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Abstract Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0–36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

Abstract This paper proposes a new Topp-Leone Exponentiated Pareto (TLEtP) distribution. The new distribution family is derived by expanding the Topp Leone-G family of distributions with additional positive shape parameters. The corresponding density and distribution functions are derived and shown. Some of the derived mathematical properties of the distribution include quantile function, ordinary and incomplete moments generating function (mgf), hazard function, survival function, odd function, probability weighted moment, and distribution of order statistic. The parameters of the distribution are estimated using Maximum Likelihood method. The proposed distribution’s validity is demonstrated by fitting two sets of real data and comparing the results with two existing same-family distributions, the Topp-Leone Pareto type I(TLPI) and Pareto (P), with the Akaike Information Criteria (AIC) and Bayesian Information Criteria (BIC), respectively. The comparison of the proposed Topp-Leone Exponentiated Pareto (TLEtP) to the Topp-Leone Pareto type I(TLPI) and Pareto (P) distribution demonstrate that the TLEtP distribution offers a better fit for the data sets than the other two distributions.

Abstract Overall quality of radiomics research has been reported as low in literature, which constitutes a major challenge to improve. Consistent, transparent, and accurate reporting is critical, which can be accomplished with systematic use of reporting guidelines. The CheckList for EvaluAtion of Radiomics research (CLEAR) was previously developed to assist authors in reporting their radiomic research and to assist reviewers in their evaluation. To take full advantage of CLEAR, further explanation and elaboration of each item, as well as literature examples, may be useful. The main goal of this work, Explanation and Elaboration with Examples for CLEAR (CLEAR-E3), is to improve CLEAR’s usability and dissemination. In this international collaborative effort, members of the European Society of Medical Imaging Informatics−Radiomics Auditing Group searched radiomics literature to identify representative reporting examples for each CLEAR item. At least two examples, demonstrating optimal reporting, were presented for each item. All examples were selected from open-access articles, allowing users to easily consult the corresponding full-text articles. In addition to these, each CLEAR item’s explanation was further expanded and elaborated. For easier access, the resulting document is available at https://radiomic.github.io/CLEAR-E3/ . As a complementary effort to CLEAR, we anticipate that this initiative will assist authors in reporting their radiomics research with greater ease and transparency, as well as editors and reviewers in reviewing manuscripts. Relevance statement Along with the original CLEAR checklist, CLEAR-E3 is expected to provide a more in-depth understanding of the CLEAR items, as well as concrete examples for reporting and evaluating radiomic research. Key points • As a complementary effort to CLEAR, this international collaborative effort aims to assist authors in reporting their radiomics research, as well as editors and reviewers in reviewing radiomics manuscripts. • Based on positive examples from the literature selected by the EuSoMII Radiomics Auditing Group, each CLEAR item explanation was further elaborated in CLEAR-E3. • The resulting explanation and elaboration document with examples can be accessed at https://radiomic.github.io/CLEAR-E3/ . Graphical Abstract

Abstract Background The high prevalence of metabolic syndrome in low- and middle-income countries is linked to an increase in Western diet consumption, characterized by a high intake of processed foods, which impacts the levels of blood sugar and lipids, hormones, and cytokines. Hematophagous insect vectors, such as the yellow fever mosquito Aedes aegypti, rely on blood meals for reproduction and development and are therefore exposed to the components of blood plasma. However, the impact of the alteration of blood composition due to malnutrition and metabolic conditions on mosquito biology remains understudied. Methods In this study, we investigated the impact of whole-blood alterations resulting from a Western-type diet on the biology of Ae. aegypti. We kept C57Bl6/J mice on a high-fat, high-sucrose (HFHS) diet for 20 weeks and followed biological parameters, including plasma insulin and lipid levels, insulin tolerance, and weight gain, to validate the development of metabolic syndrome. We further allowed Ae. aegypti mosquitoes to feed on mice and tracked how altered host blood composition modulated parameters of vector capacity. Results Our findings identified that HFHS-fed mice resulted in reduced mosquito longevity and increased fecundity upon mosquito feeding, which correlated with alteration in the gene expression profile of nutrient sensing and physiological and metabolic markers as studied up to several days after blood ingestion. Conclusions Our study provides new insights into the overall effect of alterations of blood components on mosquito biology and its implications for the transmission of infectious diseases in conditions where the frequency of Western diet-induced metabolic syndromes is becoming more frequent. These findings highlight the importance of addressing metabolic health to further understand the spread of mosquito-borne illnesses in endemic areas. Graphical Abstract

