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Abstract In EGFR-mutated lung cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges remains unclear. Here, we conduct a comprehensive analysis of apoptosis-related genes, including BCL-2 and IAP family members, using single-cell RNA sequence (scRNA-seq) and spatial transcriptomics (ST). scRNA-seq of EGFR-mutated lung cancer cell lines captures changes in apoptosis-related gene expression following EGFR-TKI treatment, most notably BCL2L1 upregulation. scRNA-seq of EGFR-mutated lung cancer patient samples also reveals high BCL2L1 expression, specifically in tumor cells, while MCL1 expression is lower in tumors compared to non-tumor cells. ST analysis of specimens from transgenic mice with EGFR-driven lung cancer indicates spatial heterogeneity of tumors and corroborates scRNA-seq findings. Genetic ablation and pharmacological inhibition of BCL2L1/BCL-XL overcome or delay EGFR-TKI resistance. Overall, our findings indicate that BCL2L1/BCL-XL expression is important for tumor cell survival as EGFR-TKI resistance emerges.

Since 2011, the Global Energy and Water cycle Exchanges (GEWEX) Water Vapor Assessment (G-VAP) has provided performance analyses for state-of-the-art reanalysis and satellite water vapour products to the GEWEX Data and Analysis Panel (GDAP) and the user community in general. A significant component of the work undertaken by G-VAP is to characterise the quality and uncertainty of these water vapour records to (i) ensure full exploitation and (ii) avoid incorrect use or interpretation of results. This study presents results from the second phase of G-VAP, where we have extended and expanded our analysis of total column water vapour (TCWV) from phase 1, in conjunction with updating the G-VAP archive. For version 2 of the archive, we consider 28 freely available and mature satellite and reanalysis data products, remapped to a regular longitude–latitude grid of 2° × 2° and on monthly time steps between January 1979 and December 2019. We first analysed all records for a “common” short period of 5 years (2005–2009), focusing on variability (spatial and seasonal) and deviation from the ensemble mean. We observed that clear-sky daytime-only satellite products were generally drier than the ensemble mean, and seasonal variability/disparity in several regions up to 12 kg m−2 related to original spatial resolution and temporal sampling. For 11 of the 28 data records, further analysis was undertaken between 1988–2014. Within this “long period”, key results show (i) trends between −1.18 ± 0.68 to 3.82 ± 3.94 kg m−2 per decade and −0.39 ± 0.27 to 1.24 ± 0.85 kg m−2 per decade were found over ice-free global oceans and land surfaces, respectively, and (ii) regression coefficients of TCWV against surface temperatures of 6.17 ± 0.24 to 27.02 ± 0.51 % K−1 over oceans (using sea surface temperature) and 3.00 ± 0.17 to 7.77 ± 0.16 % K−1 over land (using surface air temperature). It is important to note that trends estimated within G-VAP are used to identify issues in the data records rather than analyse climate change. Additionally, breakpoints have been identified and characterised for both land and ocean surfaces within this period. Finally, we present a spatial analysis of correlations to six climate indices within the long period, highlighting regional areas of significant positive and negative correlation and the level of agreement among records.

Abstract Background Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. Main body By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. Conclusion The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Abstract The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

The development of reduced models provide efficient methods that can be used to perform short term experimental data analysis or narrow down the parametric range of more sophisticated numerical approaches. Reduced models are derived by simplifying the physics description with the goal of retaining only the essential ingredients required to reproduce the phenomena under study. This is the role of the gyro-fluid code FAR3d, dedicated to analyze the linear and nonlinear stability of Alfvén Eigenmodes (AE), Energetic Particle Modes (EPM) and magnetic-hydrodynamic modes as pressure gradient driven mode (PGDM) and current driven modes (CDM) in nuclear fusion devices. Such analysis is valuable for improving the plasma heating efficiency and confinement; this can enhance the overall device performance. The present review is dedicated to a description of the most important contributions of the FAR3d code in the field of energetic particles (EP) and AE/EPM stability. FAR3d is used to model and characterize the AE/EPM activity measured in fusion devices as LHD, JET, DIII-D, EAST, TJ-II and Heliotron J. In addition, the computational efficiency of FAR3d facilitates performing massive parametric studies leading to the identification of optimization trends with respect to the AE/EPM stability. This can aid in identifying operational regimes where AE/EPM activity is avoided or minimized. This technique is applied to the analysis of optimized configurations with respect to the thermal plasma parameters, magnetic field configuration, external actuators and the effect of multiple EP populations. In addition, the AE/EPM saturation phase is analyzed, taking into account both steady-state phases and bursting activity observed in LHD and DIII-D devices. The nonlinear calculations provide: the induced EP transport, the generation of zonal structures as well as the energy transfer towards the thermal plasma and between different toroidal/helical families. Finally, FAR3d is used to forecast the AE/EPM stability in operational scenarios of future devices as ITER, CFETR, JT60SA and CFQS as well as possible approaches to optimization with respect to variations in the most important plasma parameters.

