of Previvo. S.N. is a co-author on a non-provisional patent application owned by Previvo and holds stock options in Previvo. S.T.N. and M.J.A. report consulting fees from Previvo. S.T.N., S.M., M.V.S., M.J.A., C.N. and J.E.B. are members of the Previvo Scientific Advisory Board (SAB) and hold stock options in Previvo. J.E.B and S. M are members of the Previvo Board of Directors. A.N. and K.C. are employees of Previvo Genetics. L.V.M, T.M.M, J.L.R and S. S have no conflicts to disclose. TRIAL REGISTRATION NUMBER Protocol Registration and Results System (PRS) Trial Registration Number and Name: Punta Mita Study TD-2104: Clinical Trials NCT03426007.

Ethanol (EtOH) is a substantial stressor for Saccharomyces cerevisiae. Data integration from strains with different phenotypes, including EtOH stress-responsive lncRNAs, are still not available. We covered these issues seeking systems modifications that drive the divergences between higher (HT) and lower (LT) EtOH tolerant strains under their highest stress conditions. We showed that these phenotypes are neither related to high viability nor faster population rebound after stress relief. LncRNAs work on many stress-responsive systems in a strain-specific manner promoting the EtOH tolerance. Cells use membraneless RNA/protein storage and degradation systems to endure the stress harming, and lncRNAs jointly promote EtOH tolerance. CTA1 and longevity are primer systems promoting phenotype-specific gene expression. The lower cell viability and growth under stress is a byproduct of sphingolipids and inositol phosphorylceramide dampening, acerbated in HTs by sphinganine, ERG9, and squalene overloads; LTs diminish this harm by accumulating inositol 1-phosphate. The diauxic shift drives an EtOH buffering by promoting an energy burst under stress, mainly in HTs. Analysis of mutants showed genes and lncRNAs in three strains critical for their EtOH tolerance. Finally, longevity, peroxisome, energy and lipid metabolisms, RNA/protein degradation and storage systems are the main pathways driving the EtOH tolerance phenotypes.

Acute kidney injury is a common complication following heart transplantation, and the factors contributing to acute kidney injury are not well understood. We conducted a retrospective cohort study evaluating patients who underwent heart transplantation between 2009 and 2016 at a single institution. The primary endpoint was incidence of acute kidney injury as defined by Kidney Disease Improving Global Outcomes criteria. Secondary endpoints included 30‐day hospital readmission, 30‐day mortality, and 1‐year mortality. A total of 228 heart transplant patients were included in the study for analysis. In total, 145 (64%) developed acute kidney injury, where 43 (30%) were classified as stage I, 28 (19%) as stage II, and 74 (51%) as stage III. Risk factors found to be associated with the presence of acute kidney injury included increased use of vasopressors and inotropes post‐transplant. Protective factors included cardiopulmonary bypass time

Martín, S., et al., [Context] The interstellar medium is the locus of physical processes affecting the evolution of galaxies which drive or are the result of star formation activity, supermassive black hole growth, and feedback. The resulting physical conditions determine the observable chemical abundances that can be explored through molecular emission observations at millimeter and submillimeter wavelengths. [Aims] Our goal is to unveiling the molecular richness of the central region of the prototypical nearby starburst galaxy NGC 253 at an unprecedented combination of sensitivity, spatial resolution, and frequency coverage. [Methods] We used the Atacama Large Millimeter/submillimeter Array (ALMA), covering a nearly contiguous 289 GHz frequency range between 84.2 and 373.2 GHz, to image the continuum and spectral line emission at 1.6″(∼28 pc) resolution down to a sensitivity of 30 - 50 mK. This article describes the ALMA Comprehensive High-resolution Extragalactic Molecular Inventory (ALCHEMI) large program. We focus on the analysis of the spectra extracted from the 15″ (∼255 pc) resolution ALMA Compact Array data. [Results] We modeled the molecular emission assuming local thermodynamic equilibrium with 78 species being detected. Additionally, multiple hydrogen and helium recombination lines are identified. Spectral lines contribute 5 to 36% of the total emission in frequency bins of 50 GHz. We report the first extragalactic detections of C2H5OH, HOCN, HC3HO, and several rare isotopologues. Isotopic ratios of carbon, oxygen, sulfur, nitrogen, and silicon were measured with multiple species. [Concluison] Infrared pumped vibrationaly excited HCN, HNC, and HC3N emission, originating in massive star formation locations, is clearly detected at low resolution, while we do not detect it for HCO+. We suggest high temperature conditions in these regions driving a seemingly "carbon-rich"chemistry which may also explain the observed high abundance of organic species close to those in Galactic hot cores. The Lvib/LIR ratio was used as a proxy to estimate a 3% contribution from the proto super star cluster to the global infrared emission. Measured isotopic ratios with high dipole moment species agree with those within the central kiloparsec of the Galaxy, while those derived from 13C/18O are a factor of five larger, confirming the existence of multiple interstellar medium components within NGC 253 with different degrees of nucleosynthesis enrichment. The ALCHEMI data set provides a unique template for studies of star-forming galaxies in the early Universe.