Modelling a dataset of 5230 globally listed firms through two statistical approaches reflecting the primary principles of Natural-Resource-Based Theory and Institutional Theory, respectively, this study provides evidence that sustainability initiatives developed by firms are being rewarded in the form of improved Corporate Financial Performance (CFP). Culture has a significant influence on both firm sustainability performance, captured in ESG ratings, and CFP and also interacts with other variables, including industry sector and socio-economic development of a firm’s markets. This study is unique in hypothesising and statistically proving that sustainability is a mechanism that activates the potential of culture to produce CFP. Natural-Resource-Based Theory (NRBT) and Institutional Theory (DiMaggio & Powell, 1983) provide complementary explanations for the relationship between the culture of a firm and its CFP being mediated by sustainability, effectively determining firms’ approach to the use of their resources in a sustainable or unsustainable way. Certain relationships between culture, sustainability performance, and CFP, however, are better explained by Institutional Theory than NRBT.

Abstract Adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal. While the presence of a nurturing niche is likely crucial to support the survival and function of self-renewing RMs, evidence regarding its nature is limited. Here, we identify fibro-adipogenic progenitors (FAPs) as the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. Using parabiosis in combination with FAP-deficient transgenic mice (Pdgfrα CreERT2 × DTA) or mice lacking FAP-derived CSF1 (Pdgfrα CreERT2 × Csf1 flox/null ), we show that local CSF1 from FAPs is required for the survival of both TIM4- monocyte-derived and TIM4+ self-renewing RMs in adult skeletal muscle. The spatial distribution and number of TIM4+ RMs coincide with those of dipeptidyl peptidase IV (DPPIV)+ FAPs, suggesting their role as CSF1-producing niche cells for self-renewing RMs. This finding identifies opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease.

Abstract In adrenoleukodystrophy (ALD), contrast enhancement (CE) is a disease activity marker, but there is uncertainty about the optimal delay, if any, between contrast injection and magnetic resonance imaging (MRI) acquisition to avoid false-negative results. We acquired axial two-dimensional (2D) and three-dimensional (3D) T1-weighted gradient-echo every 6 min from 0 to 36 min after contrast administration (gadobutrol 0.1 mmol/kg) in an ALD patient with enlarging white matter lesions and progressive neuropsychological symptoms, using a 3-T magnet. The image signal over time was qualitatively assessed and measured in two regions of interest. On 3D sequences, no definite CE was appreciated, whereas on 2D sequences, CE was noticed after 6 min and definitely evident after 12 min, when 73% of the maximum signal intensity was measured. In ALD subjects, contrast-enhanced 2D T1-weighted gradient-echo sequences acquired at least 10 min after contrast injection may be considered to reduce false negative results. Relevance statement Our report is the first attempt to find an optimal delay between contrast administration and T1-weighted acquisition in cALD patients in order to correctly detect disease activity and avoid false negative results. Key points • The optimal time between contrast injection and image acquisition for MRI of adrenoleukodystrophy is unknown. • Contrast enhancement predicts adrenoleukodystrophy progression and could help patient’s selection for the therapy. • We acquired two post-contrast T1-GRE-2D/3D sequences several times to find the best injection-time. • T1-weighted 2D GRE resulted more sensitive than T1-weighted 3D GRE even after long intervals from injection. • A delay of about 10 min may minimize false negatives. Graphical Abstract

Eosinophils are a type of granulocyte named after the presence of their eosin-stained granules. Traditionally, eosinophils have been best known to play prominent roles in anti-parasitic responses and mediating allergic reactions. Knowledge of their behaviour has expanded with time, and they are now recognized to play integral parts in the homeostasis of gastrointestinal, respiratory, skeletal muscle, adipose, and connective tissue systems. As such, they are implicated in a myriad of pathologies, and have been the target of several medical therapies. This review focuses on the lifespan of eosinophils, from their origins in the bone marrow, to their tissue-resident role. In particular, we wish to highlight the functions of eosinophils in non-mucosal tissues with skeletal muscle and the adipose tissues as examples, and to discuss the current understanding of their participation in diseased states in these tissues.