Abstract The MEG II experiment, based at the Paul Scherrer Institut in Switzerland, reports the result of a search for the decay $$\upmu ^+ \rightarrow {\textrm{e}}^+ \upgamma $$ μ + → e + γ from data taken in the first physics run in 2021. No excess of events over the expected background is observed, yielding an upper limit on the branching ratio of $${\mathcal {B}} (\upmu ^+ \rightarrow {\textrm{e}}^+ \upgamma ) < 7.5 \times 10^{-13}$$ B ( μ + → e + γ ) < 7.5 × 10 - 13 (90% CL). The combination of this result and the limit obtained by MEG gives $${\mathcal {B}} (\upmu ^+ \rightarrow {\textrm{e}}^+ \upgamma ) < 3.1 \times 10^{-13}$$ B ( μ + → e + γ ) < 3.1 × 10 - 13 (90% CL), which is the most stringent limit to date. A ten-fold larger sample of data is being collected during the years 2022–2023, and data-taking will continue in the coming years.

Introduction: Mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib. Methods: We identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S. Results: Mobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. Conclusions: This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance—robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

Abstract Climate services are largely supported by climate reanalyses and by satellite Fundamental (Climate) Data Records (F(C)DRs). This paper demonstrates how the development and the uptake of F(C)DR benefit from radiance simulations, using reanalyses and radiative transfer models. We identify three classes of applications, with examples for each application class. The first application is to validate assumptions during F(C)DR development. Hereto we show the value of applying advanced quality controls to geostationary European (Meteosat) images. We also show the value of a cloud mask to study the spatio‐temporal coherence of the impact of the Mount Pinatubo volcanic eruption between Advanced Very High Resolution Radiometer (AVHRR) and the High‐resolution Infrared Radiation Sounder (HIRS) data. The second application is to assess the coherence between reanalyses and observations. Hereto we show the capability of reanalyses to reconstruct spectra observed by the Spektrometer Interferometer (SI‐1) flown on a Soviet satellite in 1979. We also present a first attempt to estimate the random uncertainties from this instrument. Finally, we investigate how advanced bias correction can help to improve the coherence between reanalysis and Nimbus‐3 Medium‐Resolution Infrared Radiometer (MRIR) in 1969. The third application is to inform F(C)DR users about particular quality aspects. We show how simulations can help to make a better‐informed use of the corresponding F(C)DR, taking as examples the Nimbus‐7 Scanning Multichannel Microwave Radiometer (SMMR), the Meteosat Second Generation (MSG) imager, and the Defense Meteorological Satellite Program (DMSP) Special Sensor Microwave Water Vapor Profiler (SSM/T‐2).

Abstract Two-dimensional (2D) triangular lattice antiferromagnets (2D-TLA) often manifest intriguing physical and technological properties, due to the strong interplay between lattice geometry and electronic properties. The recently synthesized 2-dimensional transition metal dichalcogenide LiCrTe $$_2$$ 2 , being a 2D-TLA, enriched the range of materials which can present such properties. In this work, muon spin rotation ( $$\mu ^+$$ μ + SR) and neutron powder diffraction (NPD) have been utilized to reveal the true magnetic nature and ground state of LiCrTe $$_2$$ 2 . From high-resolution NPD the magnetic spin order at base-temperature is not, as previously suggested, helical, but rather collinear antiferromagnetic (AFM) with ferromagnetic (FM) spin coupling within the ab-plane and AFM coupling along the c-axis. The value if the ordered magnetic Cr moment is established as $$\mu _{\textrm{Cr}}= 2.36~\mu _{\textrm{B}}$$ μ Cr = 2.36 μ B . From detailed $$\mu ^+$$ μ + SR measurements we observe an AFM ordering temperature $$T_{\textrm{N}}\approx 125$$ T N ≈ 125 K. This value is remarkably higher than the one previously reported by magnetic bulk measurements. From $$\mu ^+$$ μ + SR we are able to extract the magnetic order parameter, whose critical exponent allows us to categorize LiCrTe $$_2$$ 2 in the 3D Heisenberg AFM universality class. Finally, by combining our magnetic studies with high-resolution synchrotron X-ray diffraction (XRD), we find a clear coupling between the nuclear and magnetic spin lattices. This suggests the possibility for a strong magnon–phonon coupling, similar to what has been previously observed in the closely related compound LiCrO $$_2$$ 2 .

Abstract Combination therapies or multi-targeted drugs have been pointed out as an option to prevent the emergence of resistant clones, which could make long-term treatment more effective and translate into better clinical outcomes for cancer patients. The NT157 compound is a synthetic tyrphostin that leads to long-term inhibition of IGF1R/IRS1-2-, STAT3- and AXL-mediated signaling pathways. Given the importance of these signaling pathways for the development and progression of lung cancer, this disease becomes an interesting model for generating preclinical evidence on the cellular and molecular mechanisms underlying the antineoplastic activity of NT157. In lung cancer cells, exposure to NT157 decreased, in a dose-dependent manner, cell viability, clonogenicity, cell cycle progression and migration, and induced apoptosis (p

IntroductionIn Asians, more than half of non-small cell lung cancers (NSCLC) are induced by epidermal growth factor receptor (EGFR) mutations. Although patients carrying EGFR driver mutations display a good initial response to EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs), additional mutations provoke drug resistance. Hence, predicting tumor dynamics before treatment initiation and formulating a reasonable treatment schedule is an urgent challenge.MethodsTo overcome this problem, we constructed a mathematical model based on clinical observations and investigated the optimal schedules for EGFR-TKI therapy.ResultsBased on published data on cell growth rates under different drugs, we found that using osimertinib that are efficient for secondary resistant cells as the first-line drug is beneficial in monotherapy, which is consistent with published clinical statistical data. Moreover, we identified the existence of a suitable drug-switching time; that is, changing drugs too early or too late was not helpful. Furthermore, we demonstrate that osimertinib combined with erlotinib or gefitinib as first-line treatment, has the potential for clinical application. Finally, we examined the relationship between the initial ratio of resistant cells and final cell number under different treatment conditions, and summarized it into a therapy suggestion map. By performing parameter sensitivity analysis, we identified the condition where osimertinib-first therapy was recommended as the optimal treatment option.DiscussionThis study for the first time theoretically showed the optimal treatment strategies based on the known information in NSCLC. Our framework can be applied to other types of cancer in the future.

