Cutaneous Leishmania major infection elicits a rapid T cell response that is insufficient to clear residually infected cells, possibly due to the accumulation of regulatory T cells in healed skin. ...Here, we used Leishmania-specific TCR transgenic mice as a sensitive tool to characterize parasite-specific effector and immunosuppressive responses in vivo using two-photon microscopy. We show that Leishmania-specific Tregs displayed higher suppressive activity compared to polyclonal Tregs, that was mediated through IL-10 and not through disrupting cell-cell contacts or antigen presentation. In vivo expansion of endogenous Leishmania-specific Tregs resulted in disease reactivation that was also IL-10 dependent. Interestingly, lack of Treg expansion that recognized the immunodominant Leishmania peptide PEPCK was sufficient to restore robust effector Th1 responses and resulted in parasite control exclusively in male hosts. Our data suggest a stochastic model of Leishmania major persistence in skin, where cellular factors that control parasite numbers are counterbalanced by Leishmania-specific Tregs that facilitate parasite persistence.
Background
Although intensity‐modulated radiation therapy and volumetric arc therapy have revolutionized photon external beam therapies, the technological advances associated with electron beam ...therapy have fallen behind. Modern linear accelerators contain technologies that would allow for more advanced forms of electron treatments, such as beam collimation, using the conventional photon multi‐leaf collimator (MLC); however, no commercial solutions exist that calculate dose from such beam delivery modes. Additionally, for clinical adoption to occur, dose calculation times would need to be on par with that of modern dose calculation algorithms.
Purpose
This work developed a graphics processing unit (GPU)‐accelerated Monte Carlo (MC) engine incorporating the Varian TrueBeam linac head geometry for a rapid calculation of electron beams collimated using the conventional photon MLC.
Methods
A compute unified device architecture framework was created for the following: (1) transport of electrons and photons through the linac head geometry, considering multiple scattering, Bremsstrahlung, Møller, Compton, and pair production interactions; (2) electron and photon propagation through the CT geometry, considering all interactions plus the photoelectric effect; and (3) secondary particle cascades through the linac head and within the CT geometry. The linac head collimating geometry was modeled according to the specifications provided by the vendor, who also provided phase‐space files. The MC was benchmarked against EGSnrc/DOSXYZnrc/GEANT by simulating individual interactions with simple geometries, pencil, and square beam dose calculations in various phantoms. MC‐calculated dose distributions for MLC and jaw‐collimated electron fields were compared to measurements in a water phantom and with radiochromic film.
Results
Pencil and square beam dose distributions are in good agreement with DOSXYZnrc. Angular and spatial distributions for multiple scattering and secondary particle production in thin slab geometries are in good agreement with EGSnrc and GEANT. Dose profiles for MLC and jaw‐collimated 6–20‐MeV electron beams showed an average absolute difference of 1.1 and 1.9 mm for the FWHM and 80%–20% penumbra from measured profiles. Percent depth doses showed differences of <5% for as compared to measurement. The computation time on an NVIDIA Tesla V100 card was 2.5 min to achieve a dose uncertainty of <1%, which is ∼300 times faster than published results in a similar geometry using a single‐CPU core.
Conclusions
The GPU‐based MC can quickly calculate dose for electron fields collimated using the conventional photon MLC. The fast calculation times will allow for a rapid calculation of electron fields for mixed photon and electron particle therapy.
ICON‐A is the new icosahedral nonhydrostatic (ICON) atmospheric general circulation model in a configuration using the Max Planck Institute physics package, which originates from the ECHAM6 general ...circulation model, and has been adapted to account for the changed dynamical core framework. The coupling scheme between dynamics and physics employs a sequential updating by dynamics and physics, and a fixed sequence of the physical processes similar to ECHAM6. To allow a meaningful initial comparison between ICON‐A and the established ECHAM6‐LR model, a setup with similar, low resolution in terms of number of grid points and levels is chosen. The ICON‐A model is tuned on the base of the Atmospheric Model Intercomparison Project (AMIP) experiment aiming primarily at a well balanced top‐of atmosphere energy budget to make the model suitable for coupled climate and Earth system modeling. The tuning addresses first the moisture and cloud distribution to achieve the top‐of‐atmosphere energy balance, followed by the tuning of the parameterized dynamic drag aiming at reduced wind errors in the troposphere. The resulting version of ICON‐A has overall biases, which are comparable to those of ECHAM6. Problematic specific biases remain in the vertical distribution of clouds and in the stratospheric circulation, where the winter vortices are too weak. Biases in precipitable water and tropospheric temperature are, however, reduced compared to the ECHAM6. ICON‐A will serve as the basis of further development and as the atmosphere component to the coupled model, ICON‐Earth system model (ESM).