Background: Fibro-adipogenic progenitors (FAP) are muscle resident mesenchymal stem cells pivotal for regulation of myofiber repair. Experimental results show in addition involvement in a range of other pathological conditions and potential for pharmacological intervention. FAP histopathology in human muscle biopsies is largely unknown, but has potential to inform translational research. Methods: CD10+ FAPs in 32 archival muscle biopsies from 8 groups (normal, dermatomyositis, inclusion body myositis (IBM), anti-synthetase syndrome, immune-mediated necrotizing myopathy (IMNM), denervation, type 2 atrophy, rhabdomyolysis) were visualized by CD10 immunohistochemistry and their histology compared. Groups are compared by semi-quantitative scoring. Results: Histological activation of endomysial CD10+ FAPs includes prominent expansion of a network of cell processes surrounding muscle fibers, as well as endomysial cell clusters evidencing proliferation. Prominence of periarteriolar processes is a notable feature in some pathologies. FAP activation is often associated with fiber degeneration/regeneration, foci of inflammation, and denervation in keeping with experimental results. Type 2 atrophy shows no evidence of FAP activation. Dermatomyositis and anti-synthetase syndrome associated myositis demonstrate diffuse activation. Conclusion: Assessment of CD10+ FAP activation is routinely possible using CD10 immunohistochemistry and demonstrates several patterns in keeping with preclinical results. Prominent expansion of FAP processes surrounding myofibers suggests enhanced interaction between myofiber/basement membranes and FAPs during activation. The presence of diffuse FAP activation in dermatomyositis biopsies unrelated to fiber repair raises the possibility of FAP activation as part of the autoimmune process. Future diagnostic applications, clinical significance and therapeutic potential remain to be elucidated.

Electrocardiogram changes during stress tests are well standardized and understood. We present and explain a reversible QRS morphology change at peak exercise previously unreported. (Level of Difficulty: Intermediate.)

Contemporary understanding of the impacts of climate change on global drought characteristics (e.g., intensities, extents) is still limited and not well understood. This knowledge is critical because projected changes in climate are expected to impact on future water availability as well as influence decisions on how water resources are allocated. The main aim of this study is to improve understanding of drought characteristics (extents and duration) in the Anthropocene where rapid changes in the environment are caused by the composite influence of human activities and climate change. Multi-scale earth observation data (1980−2020) and the Coupled Model Intercomparison Project Phase 6 climate models, which incorporate the Shared Socioeconomic Pathways (2040−2070and 2070−2100) are used to assess these characteristics as well as identify climatic hotspots where changes in drought characteristics could drive groundwater hydrology. Results show that towards the end of the 21st century, global land areas under drought will significantly decrease but their durations will not. Generally, there is evidence of significant decline in the proportion of areas that will experience various drought intensities (moderate, severe and extreme drought) in the future and for each category, drought affected areas will not reach 30% on average. Moreover, some regions are potential hotspots of climate–groundwater interactions where drought events could directly impact on groundwater. This is because of the varying degree of strong correlations (positive and negative) between climate and groundwater data in some areas (e.g., Australia, Europe, Southern Africa, Asia). The relatively strong negative correlations in some of these hotspots are indicative of the presence of considerable lags, that could be caused by aridity as well as human groundwater footprints.