The DFNA58 locus contains a genomic duplication involving three protein-coding genes (CNRIP1, PLEK, and PPP3R1′s exon 1) and other uncharacterized lncRNA genes (LOC101927723, LOC107985892 and LOC102724389). To clarify the role of these genes in hearing and precisely determine their role in hearing loss, four iPSC lines were generated from two carriers and two noncarriers of the duplication.

ObjectivesTo evaluate whether tumor extracellular volume fraction (fECV) on contrast-enhanced computed tomography (CT) aids in the differentiation between intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC).MethodsIn this retrospective study, 113 patients with pathologically confirmed ICC (n = 39) or HCC (n = 74) who had undergone preoperative contrast-enhanced CT were enrolled. Enhancement values of the tumor (Etumor) and aorta (Eaorta) were obtained in the precontrast and equilibrium phase CT images. fECV was calculated using the following equation: fECV [%] = Etumor/Eaorta × (100 – hematocrit [%]). fECV values were compared between the ICC and HCC groups using Welch’s t-test. The diagnostic performance of fECV for differentiating ICC and HCC was assessed using receiver-operating characteristic (ROC) analysis. fECV and the CT imaging features of tumors were evaluated by two radiologists. Multivariate logistic regression analysis was performed to identify factors predicting a diagnosis of ICC.ResultsMean fECV was significantly higher in ICCs (43.8% ± 13.2%) than that in HCCs (31.6% ± 9.0%, p < 0.001). The area under the curve for differentiating ICC from HCC was 0.763 when the cutoff value of fECV was 41.5%. The multivariate analysis identified fECV (unit OR: 1.10; 95% CI: 1.01–1.21; p < 0.05), peripheral rim enhancement during the arterial phase (OR: 17.0; 95% CI: 1.29–225; p < 0.05), and absence of washout pattern (OR: 235; 95% CI: 14.03–3933; p < 0.001) as independent CT features for differentiating between the two tumor types.ConclusionsA high value of fECV, peripheral rim enhancement during the arterial phase, and absence of washout pattern were independent factors in the differentiation of ICC from HCC.

Superconducting (SC) tokamak JT-60SA plays an essential role in fusion research and development by supporting and complementing the ITER project, providing directions to the DEMO design activity and fostering next generation scientists and engineers. Since the short circuit incident at the terminal joints of equilibrium field coil #1 during the integrated commissioning (IC) in March 2021, both EU and JA implementing agencies (IAs) have examined how to ensure safe operation of JT-60SA by mitigating the risk of possible discharge occurrence inside the cryostat. Based on the experience of the global Paschen tests, the IAs have established a strategy of risk mitigation measures, which is a combination of (i) reinforcement of insulation, (ii) avoiding unnecessary voltage application to the coil systems and (iii) immediate de-energization of the coils when deteriorated vacuum conditions are detected. Thanks to the considerable efforts of the Integrated Project Team members, the IC restarted in May 2023. After confirmation of the SC state of the coil systems (TF, EF and CS), the coil energization test and the plasma operation phase 1 (OP-1) started. The first plasma was successfully achieved on 23 October 2023 with a limited value of voltage and current applied to the coils. The plasma configuration control was also confirmed with low plasma current and low auxiliary heating power conditions. Based on the IO–F4E–QST collaboration, activities of JT-60SA have been shared with the IO and provided an important lesson for ITER assembly and commissioning, and will provide an outstanding contribution to fusion research at large. After OP-1, maintenance & enhancement phase 1 (M/E-1) starts from January 2024, in which in-vessel components are installed, and heating and diagnostic systems are extensively upgraded to allow a high power heating experiment planned in OP-2. In order to make the best use of JT-60SA, a newly organized JT-60SA experiment team will refine the research plan for the future high heating power operation phase.

Recently, experiments on basic plasma physics issues for solving future problems in fusion energy have been performed on a Large Helical Device. There are several problems to be solved in future devices for fusion energy. Emerging issues in burning plasma are: alpha-channeling (ion heating by alpha particles), turbulence and transport in electron dominant heating helium ash exhaust, reduction of the divertor heat load. To solve these problems, understanding the basic plasma physics of (1) wave–particle interaction through (inverse) Landau damping, (2) characteristics of electron-scale (high- k ) turbulence, (3) ion mixing and the isotope effect, and (4) turbulence spreading and detachment, is necessary. This overview discusses the experimental studies on these issues and turbulent transport in multi-ion plasma and other issues in the appendix.