Plain Language Summary
ICON‐A is a new atmospheric model as needed for research on the general circulation of the atmosphere, or as atmospheric component in an Earth system model, as used in climate research. This article describes the construction of the atmospheric model, in particular how two major parts are coupled to each other: “dynamics” and “physics.” Dynamics is the part that solves the equations for the atmospheric motion, temperature, density, and concentrations of water vapor, cloud water, and cloud ice. Physics is the part that computes the changes in these fields related to processes like radiation, cloud condensation, or turbulence. These physical changes depend on the state of the atmosphere as computed by the dynamics, and the changes computed by physics force change in the dynamics. The article documents the details of this construction. Further, the article describes how the physics is tuned to obtain a good representation of the general circulation of the period 1979 to 1988 in comparison to observations. A more detailed evaluation of such simulations is presented in a companion article by Crueger et al. (2018, https://doi.org/10.1029/2017MS001233).
Key Points
Physics package for climate modeling is coupled to a nonhydrostatic dynamical core
Tuning in five steps to obtain a balanced net radiation at top of atmosphere
Overall biases of ICON‐A are comparable to ECHAM6.3, but circulation biases remain due to problems with parameterized drag
Trends in indices based on daily temperature and precipitation are examined for two periods: 1948-2016 for all stations in Canada and 1900-2016 for stations in the south of Canada. These indices, a ...number of which reflect extreme events, are considered to be impact relevant. The results show changes consistent with warming, with larger trends associated with cold temperatures. The number of summer days (when daily maximum temperature >25°C) has increased at most locations south of 65°N, and the number of hot days (daily maximum temperature >30°C) and hot nights (daily minimum temperature >22°C) have increased at a few stations in the most southerly regions. Very warm temperatures in both summer and winter (represented by the 95th percentile of their daily maximum and minimum temperatures, respectively) have increased across the country, with stronger trends in winter. Warming is more pronounced for cold temperatures. The frost-free season has become longer with fewer frost days, consecutive frost days, and ice days. Very cold temperatures in both winter and summer (represented by the 5th percentile of their daily maximum and minimum temperatures, respectively) have increased substantially across the country, again with stronger trends in the winter. Changes in other temperature indices are consistent with warming. The growing season is now longer, and the number of growing degree-days has increased. The number of heating degree-days has decreased across the country, while the number of cooling degree-days has increased at many stations south of 55°N. The frequency of annual and spring freeze-thaw days shows an increase in the interior provinces and a decrease in the remainder of the country. Changes in precipitation indices are less spatially coherent. An increase in the number of days with rainfall and heavy rainfall is found at several locations in the south. A decrease in the number of days with snowfall and heavy snowfall is observed in the western provinces, while an increase is found in the north. There is no evidence of significant changes in the annual highest 1-day rainfall and 1-day snowfall. The maximum number of consecutive dry days has decreased, mainly in the south.
Abstract
Concentrations of heavy metals in Yellowfin and Skipjack tuna fishes from the Laccadive sea were determined by inductively coupled plasma optical emission spectroscopy (ICP-OES) to evaluate ...the human health hazards via their consumption. The samples were collected from different atolls of Maldives to ensure a good representation of sample distribution. The metal concentration in tuna fish is found to be below the maximum tolerable limit set by different international organisations. The target hazard quotient values for individual metals were well below the limiting value of 1, indicating an insignificant health risk via the dietary intake of fish. The maximum targeted cancer risk value was 10 −4, indicating low carcinogenic risk from the consumption of tuna fish from the Maldives. Hence, the consumption of tuna from the Laccadive Sea is safe for human health.
The "death cap", Amanita phalloides, is the world's most poisonous mushroom, responsible for 90% of mushroom-related fatalities. The most fatal component of the death cap is α-amanitin. Despite its ...lethal effect, the exact mechanisms of how α-amanitin poisons humans remain unclear, leading to no specific antidote available for treatment. Here we show that STT3B is required for α-amanitin toxicity and its inhibitor, indocyanine green (ICG), can be used as a specific antidote. By combining a genome-wide CRISPR screen with an in silico drug screening and in vivo functional validation, we discover that N-glycan biosynthesis pathway and its key component, STT3B, play a crucial role in α-amanitin toxicity and that ICG is a STT3B inhibitor. Furthermore, we demonstrate that ICG is effective in blocking the toxic effect of α-amanitin in cells, liver organoids, and male mice, resulting in an overall increase in animal survival. Together, by combining a genome-wide CRISPR screen for α-amanitin toxicity with an in silico drug screen and functional validation in vivo, our study highlights ICG as a STT3B inhibitor against the mushroom toxin.