Abstract There are no therapeutics that directly enhance chronic endothelial nitric oxide (NO) release, which is typically associated with vascular homeostasis. In contrast, angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs) can attenuate AngII-mediated oxidative stress, which often leads to increased endothelial NO bioavailability. Herein, we investigate the potential presence of direct, AngII/AT1R-independent ARB class effects on endothelial NO release and how this may result in enhanced aortic wall homeostasis and endothelial NO-specific transcriptome changes. Treatment of mice with four different ARBs induced sustained, long-term inhibition of vascular contractility by up to 82% at 16 weeks and 63% at 2 weeks, an effect reversed by L-NAME and absent in endothelial NO synthase (eNOS) KO mice or angiotensin converting enzyme inhibitor captopril-treated animals. In absence of AngII or in tissues with blunted AT1R expression or incubated with an AT2R blocker, telmisartan reduced vascular tone, supporting AngII/AT1R-independent pleiotropism. Finally, telmisartan was able to inhibit aging- and Marfan syndrome (MFS)-associated aortic root widening in NO-sensitive, BP-independent fashions, and correct aberrant TGF-β signaling. RNAseq analyses of aortic tissues identified early eNOS-specific transcriptome reprogramming of the aortic wall in response to telmisartan. This study suggests that ARBs are capable of major class effects on vasodilatory NO release in fashions that may not involve blockade of the AngII/AT1R pathway. Broader prophylactic use of ARBs along with identification of non-AngII/AT1R pathways activated by telmisartan should be investigated.

A critical factor in the logistic management of firms is the degree of efficiency of the operations in distribution centers. Of particular interest is the pick-up process, since it is the costliest operation, amounting to 50 and up to 75% of the total cost of the activities in storage facilities. In this paper we jointly address the order batching problem (OBP) and the order picking problem (OPP). The former problem amounts to find optimal batches of goods to be picked up, by restructuring incoming orders by either splitting up large orders or combining small orders into larger ones that can then be picked in a single picking tour. The OPP, in turn, involves identifying optimal sequences of visits to the storage positions in which the goods to be included in each batch are stored. We seek to design a plan that minimizes the total operational cost of the pick-up process, proportional to the displacement times around the storage area as well as to all the time spent in pick-ups and finishing up orders to be punctually delivered. Earliness or tardiness will induce inefficiency costs, be it because of the excessive use of space or breaches of contracts with customers. Tsai, Liou and Huang in 2008 have generated 2D and 3D instances. In previous works we have addressed the 2D ones, achieving very good results. Here we focus on 3D instances (the articles are placed at different levels in the storage center), which involve a higher complexity. This contributes to improve the performance of the hybrid evolutionary algorithm (HEA) applied in our previous works.

BackgroundSeveral viral and bacterial infections, including COVID-19, may lead to both thrombotic and hemorrhagic complications. Previously, it has been demonstrated an “in vitro” pathogenic effect of “antiphospholipid” antibodies (aPLs), which are able to activate a proinflammatory and procoagulant phenotype in monocytes, endothelial cells and platelets. This study analyzed the occurrence of aPL IgG in patients with acute ischemic stroke (AIS) during COVID-19, evaluating the effect of Ig fractions from these patients on signaling and functional activation of platelets.Materials and methodsSera from 10 patients with AIS during COVID-19, 10 non-COVID-19 stroke patients, 20 COVID-19 and 30 healthy donors (HD) were analyzed for anti-cardiolipin, anti-β2-GPI, anti-phosphatidylserine/prothrombin and anti-vimentin/CL antibodies by ELISA. Platelets from healthy donors were incubated with Ig fractions from these patients or with polyclonal anti-β2-GPI IgG and analyzed for phospho-ERK and phospho-p38 by western blot. Platelet secretion by ATP release dosage was also evaluated.ResultsWe demonstrated the presence of aPLs IgG in sera of patients with AIS during COVID-19. Treatment with the Ig fractions from these patients or with polyclonal anti-β2-GPI IgG induced a significant increase of phospho-ERK and phospho-p38 expression. In the same vein, platelet activation was supported by the increase of adenyl nucleotides release induced by Ig fractions.ConclusionsThis study demonstrates the presence of aPLs in a subgroup of COVID-19 patients who presented AIS, suggesting a role in the mechanisms contributing to hypercoagulable state in these patients. Detecting these antibodies as a serological marker to check and monitor COVID-19 may contribute to improve the risk stratification of thromboembolic manifestations in these patients.

Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.

Background and purposeAcute ischemic stroke (AIS) is a fearful complication of Coronavirus Disease-2019 (COVID-19). Aims of this study were to compare clinical/radiological characteristics, endothelial and coagulation dysfunction between acute ischemic stroke (AIS) patients with and without COVID-19 and to investigate if and how the SARS-CoV-2 spike protein (SP) was implicated in triggering platelet activation.MethodsWe enrolled AIS patients with COVID-19 within 12 h from onset and compared them with an age- and sex-matched cohort of AIS controls without COVID-19. Neuroimaging studies were performed within 24 h. Blood samples were collected in a subset of 10 patients.ResultsOf 39 AIS patients, 22 had COVID-19 and 17 did not. Admission levels of Factor VIII and von Willebrand factor antigen were significantly higher in COVID-19 patients and positively correlated with the infarct volume. In multivariate linear regression analyses, COVID-19 was an independent predictor of infarct volume (B 20.318, Beta 0.576, 95%CI 6.077–34.559; p = 0.011). SP was found in serum of 2 of the 10 examined COVID-19 patients. Platelets from healthy donors showed a similar degree of procoagulant activation induced by COVID-19 and non-COVID-19 patients' sera. The anti-SP and anti-FcγRIIA blocking antibodies had no effect in modulating platelet activity in both groups.ConclusionsSARS-CoV-2 infection seems to play a major role in endothelium activation and infarct volume extension during AIS.

Differential equations are ubiquitous in many fields of study, yet not all equations, whether ordinary or partial, can be solved analytically. Traditional numerical methods such as time-stepping schemes have been devised to approximate these solutions. With the advent of modern deep learning, neural networks have become a viable alternative to traditional numerical methods. By reformulating the problem as an optimisation task, neural networks can be trained in a semi-supervised learning fashion to approximate nonlinear solutions. In this paper, neural solvers are implemented in TensorFlow for a variety of differential equations, namely: linear and nonlinear ordinary differential equations of the first and second order; Poisson’s equation, the heat equation, and the inviscid Burgers’ equation. Different methods, such as the naive and ansatz formulations, are contrasted, and their overall performance is analysed. Experimental data is also used to validate the neural solutions on test cases, specifically: the spring-mass system and Gauss’s law for electric fields. The errors of the neural solvers against exact solutions are investigated and found to surpass traditional schemes in certain cases. Although neural solvers will not replace the computational speed offered by traditional schemes in the near future, they remain a feasible, easy-to-implement substitute when all else fails.

Abstract Background Disease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. We sought to characterise in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and shortly after induction chemotherapy using paired samples from six patients with primary refractory AML. Methods Leukemic blasts were isolated by fluorescence-activated cell sorting. Fluorescence in situ hybridization (FISH), targeted genetic sequencing and detailed immunophenotypic analysis were used to confirm that sorted cells were leukemic. Sorted blasts were subjected to RNA sequencing. Lentiviral vectors expressing short hairpin RNAs were used to assess the effect of FOXM1 knockdown on colony forming capacity, proliferative capacity and apoptosis in cell lines, primary AML cells and CD34+ cells from healthy donors. Results Molecular genetic analysis revealed early clonal selection occurring after induction chemotherapy. Immunophenotypic characterisation found leukemia-associated immunophenotypes in all cases that persisted following treatment. Despite the genetic heterogeneity of the leukemias studied, transcriptional analysis found concerted changes in gene expression in resistant blasts. Remarkably, the gene expression signature suggested that post-chemotherapy blasts were more proliferative than those at presentation. Resistant blasts also appeared less differentiated and expressed leukemia stem cell (LSC) maintenance genes. However, the proportion of immunophenotypically defined LSCs appeared to decrease following treatment, with implications for the targeting of these cells on the basis of cell surface antigen expression. The refractory gene signature was highly enriched with targets of the transcription factor FOXM1. shRNA knockdown experiments demonstrated that the viability of primary AML cells, but not normal CD34+ cells, depended on FOXM1 expression. Conclusions We found that chemorefractory blasts from leukemias with varied genetic backgrounds expressed a common transcriptional program. In contrast to the notion that LSC quiescence confers resistance to chemotherapy we find that refractory blasts are both actively proliferating and enriched with LSC maintenance genes. Using primary patient material from a relevant clinical context we also provide further support for the role of FOXM1 in chemotherapy resistance, proliferation and stem cell function in AML.