SummaryEstablishing new experimental animal models to assess the safety and immune response to the antigen used in the development of COVID-19 vaccine is an imperative issue. Based on the advantages of using zebrafish as a model in research, herein we suggest doing this to test the safety of the putative vaccine candidates and to study immune response against the virus. We produced a recombinant N-terminal fraction of the Spike SARS-CoV-2 protein and injected it into adult female zebrafish. The specimens generated humoral immunity and passed the antibodies to the eggs. However, they presented adverse reactions and inflammatory responses similar to severe cases of human COVID-19. The analysis of the structure and function of zebrafish and human Angiotensin-converting enzyme 2, the main human receptor for virus infection, presented remarkable sequence similarities. Moreover, bioinformatic analysis predicted protein-protein interaction of the Spike SARS-CoV-2 fragment and the Toll-like receptor pathway. It might help in the choice of future therapeutic pharmaceutical drugs to be studied. Based on the in vivo and in silico results presented here, we propose the zebrafish as a model for translational research into the safety of the vaccine and the immune response of the vertebrate organism to the SARS-CoV-2 virus.

Pneumococcal serotype replacement is an important issue after the introduction of pneumococcal conjugate vaccine (PCV) in children. After the introduction of 13-valent PCV, the incidence of invasive pneumococcal diseases (IPD) caused by Streptococcus pneumoniae serotype 12F (Sp12F) have increased in some countries; however, an outbreak of Sp12F has not reported in the post-13-valent PCV era. We experienced a local outbreak of Sp12F during March through May 2016 in Tsuruoka city, Japan after the introduction of 13-valent PCV in 2013. The IPD patients were two children and seven adults, three of whom died with a rapid disease progress. Although the clear transmission route was not determined, eight of the nine patients (89%) had close contact with children, which suggests that transmitted colonisation of Sp12F among children and adults might be the source of transmission. Continuous monitoring of IPDs, along with the determination of pneumococcal serotypes, is warranted in the post–13-valent PCV era. New IPD control strategies may be needed if this fatal outbreak continues to occur.

After controlled ovarian stimulation (COS) and IUI, is it clinically feasible to recover in vivo conceived and matured human blastocysts by uterine lavage from fertile women for preimplantation genetic testing for aneuploidy (PGT-A) and compare their PGT-A and Gardner scale morphology scores with paired blastocysts from IVF control cycles?In a consecutive series of 134 COS cycles using gonadotrophin stimulation followed by IUI, uterine lavage recovered 136 embryos in 42% (56/134) of study cycles, with comparable in vivo and in vitro euploidy rates but better morphology in in vivo embryos.In vivo developed embryos studied in animal models possess different characteristics compared to in vitro developed embryos of similar species. Such comparative studies between in vivo and in vitro human embryos have not been reported owing to lack of a reliable method to recover human embryos.We performed a single-site, prospective controlled trial in women (n = 81) to evaluate the safety, efficacy and feasibility of a novel uterine lavage catheter and fluid recovery device. All lavages were performed in a private facility with a specialized fertility unit, from August 2017 to June 2018. Subjects were followed for 30 days post-lavage to monitor for clinical outcomes and delayed complications. In 20 lavage subjects, a single IVF cycle (control group) with the same ovarian stimulation protocol was performed for a comparison of in vivo to in vitro blastocysts.Women were stimulated with gonadotrophins for COS. The ovulation trigger was given when there were at least two dominant follicles ≥18 mm, followed by IUI of sperm. Uterine lavage occurred 4-6 days after the IUI. A subset of 20 women had a lavage cycle procedure followed by an IVF cycle (control IVF group). Recovered embryos were characterized morphologically, underwent trophectoderm (TE) biopsy, vitrified and stored in liquid nitrogen. Biopsies were analyzed using the next-generation sequencing technique. After lavage, GnRH antagonist injections were administered to induce menstruation.A total of 134 lavage cycles were performed in 81 women. Uterine lavage recovered 136 embryos in 56 (42%) cycles. At the time of cryopreservation, there were 40 (30%) multi-cell embryos and 96 (70%) blastocysts. Blastocysts were of good quality, with 74% (70/95) being Gardener grade 3BB or higher grade. Lavage blastocysts had significantly higher morphology scores than the control IVF embryos as determined by chi-square analysis (P 0.05). This is the first study to recover in vivo derived human blastocysts following ovarian stimulation for embryo genetic characterization. Recovered blastocysts showed rates of chromosome euploidy similar to the rates found in the control IVF embryos. In 11 cycles (8.2%), detectable levels of hCG were present 13 days after IUI, which regressed spontaneously in two cases and declined after an endometrial curettage in two cases. Persistent hCG levels were resolved after methotrexate in three cases and four cases received both curettage and methotrexate.The first objective was to evaluate the feasibility of uterine lavage following ovarian stimulation to recover blastocysts for analysis, and that goal was achieved. However, the uterine lavage system was not completely optimized in our earlier experience to levels that were achieved late in the clinical study and will be expected in clinical service. The frequency of chromosome abnormalities of in vivo and IVF control embryos was similar, but this was a small-size study. However, compared to larger historical datasets of in vitro embryos, the in vivo genetic results are within the range of high-quality in vitro embryos.Uterine lavage offers a nonsurgical, minimally invasive strategy for recovery of embryos from fertile women who do not want or need IVF and who desire PGT, fertility preservation of embryos or reciprocal IVF for lesbian couples. From a research and potential clinical perspective, this technique provides a novel platform for the use of in vivo conceived human embryos as the ultimate benchmark standard for future and current ART methods.Previvo Genetics, Inc., is the sole sponsor for the Punta Mita, Mexico, clinical study. S.M. performs consulting for CooperGenomics. J.E.B. and S.A.C. are co-inventors on issued patents and patents owned by Previvo and ownshares of Previvo. S.N. is a co-author on a non-provisional patent application owned by Previvo and holds stock options in Previvo. S.T.N. and M.J.A. report consulting fees from Previvo. S.T.N., S.M., M.V.S., M.J.A., C.N. and J.E.B. are members of the Previvo Scientific Advisory Board (SAB) and hold stock options in Previvo. J.E.B and S. M are members of the Previvo Board of Directors. A.N. and K.C. are employees of Previvo Genetics. L.V.M, T.M.M, J.L.R and S. S have no conflicts to disclose.Protocol Registration and Results System (PRS) Trial Registration Number and Name: Punta Mita Study TD-2104: Clinical Trials NCT03426007.

Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, single-arm, phase I/II clinical trial in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E. Patients with CRPC who were docetaxel-resistant or could not receive docetaxel treatment were eligible. HVJ-E was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a 3+3 dose-escalation design. The primary end points were to evaluate safety and tolerability of HVJ-E. The secondary end points were to analyze tumor immunity and antitumor effect. The study is registered at UMIN Clinical Trials Registry, number UMIN000006142. Seven patients were enrolled, and six patients received HVJ-E. Grade 2 or 3 adverse events (Common Terminology Criteria for Adverse Events Ver. 4.0) were urinary retention and lymphopenia from which the patients recovered spontaneously. No Grade 4 adverse events were observed. Radiographically, three patients had stable disease in the low-dose group, and one patient had stable disease and two had progressive disease in the high-dose group. The prostate-specific antigen (PSA) declined from 14 to 1.9 ng ml−1 in one patient in the low-dose group after two cycles of HVJ-E treatment, and the PSA response rate was 16.6%. NK cell activity was elevated from day 12 to day 28 after HVJ-E administration, whereas serum interleukin-6, interferon (IFN)-α, IFN-β and IFN-γ levels were not affected by HVJ-E treatment. Intratumoral and subcutaneous injections of HVJ-E are feasible and PSA response was observed in a subgroup of CRPC patients.

Purpose Aortic valve incompetence (AI) is a serious complication that develops in 20% of LVAD patients within 12 months of implantation. Many LVAD patients with AI also develop mitral regurgitation (MR). Our goal in this study was to measure systemic flow (Qsys) and LVAD flow (QLVAD) during AI, MR and AI+MR. Methods A mock circulatory loop with a dilated silicone LV and bioprosthetic valves was attached to a HeartMate II LVAD (Abbott Labs), and pressure and flow measured in the LV, LVAD and aorta. A Pre-LVAD ejection fraction of 20% without any valve dysfunction was established, followed LVAD support at speeds of 8, 9.4 and 11krpm. AI and MR were created with small stents that were non-obstructive to forward flow but prevented the leaflets from fully closing. Four conditions were tested: Normal, AI, MR and AI and MR combined. Average flow was obtained from ten cycles of data, and Q calculated as QLVAD/Qsys. Results Pre-LVAD AI, MR and AI+MR produced a 28%, 12% and 45% reduction in Qsys, respectively. LVAD support at 9.4krpm increased Normal Qsys to 3.6 L/min with 95% of flow through the LVAD. MR reduced Qsys by 16% and QLVADby 21%; AI reduced by Qsys by 24% but QLVADby only 5%; and AI+MR reduced Qsys by 25% and QLVADby 7%, which was comparable to AI alone. In all conditions except AI+MR, Q increases with LVAD speed indicating that QLVAD increases faster than Qsys. This trend reverses when MR is present, reducing the impact of AI as LVAD speed is increased. Conclusion The major finding of these studies is that MR does not worsen Qsys when it coincides with AI and LVAD support. AI and MR occur during different phases of the cardiac cycle and sum in the absence of LVAD support. When an LVAD is added without valve dysfunction, QLVADis evenly distributed across systole and diastole. AI and MR reduces systolic and increases diastolic QLVAD, but AI+MR restores the original distribution. AI+MR produces the same overall Qsys but QLVADoccurs more evenly throughout the cardiac cycle resulting in a greater sensitivity to LVAD speed changes.