The avalanche type of transport can induce a long-radial transport and thus can contribute to the global profile formation. In this study, we observed the heat perturbations exhibiting avalanche-like transport in the stellarator/heliotron device, Heliotron J, and the tokamak device, JT-60U. We found that the electron heat propagation in Heliotron J is mainly generated from the heating source region. The relatively high value of the Hurst exponent, which is a signature of avalanches, depends on the total heating power. On the other hand, the electron and ion heat avalanches measured in JT-60U tend to spread from the local peak of the temperature gradient and are not influenced by the heating source profiles. The contrasting features of avalanches in stellarator/heliotrons and tokamaks potentially imply the difference in the temperature profile formation, such as the presence of stiffness.

Remote sensing study of asteroids will soon enter a new era with an increasing amount of data available thanks to the JWST, especially in the mid-infrared (MIR) range that allows identification of mineral species. It will then be possible to establish a taxonomy, as is currently available in the visible–near-infrared range, based on MIR spectral parameters. It had been previously shown that the MIR range is very sensitive to space weathering (SpWe) effects. Thus, it is crucial to determine which spectral changes are involved to disentangle initial composition from surface aging and provide tools to interpret future remote sensing data of asteroids. We present here MIR measurements of a wide variety of ion-irradiated carbonaceous chondrites as a simulation of the solar wind SpWe component. We evaluate several parameters (the Christiansen feature and Reststrahlen band positions, the width of the main Si–O band) and test different measurement conditions (ion energy and geometry of observation). We highlight a dependency of the spectral changes with the initial composition, as hydrated samples are more affected than anhydrous ones. We confirm the role of the geometry in the detection of SpWe effects as already shown in the near-infrared, with a competition effect between the depth probed by photons and the implantation depth of ions (function of the energy used). We will discuss the results in the framework of future observations and Ryugu’s and Bennu’s samples studied in the laboratory.

Abstract Understanding pellet ablation physics is crucial to realizing efficient fueling into a high temperature plasma for the steady state operation of ITER and future fusion reactors. Here we report the first observation of the formation of fluctuation structures in the pellet plasmoid during the pellet ablation process by a fast camera in a medium-sized fusion device, Heliotron J. The fluctuation has a normalized fluctuation level of ~ 15% and propagates around the moving pellet across the magnetic field. By comparing the fluctuation structures with the shape of magnetic field lines calculated with the field line tracing code, we successfully reconstruct the spatio-temporal structure of the fluctuations during the pellet ablation process. The fluctuations are located at the locations displaced toroidally from the pellet and propagate in the cross-field direction around the pellet axis along the field line, indicating a three-dimensional behavior and structure of fluctuations. The fluctuation would be driven by a strong inhomogeneity formed around the pellet and invoke the relaxation of the gradient through a cross-field transport induced by the fluctuations, which could affect the pellet ablation and pellet fueling processes. Such fluctuations can be ubiquitously present at the inhomogeneity formed around a pellet in the pellet ablation process in fusion devices.

Only one-third of middle school students in Hawai‘i demonstrated proficiency in grade-level mathematics in 2019. This means that most students enter high school without a strong knowledge of foundational mathematics concepts that are essential for success in high school mathematics courses. This case study investigated two instructional intervention tools designed to help high school students who were struggling in mathematics strengthen their knowledge of and skill in foundational mathematics content. This study utilized two intervention tools, a double dose program where students received two full periods of mathematics instruction, and conceptual mathematics games. The tools were implemented to ninth grade students in a mathematics classroom at private high school in Honolulu, Hawai‘i. The primary focus of the study was to investigate the effects of the intervention tools on progress monitoring assessment scores for struggling learners. However, this study also investigated the effects on the assessment scores for non-struggling learners. While the findings showed that the use of games had a positive effect on scores for struggling learners, the double dose program did not show strong positive results for either struggling or non-struggling students. Implications for a future study are to analyze scores on games and observe the conditions of the supplementary course to investigate the effect on assessment scores.

Application of magnetic refrigeration (MR) for hydrogen liquefaction is limited by lack of MR materials with a large magnetocaloric effect (MCE). Here the authors show a series of MR materials with a large and reversible MCE operating at a full temperature range required for hydrogen liquefaction.

Introduction: EGFR exon 20 insertion mutations account for 5% to 10% of EGFR-mutated NSCLC. CLN-081 (formerly known as TAS6417), a novel covalent EGFR tyrosine kinase inhibitor, exhibits pan-mutation selective efficacy, including exon 20 insertions, in the clinical setting. Nevertheless, some patients may not respond to CLN-081 and resistance to CLN-081 may emerge over time in others. Methods: We exposed Ba/F3 cells transduced with EGFR exon 20 insertions (Y764_V765 insHH or A767_S768insSVD) to increasing concentrations of CLN-081 to generate resistant cells and then subjected their complementary DNA to sequencing to identify acquired mutations. We then evaluated effects of small molecules on engineered Ba/F3 cells on the basis of proliferation assays, Western blotting, and xenograft models. Results: All CLN-081 resistant clones harbored the EGFR C797S mutation. Ba/F3 cells with C797S (Ba/F3-C797S) were resistant to EGFR tyrosine kinase inhibitors targeting EGFR exon 20 insertion mutations, including CLN-081. Pimitespib, a selective heat shock protein 90 inhibitor, induced apoptosis in Ba/F3-C797S cells in vitro and inhibited growth of Ba/F3-C797S tumors in vivo. Ba/F3 cells with A763_Y764insFQEA-C797S remained sensitive to erlotinib. Conclusions: We conclude that the EGFR C797S mutation confers resistance to CLN-081. Our preclinical data suggest a potential small molecule to overcome CLN-081 resistance, which may benefit patients with lung cancer with EGFR exon 20 insertions.