Because of their peculiar genomic and chromosomal characteristics, reptiles are extraordinary model organisms to study karyotype and sex chromosome evolution, but despite the growing interest in their evolutionary cytogenetics, only a small fraction of species have a known karyotype. We performed a comparative cytogenetic analysis on Elaphe quatuorlineata and Zamenis lineatus, using classic and molecular techniques. We provide the karyotype of these two species and an assessment of their chromosomal features. Chromosome analysis was performed with standard karyotyping, C-banding, sequential C-banding + CMA3 + DAPI and Ag-NOR staining. On E. quatuorlineata, we also performed CMA3-methyl green staining and Fluorescence in situ Hybridization mapping NOR loci (NOR-FISH). Elaphe quatuorlineata and Z. lineatus show a very similar karyotype of 2n = 36, with 8 macro- and 10 microchromosome pairs, but differ in the morphology of the pair 8, which resulted submetacentric in the former and metacentric in the latter species. By comparing our data to those available from the literature on congeneric species, we analysed the occurrence of primitive and derivate chromosomal characters and provide cytotaxonomic insights, which further support the species status of Z. lineatus. In both species, the 4th pair was identified as the sex chromosome pair (ZZ/ZW) and NORs were localized on a microchromosome pair. We finally highlight in both genera Elaphe and Zamenis different stages of heterochromatinization of the W chromosome, in agreement with the progressive diversification model of sex chromosome as already shown in different reptile taxa.

Abstract Striated muscle is a highly plastic and regenerative organ that regulates body movement, temperature, and metabolism—all the functions needed for an individual’s health and well-being. The muscle connective tissue’s main components are the extracellular matrix and its resident stromal cells, which continuously reshape it in embryonic development, homeostasis, and regeneration. Fibro-adipogenic progenitors are enigmatic and transformative muscle-resident interstitial cells with mesenchymal stem/stromal cell properties. They act as cellular sentinels and physiological hubs for adult muscle homeostasis and regeneration by shaping the microenvironment by secreting a complex cocktail of extracellular matrix components, diffusible cytokines, ligands, and immune-modulatory factors. Fibro-adipogenic progenitors are the lineage precursors of specialized cells, including activated fibroblasts, adipocytes, and osteogenic cells after injury. Here, we discuss current research gaps, potential druggable developments, and outstanding questions about fibro-adipogenic progenitor origins, potency, and heterogeneity. Finally, we took advantage of recent advances in single-cell technologies combined with lineage tracing to unify the diversity of stromal fibro-adipogenic progenitors. Thus, this compelling review provides new cellular and molecular insights in comprehending the origins, definitions, markers, fate, and plasticity of murine and human fibro-adipogenic progenitors in muscle development, homeostasis, regeneration, and repair.