Additional file 4: TableS4. Solutions to encourage IOP

Additional file 3: TableS3. Challenges to encourage IOP

Additional file 1: TableS1. Perception of the integration of oncology and palliative care programs in Japan

Additional file 2: TableS2. Qualitative analysis of opinions toward the integration of oncology and palliative care

Background:Telemedicine can be performed using a conventional videophone or web conferencing system. Then, joint lesions can only be observed and inferred from two-dimensional images, and it is difficult to perform accurate joint assessments, which is essential for the management of rheumatoid arthritis (RA).Objectives:To develop the next-generation online telemedicine system utilizing mixed reality for RA.Methods:We have developed a system that can assess joints accurately in three-dimensions images in real-time, using Azure Kinect DK (depth sensor)/ HoloLens 2 (headset), which are mixed reality technologies, and Teams (online interview/chat) provided by Microsoft. Furthermore, by applying artificial intelligence (AI), we plan to implement additionally to this system 1) a function to quickly catch and automatically evaluate the patient’s anxiety and changes in facial expressions at the time of examination, 2) a function to record dialogue with the patient in chronological order, 3) a function to support the detection of swollen joints, and 4) function to automatically analyze the questionnaire.Results:This system remotely connects a rheumatologist in the Nagasaki University Hospital (Nagasaki City, urban area) and a patient with RA and a non- rheumatologist in the Goto Central Hospital (Goto Island, rural area). A three-dimensional hologram of the patient’s hand projected in front of a rheumatologist. Using this system, we are able to evaluate joints more accurately than using a conventional videophone or web conferencing system.Conclusion:It is expected that this system will enable remote medical care specializing in rheumatology, which is standardized at a high level even in areas without rheumatologists such as remote islands and remote areas. This system remotely connects Nagasaki City and Goto Island, but due to the performance of the system, it is not limited to these areas and it is possible to connect rheumatologists to any area that can be connected to the network. It is also effective for the purpose of avoiding the risk of infection during long-distance hospital visits under the epidemic of COVID-19 infection.References:[1]Mov Disord. 2020;35:1719-1720.Disclosure of Interests:Shin-ya Kawashiri Speakers bureau: Speaker fees from AbbVie, Asahi Kasei, Astellas, Chugai, Eisai, Eli Lilly, Mitsubishi Tanabe, Novartis, and ONO., Grant/research support from: Research grants from Pfizer., Fumiaki Nonaka: None declared, Shinji Chiba: None declared, Tomoyuki Honda: None declared, Tomohiko Nakajima: None declared, Tomoyuki Ishikawa: None declared, Atsushi Kawakami Speakers bureau: Speaker fees from AbbVie, Actelion, Asahi Kasei, Astellas, Boehringer Ingelheim, Celltrion, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, GSK, Janssen, Kowa, MedPeer, Mitsubishi Tanabe, Novartis, ONO, Pfizer, Taisho, and Takeda., Grant/research support from: Grants and research support from AbbVie, Actelion, Asahi Kasei, Astellas, AYUMI, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Hakko Kirin, MSD, Neopharma, Novartis, ONO, Sanofi, Taisho, Takeda Science Foundation, and Teijin

Though hundreds to thousands of reports have described the distribution of B chromosomes among diverse eukaryote groups, a comprehensive theory of their biological role has not yet clearly emerged. B chromosomes are classically understood as a sea of repetitive DNA sequences that are poor in genes and are maintained by a parasitic-drive mechanism during cell division. Recent developments in high-throughput DNA/RNA analyses have increased the resolution of B chromosome biology beyond those of classical and molecular cytogenetic methods; B chromosomes contain many transcriptionally active sequences, including genes, and can modulate the activity of autosomal genes. Furthermore, the most recent knowledge obtained from omics analyses, which is associated with a systemic view, has demonstrated that B chromosomes can influence cell biology in a complex way, possibly favoring their own maintenance and perpetuation.