Autoimmune diseases such as rheumatoid arthritis and type 1 diabetes are increasingly common global problems. Concerns about increases in the prevalence of such diseases and the limited efficacy of conventional treatment regimens necessitates new therapies to address these challenges. Autoimmune disease severity and dysbiosis are interconnected. Although probiotics have been established as a therapy to rebalance the microbiome and suppress autoimmune symptoms, these microbes tend to lack a number of advantageous qualities found in non-commensal bacteria. Through attenuation and genetic manipulation, these non-commensal bacteria have been engineered into recombinant forms that offer malleable platforms capable of addressing the immune imbalances found in RA and T1D. Such bacteria have been engineered to express valuable gene products known to suppress autoimmunity such as anti-inflammatory cytokines, autoantigens, and enzymes synthesizing microbial metabolites. This review will highlight current and emerging trends in the field and discuss how they may be used to prevent and control autoimmune diseases.

Summary: In the hippocampus, environmental changes elicit rearrangement of active neuronal ensembles or remapping of place cells. However, it remains elusive how the brain ensures a consistent representation of a certain environment itself despite salient events occurring there. Here, we longitudinally tracked calcium dynamics of dorsal hippocampal CA1 neurons in mice subjected to contextual fear conditioning and extinction training. Overall population activities were significantly changed by fear conditioning and were responsive to footshocks and freezing. However, a small subset of neurons, termed environment cells, were consistently active in a specific environment irrespective of experiences. A decoder modeling study showed that these cells, but not place cells, were able to predict the environment to which the mouse was exposed. Environment cells might underlie the constancy of cognition for distinct environments across time and events. Additionally, our study highlights the functional heterogeneity of cells in the hippocampus.

The presentation of viral antigens to T cells via the MHC molecules is a critical component of the host response to viral infection. Here the authors suggest SARS-CoV-2 possesses the immune evasion strategy against the MHC class I pathway by targeting key transcriptional regulators.

Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ∆vjbR, Bm∆vjbR::tnaA) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T (Treg) cells. We demonstrated that treatment with Bm∆vjbR::tnaA polarized macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Treg cells, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity, and reducing inflammation by remodeling the IME and augmenting Treg cell function.

In cancer, tumor cells and their neoplastic microenvironment can sculpt the immunogenic phenotype of a developing tumor. In this context, natural killer (NK) cells are subtypes of lymphocytes of the innate immune system recognized for their potential to eliminate neoplastic cells, not only through direct cytolytic activity but also by favoring the development of an adaptive antitumor immune response. Even though the protective effect against leukemia due to NK-cell alloreactivity mediated by the absence of the KIR-ligand has already been shown, and some data on the role of NK cells in myeloproliferative neoplasms (MPN) has been explored, their mechanisms of immune escape have not been fully investigated. It is still unclear whether NK cells can affect the biology of BCR-ABL1-negative MPN and which mechanisms are involved in the control of leukemic stem cell expansion. Aiming to investigate the potential contribution of NK cells to the pathogenesis of MPN, we characterized the frequency, receptor expression, maturation profile, and function of NK cells from a conditional Jak2V617F murine transgenic model, which faithfully resembles the main clinical and laboratory characteristics of human polycythemia vera, and MPN patients. Immunophenotypic analysis was performed to characterize NK frequency, their subtypes, and receptor expression in both mutated and wild-type samples. We observed a higher frequency of total NK cells in JAK2V617F mutated MPN and a maturation arrest that resulted in low-numbered mature CD11b+ NK cells and increased immature secretory CD27+ cells in both human and murine mutated samples. In agreement, inhibitory receptors were more expressed in MPN. NK cells from Jak2V617F mice presented a lower potential for proliferation and activation than wild-type NK cells. Colonies generated by murine hematopoietic stem cells (HSC) after mutated or wild-type NK co-culture exposure demonstrated that NK cells from Jak2V617F mice were deficient in regulating differentiation and clonogenic capacity. In conclusion, our findings suggest that NK cells have an immature profile with deficient cytotoxicity that may lead to impaired tumor surveillance in MPN. These data provide a new perspective on the behavior of NK cells in the context of myeloid malignancies and can contribute to the development of new therapeutic strategies, targeting onco-inflammatory pathways that can potentially control transformed HSCs.

Abstract Background Patients with non‐small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third‐generation EGFR‐TKIs overcome this resistance by selectively inhibiting EGFR with EGFR‐TKI‐sensitizing and T790M mutations, acquired resistance to third‐generation EGFR‐TKIs invariably develops. Methods Next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M‐mutated NSCLC patient who had progressed after a third‐generation EGFR‐TKI, TAS‐121. EGFR‐mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR‐TKIs and a heat shock protein 90 (HSP90) inhibitor. Results NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M‐mutated cell line was sensitive to osimertinib or TAS‐121 in vitro, EGFR‐overexpressing cell lines displayed resistance to these EGFR‐TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third‐generation EGFR‐TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. Conclusions EGFR amplification confers resistance to third‐generation EGFR‐TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification‐mediated resistance.