The Bemisia tabaci Mediterranean (MED) cryptic species is an invasive pest, distributed worldwide, with high ecological adaptability and thermotolerance. DNA methylation (a reversible chromatin ...modification) is one possible change that may occur within an organism subjected to environmental stress. To assess the effects of temperature stress on DNA methyltransferase 3 (Dnmt3) in MED, we cloned and sequenced BtDnmt3 and identified its functions in response to high and low temperatures. The full‐length cDNA of BtDnmt3 was 3913 bp, with an open reading frame of 1962 bp, encoding a 73.89 kDa protein. In situ hybridization showed that BtDnmt3 was expressed mainly in the posterior region. BtDnmt3 messenger RNA expression levels were significantly down‐regulated after exposure to heat shock and significantly up‐regulated after exposure to cold shock. Furthermore, after feeding on double‐stranded RNA specific for BtDnmt3, both heat resistance and cold resistance were significantly decreased, suggesting that BtDnmt3 is associated with thermal stress response and indicating a differential response to high‐ and low‐temperature stress in MED. Together, these results highlight a potential role for DNA methylation in thermal resistance, which is a process important to successful invasion and colonization of an alien species in various environments.
Background
Chemoresistance is the major cause of therapeutic failure in triple negative breast cancer (TNBC). In this work, we investigated the molecular mechanism for the development of TNBC ...chemoresistance.
Methods
mRNA and protein levels of ST8SIA1 were analyzed in chemosensitive and chemoresistant TNBC cells and tissues. Proliferation and survival assays were performed to determine the role of ST8SIA1 in TNBC chemoresistance.
Results
We found that ST8SIA1 mRNA and protein levels were increased in multiple TNBC cell lines after prolonged exposure to chemotherapeutic drugs. Consistently, retrospective study demonstrated that the majority of TNBC patients who developed chemoresistance displayed upregulation of ST8SIA1. We further found that chemoresistant TNBC cells were more sensitive than chemosensitive cells to ST8SIA1 inhibition in decreasing growth and viability. Consistently, ST8SIA1 inhibition augmented the efficacy of chemotherapy in TNBC cells. Mechanism studies demonstrated that ST8SIA1 inhibition led to suppression of FAK/Akt/mTOR and Wnt/β-catenin signalling pathways.
Conclusions
These findings provide an explanation for the heterogeneity of chemotherapy responses across TNBC individuals and reveal the supportive roles of ST8SIA1in TNBC chemoresistance.
Magnon transistors that can effectively regulate magnon transport by an electric field are desired for magnonics, which aims to provide a Joule-heating free alternative to the conventional ...electronics owing to the electric neutrality of magnons (the key carriers of spin-angular momenta in the magnonics). However, also due to their electric neutrality, magnons have no access to directly interact with an electric field and it is thus difficult to manipulate magnon transport by voltages straightforwardly. Here, we demonstrated a gate voltage (V_{g}) applied on a nonmagnetic metal and magnetic insulator (MI) interface that bent the energy band of the MI and then modulated the probability for conduction electrons in the nonmagnetic metal to tunnel into the MI, which can consequently enhance or weaken the spin-magnon conversion efficiency at the interface. A voltage-controlled magnon transistor based on the magnon-mediated electric current drag (MECD) effect in a Pt-Y_{3}Fe_{5}O_{12}-Pt sandwich was then experimentally realized with V_{g} modulating the magnitude of the MECD signal. The obtained efficiency (the change ratio between the MECD voltage at ±V_{g}) reached 10%/(MV/cm) at 300 K. This prototype of magnon transistor offers an effective scheme to control magnon transport by a gate voltage.
Purpose: There are no effective treatments currently available for optic nerve transection injuries. Stem cell therapy represents a feasible future treatment option. This study investigated the ...therapeutic potential of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in rats with optic nerve injury. Methods: Sprague-Dawley (SD) rats were divided into three groups: a no-treatment control group (n = 6), balanced salt solution (BSS) treatment group (n = 6), and hUC-MSCs treatment group (n = 6). Visual functions were assessed by flash visual evoked potential (fVEP) at baseline, Week 3, and Week 6 after optic nerve crush injury. Right eyes were enucleated after 6 weeks for histology. Results: The fVEP showed shortened latency delay and increased amplitude in the hUC-MSCs treated group compared with control and BSS groups. Higher cellular density was detected in the hUC-MSC treated group compared with the BSS and control groups. Co-localized expression of STEM 121 and anti-S100B antibody was observed in areas of higher nuclear density, both in the central and peripheral regions. Conclusion: Peribulbar transplantation of hUC-MSCs demonstrated cellular integration that can potentially preserve the optic nerve function with a significant shorter latency delay in fVEP and higher nuclear density on histology, and immunohistochemical studies observed cell migration particularly to the peripheral regions of the optic nerve.
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