Abstract Checkpoint blockade-mediated immunotherapy is emerging as an effective treatment modality for multiple cancer types. However, cancer cells frequently evade the immune system, compromising the effectiveness of immunotherapy. It is crucial to develop screening methods to identify the patients who would most benefit from these therapies because of the risk of the side effects and the high cost of treatment. Here we show that expression of the MHC class I transactivator (CITA), NLRC5, is important for efficient responses to anti-CTLA-4 and anti-PD1 checkpoint blockade therapies. Melanoma tumors derived from patients responding to immunotherapy exhibited significantly higher expression of NLRC5 and MHC class I-related genes compared to non-responding patients. In addition, multivariate analysis that included the number of tumor-associated non-synonymous mutations, predicted neo-antigen load and PD-L2 expression was capable of further stratifying responders and non-responders to anti-CTLA4 therapy. Moreover, expression or methylation of NLRC5 together with total somatic mutation number were significantly correlated with increased patient survival. These results suggest that NLRC5 tumor expression, alone or together with tumor mutation load constitutes a valuable predictive biomarker for both prognosis and response to anti-CTLA-4 and potentially anti-PD1 blockade immunotherapy in melanoma patients.

Abstract Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.

Abstract We present the first direct search for lepton flavour violating muon decay mediated by a new light particle X, $$\upmu ^+ \rightarrow \mathrm {e}^+\mathrm {X}, \mathrm {X} \rightarrow \upgamma \upgamma \ $$ μ + → e + X , X → γ γ . This search uses a dataset resulting from $$7.5\times 10^{14}$$ 7.5 × 10 14 stopped muons collected by the MEG experiment at the Paul Scherrer Institut in the period 2009–2013. No significant excess is found in the mass region 20–45 MeV/c $$^2$$ 2 for lifetimes below 40 ps, and we set the most stringent branching ratio upper limits in the mass region of 20–40 MeV/c $$^2$$ 2 , down to $${\mathcal {O}}(10^{-11})$$ O ( 10 - 11 ) at 90% confidence level.

Background Hepatocellular carcinoma (HCC) with tumour thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is a rare advanced disease state with a poor prognosis. The aim of this study was to examine survival after surgical resection. Methods Patients with HCC and TT of either the IVC or RA, who underwent liver resection between February 1997 and July 2017, were included. Their short‐ and long‐term outcomes and surgical details were analysed retrospectively. Results Thirty‐seven patients were included; 16 patients had TT in the IVC below the diaphragm, eight had TT in the IVC above the diaphragm, and 13 had TT entering the RA. Twelve patients had advanced portal vein TT (portal vein invasion (Vp) greater than Vp3 and Vp4), ten had bilobar disease, and 12 had extrahepatic disease. There were no in‐hospital deaths, although two patients died within 90 days. Median survival did not differ between patients who had resection with curative intent (18·7 months) and those with residual tumour in the lung only (20·7 months), but survival was poor for patients with residual tumour in the liver (8·3 months). Conclusion Liver resection with thrombectomy for advanced HCC with TT in the IVC or RA is safe and feasible, leading to moderate survival.

This study investigates the effects of electron cyclotron current drive (ECCD) on the linear and nonlinear dynamics of energetic-particle (EP)-driven magnetohydrodynamics (MHD) instability (mode) in Heliotron J (HJ), using MEGA, a nonlinear hybrid EP-MHD simulation code. The effects of ECCD are included through the modification of the equilibrium magnetic field. Five MHD equilibria with plasma currents ( $I_\textrm p$ ) of −2.00, −1.00, 0.00, 0.50, and 1.00 kA are considered, where negative and positive $I_\textrm p$ represent counter and co-ECCD, respectively. To account for the EP finite charge-exchange loss observed in HJ, a bump-on-tail velocity distribution is assumed for EP. The study finds that the stabilization trends in terms of the linear growth rate ( $\gamma \omega_A^{-1}$ ) are qualitatively similar to the FAR3D linear simulation and experimental results. In addition to the enhancements of the local magnetic shear and continuum damping by ECCD as proposed in previous studies, the study suggests that changes in the linear EP and shear Alfvén wave resonance are another important factor, especially for the $n/m = 1/2$ mode. The study shows that in the currentless equilibrium, the high-velocity toroidicity-induced resonance between the $n/m = 1/2$ mode and the co-passing EP ( $L = -1$ ) has the highest EP energy transfer rate, but is located slightly below the NBI injection velocity. The co-ECCD and cntr-ECCD can shift this resonance into higher and lower velocity regions, respectively. This can lead to resonance removal for co-ECCD, while cntr-ECCD can initially increase the number of resonant EPs for a small value of shift. If the shift of the resonance by cntr-ECCD is sufficiently large, the study observes stabilization due to the reduction in the EP population in the low-velocity region. The study also finds that changes in resonance affect nonlinear dynamics such as EP transport and frequency chirping. The convective transport of the co- and counter-passing EPs can be controlled, which can only be achieved for energetic-particle-mode due to the asymmetry in the resonance velocity between co- and cntr-passing EPs. The changes in the frequency chirping from the downward chirping branch to the upward chirping branch can also be explained by the changes in the resonance velocity caused by ECCD.

Introduction: EGFR exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR tyrosine kinase inhibitors (EGFR TKIs). Novel EGFR TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S). Methods: We used models of EGFR mutations to probe representative first, second, third generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance. Results: Cells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH, and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit the phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to greater than 200-fold resistance in proliferation assays probing mobocertinib and osimertinib. A review of clinical studies of mobocertinib disclosed responses that could be lasting. Conclusions: This is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; and EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

Introduction: The EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation (∼5% to 6% of exon 20 insertions), which, at the structural and enzyme kinetic level, more closely resembles EGFR tyrosine kinase inhibitor (TKI)–sensitizing mutants, such as EGFR exon 19 indels and L858R. A limited number of preclinical models and clinical reports have studied the response of this mutant to EGFR TKIs. Methods: We used models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative first- (gefitinib, erlotinib), second- (afatinib), third-generation (osimertinib), and in-development EGFR exon 20–specific (poziotinib, mobocertinib [TAK-788]) TKIs. We also compiled outcomes of EGFR-A763_Y764insFQEA-mutated lung cancers treated with EGFR TKIs. Results: Cells driven by EGFR-A763_Y764insFQEA were consistently sensitive to EGFR TKIs (as opposed to those driven by typical EGFR exon 20 insertions [A767_V769dupASV, D770_N771insSVD and H773_V774insH]), which were only inhibited by in-development EGFR TKIs at doses below those affecting wild-type EGFR. Most case instances (62.5% [95% confidence interval: 39%–86%], n = 16) with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinically available EGFR TKIs (including osimertinib) and to in-development EGFR exon 20-specific TKIs (including mobocertinib) with prolonged periods of progression-free survival in some cases. Median overall survival for EGFR TKI–treated cases was 22 months (95% confidence interval: 16–25). Mechanisms of acquired TKI resistance of this mutant remain underreported, but do seem to align with those of common mutations. Conclusions: To our knowledge, this is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sensitive to clinically available first-, second-, third-generation, and in-development EGFR TKIs.

Abstract Background Liver organoid technology holds great promises to be used in large-scale population-based drug screening and in future regenerative medicine strategies. Recently, some studies reported robust protocols for generating isogenic liver organoids using liver parenchymal and non-parenchymal cells derived from induced pluripotent stem cells (iPS) or using isogenic adult primary non-parenchymal cells. However, the use of whole iPS-derived cells could represent great challenges for a translational perspective. Methods Here, we evaluated the influence of isogenic versus heterogenic non-parenchymal cells, using iPS-derived or adult primary cell lines, in the liver organoid development. We tested four groups comprised of all different combinations of non-parenchymal cells for the liver functionality in vitro. Gene expression and protein secretion of important hepatic function markers were evaluated. Additionally, liver development-associated signaling pathways were tested. Finally, organoid label-free proteomic analysis and non-parenchymal cell secretome were performed in all groups at day 12. Results We show that liver organoids generated using primary mesenchymal stromal cells and iPS-derived endothelial cells expressed and produced significantly more albumin and showed increased expression of CYP1A1, CYP1A2, and TDO2 while presented reduced TGF-β and Wnt signaling activity. Proteomics analysis revealed that major shifts in protein expression induced by this specific combination of non-parenchymal cells are related to integrin profile and TGF-β/Wnt signaling activity. Conclusion Aiming the translation of this technology bench-to-bedside, this work highlights the role of important developmental pathways that are modulated by non-parenchymal cells enhancing the liver organoid maturation.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and mobocertinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.

Nutritional intake impacts the human epigenome by directing epigenetic pathways in normal cell development via as yet unknown molecular mechanisms. Consequently, imbalance in the nutritional intake is able to dysregulate the epigenetic profile and drive cells towards malignant transformation. Here we present a novel epigenetic effect of the essential nutrient, NAD. We demonstrate that impairment of DNMT1 enzymatic activity by NAD-promoted ADP-ribosylation leads to demethylation and transcriptional activation of the CEBPA gene, suggesting the existence of an unknown NAD-controlled region within the locus. In addition to the molecular events, NAD- treated cells exhibit significant morphological and phenotypical changes that correspond to myeloid differentiation. Collectively, these results delineate a novel role for NAD in cell differentiation, and indicate novel nutri-epigenetic strategies to regulate and control gene expression in human cells.

We have examined for the first time the hydrogen evolution reaction (HER) activity at the (111), (100), and (110) faces of well-defined Pt-skin/Pt3Co single crystal electrodes in H2-saturated 0.1 M HClO4 solution in order to clarify the mechanism for the increased HER activities at Pt-skin/Pt-M (M = Co, Fe) nanoparticles dispersed on a carbon support, which we recently developed as highly active cathode catalysts for proton exchange membrane electrolyte water electrolysis. The HER current densities at −0.02 V vs. RHE for the Pt-skin/Pt3Co single crystal rotating disk electrodes increased in the order (100)

The aim of the present study is to analyze the effect of the electron cyclotron heating (ECH) on the linear stability of Alfvén eigenmodes (AEs) and energetic particle modes (EPMs) triggered by energetic ions in Heliotron J plasma. The analysis is performed using the FAR3d code that solves a reduced MHD model to describe the thermal plasma coupled with a gyrofluid model for the energetic particle (EP) species. The simulations reproduce the AE/EPM stability trends observed in the experiments as the electron temperature ( T _e ) increases, modifying the thermal plasma β , EP β and EP slowing-down time. Particularly, the $n/m = 1/2$ EPM and $2/4$ Global AE are stabilized in the low-bumpiness (LB) configuration due to an enhancement of the continuum, finite Larmor radius and e-i Landau damping effects as the thermal β increases. On the other hand, a larger ECH injection power cannot stabilize the AE/EPM in medium-bumpiness and high-bumpiness (HB) configurations because the damping effects are weaker compared to the LB case, unable to balance the further destabilization induced by an enhanced EP resonance as the EP slowing-down time and EP β increases with T _e .

Abstract Background Many survivors of the Great East Japan Earthquake that occurred in 2011 were at risk of deteriorating health, especially elderly people living in disaster-stricken areas. The objectives of this prospective study were: a) to clarify the different lifestyle and psychosocial factors associated with frailty by sex among the non-disabled elderly survivors, and b) to describe the differences in characteristics stratified by the degree of disaster-related housing damage. Methods We followed 2261 Japanese survivors aged ≥65 years (45.3% male; mean age, 71.7 years) without disability or frailty who completed a self-administered questionnaire at baseline. All participants completed a baseline questionnaire in 2011 and at least one identical follow-up questionnaire between 2012 and 2015 regarding lifestyle (smoking status, alcohol intake, physical activity, sedentary lifestyle, and dietary intake) and psychosocial factors (self-rated health, standard of living, psychological distress, and social networks). Frailty was defined as a score of ≥5 on the Kihon Checklist, which is used by the Japanese government to certify the need for long-term care insurance. Adjusted odds ratios and 95% confidence intervals with frailty as the dichotomous dependent variable and health factors as the independent variables were calculated using a multilevel model for repeated measures by sex, followed by stratification analyses by the degree of housing damage. Results Over the 4-year study period, 510 participants (22.6%) developed frailty. In the post-disaster setting, many of the psychosocial factors remained more prevalent 4 years later among survivors with extensive housing damage. The presence of risk factors regarding the development of frailty differed by the degree of housing damage. Among men, psychological distress, in parallel with a poor social network, was related to frailty among only the participants with extensive housing damage and those living in temporary housing, whereas among women, worsening psychological distress was associated only with no damage and no displaced survivors. Among women with extensive damage and displacement, health outcomes such as overweight and diabetes and poor social networks were strongly related to frailty. Conclusions Lifestyle and psychosocial factors associated with the risk of frailty differ by sex and the degree of housing damage.

The Global Energy and Water cycle Exchanges (GEWEX) Data and Assessments Panel (GDAP) initiated the GEWEX Water Vapor Assessment (G-VAP), which has the main objectives to quantify the current state of the art in water vapour products being constructed for climate applications and to support the selection process of suitable water vapour products by GDAP for its production of globally consistent water and energy cycle products. During the construction of the G-VAP data archive, freely available and mature satellite and reanalysis data records with a minimum temporal coverage of 10 years were considered. The archive contains total column water vapour (TCWV) as well as specific humidity and temperature at four pressure levels (1000, 700, 500, 300 hPa) from 22 different data records. All data records were remapped to a regular longitude–latitude grid of 2° × 2°. The archive consists of four different folders: 22 TCWV data records covering the period 2003–2008, 11 TCWV data records covering the period 1988–2008, as well as 7 specific humidity and 7 temperature data records covering the period 1988–2009. The G-VAP data archive is referenced under the following digital object identifier (doi): https://doi.org/10.5676/EUM_SAF_CM/GVAP/V001. Within G-VAP, the characterization of water vapour products is, among other ways, achieved through intercomparisons of the considered data records, as a whole and grouped into three classes of predominant retrieval condition: clear-sky, cloudy-sky and all-sky. Associated results are shown using the 22 TCWV data records. The standard deviations among the 22 TCWV data records have been analysed and exhibit distinct maxima over central Africa and the tropical warm pool (in absolute terms) as well as over the poles and mountain regions (in relative terms). The variability in TCWV within each class can be large and prohibits conclusions about systematic differences in TCWV between the classes.

Abstract Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation.

Nonlethal wildlife tourism has potential to support the sustainable use of protected rainforests; however, activities associated with tourism may negatively affect ecology and wildlife behaviour. Abundance and diel activity pattern of wildlife is crucial to understand how they respond to environmental factors. In the present study, we examined whether human activities impact the spatiotemporal patterns of wild mammal communities in a tourist area of Endau-Rompin (Peta) National Park, Malaysia. Using video camera traps, we assessed the detection rates and diel activity patterns of wild mammals along roads in an area near tourist lodgings and a remote area. During a 250-day camera trapping survey, we identified at least 21 species of medium and large mammal. Although the volume of car and motorcycle traffic was significantly higher in the visitor area than the remote area, there were no significant differences in the detection rates of most mammals between the two areas. The diel activity patterns of four species did not differ between the two areas. However, Tragulus species showed different diel activity patterns in the visitor and remote areas, possibly a response to predators, as large carnivores were not observed in the visitor area. These findings emphasise the importance of considering not only direct human impacts but also indirect impacts through interspecific interactions. [ABSTRACT FROM AUTHOR]