The terrestrial water storage anomaly (TWSA) from the previous Gravity Recovery and Climate Experiment (GRACE) covers a relatively short period (15 years) with several missing periods. This study explores the boosted regression trees (BRT) and the artificial neural network (ANN) to reconstruct the TWSA series between 1982 and 2014 over the Yangtze River basin (YRB). Both algorithms are trained with several hydro-climatic variables (e.g., precipitation, soil moisture, and temperature) and climate indices for the YRB. The results from this study show that the BRT is capable of reconstructing TWSA and shows Nash–Sutcliffe efficiency (NSE) of 0.89 and a root-mean-square error (RMSE) of 18.94 mm during the test stage, outperforming ANN in about 2.3% and 7.4%, respectively. As a step further, the reliability of this technique in reconstructing TWSA beyond the GRACE era was also evaluated. Hence, a closed-loop simulation using the artificial TWSA series over 1982–2014 under the same scenarios for the actual GRACE data shows that BRT can predict TWSA (NSE of 0.92 and RMSE of 6.93 mm). Again, the BRT outperformed the ANN by approximately 1.1% and 5.3%, respectively. This study provides a new perspective for reconstructing and filling the gaps in the GRACE–TWSA series over data-scarce regions, which is desired for hydrological drought characterization and environmental studies. BRT offers such an opportunity for the GRACE Follow-On mission to predict 11 months of missing TWSA data by relying on a limited number of predictive variables, hence being adjudged to be more economical than the ANN.

Abstract A chronic low-grade inflammation within adipose tissue (AT) seems to be the link between obesity and some of its associated diseases. One hallmark of this AT inflammation is the accumulation of AT macrophages (ATMs) around dead or dying adipocytes, forming so-called crown-like structures (CLS). To investigate the dynamics of CLS and their direct impact on the activation state of ATMs, we established a laser injury model to deplete individual adipocytes in living AT from double reporter mice (GFP-labeled ATMs and tdTomato-labeled adipocytes). Hence, we were able to detect early ATM-adipocyte interactions by live imaging and to determine a precise timeline for CLS formation after adipocyte death. Further, our data indicate metabolic activation and increased lipid metabolism in ATMs upon forming CLS. Most importantly, adipocyte death, even in lean animals under homeostatic conditions, leads to a locally confined inflammation, which is in sharp contrast to other tissues. We identified cell size as cause for the described pro-inflammatory response, as the size of adipocytes is above a critical threshold size for efferocytosis, a process for anti-inflammatory removal of dead cells during tissue homeostasis. Finally, experiments on parabiotic mice verified that adipocyte death leads to a pro-inflammatory response of resident ATMs in vivo, without significant recruitment of blood monocytes. Our data indicate that adipocyte death triggers a unique degradation process and locally induces a metabolically activated ATM phenotype that is globally observed with obesity.

At the end of November 2021, a large area of Puglia (an administrative region in Southern Italy) was officially nominated as new aUGGp (aspiring UNESCO Global Geopark) by the Italian National Commission of UNESCO. This area comprises the northwestern part of the Murge territory, where a Cretaceous sector of the Apulia Carbonate Platform crops out, and part of the adjacent Premurge territory, where the southwestward lateral continuation of the same platform (being flexed toward the Southern Apennines Chain) is covered by thin Plio-Quaternary foredeep deposits. The worldwide geological uniqueness of the aspiring Geopark (Murge aUGGp) is that the area is the only in situ remnant of the Adria Plate, the old continental plate almost entirely squeezed between the Africa and Eurasia Plates. In such a context, the Murge area (part of the Apulia Foreland) is a virtually undeformed sector of Adria, while other territories of the plate are and/or were involved in the subduction/collision processes. In the aspiring Geopark, the crust of Adria is still rooted to its mantle, and the Cretaceous evolution of the continent is widely recorded in the Murge area thanks to the shallow-water carbonate succession of one of the largest peri-Tethys carbonate platforms (the Apulia Carbonate Platform). The aspiring Geopark also comprises the Premurge area, which represents the outer Southern Apennines foredeep, whose Plio-Quaternary evolution is spectacularly exposed thanks to an “anomalous” regional middle-late Quaternary uplift. Despite the presence of numerous geological singularities of international importance, it would be important, from a geotourist point of view, to propose a regional framework of the geology of the aUGGp before introducing visitors to the significance of the individual geosites, whose importance could be amplified if included in the geoevolutionary context of the Murge aUGGp.

This paper presents a complete procedure on prototyping using the FPGA of the STEMlab board and is intended to serve as a guide for developers, students and researchers interested in speeding up their projects and experiments. Due to the reconfigurability of its internal circuitry, being as simple as a code modification (using hardware description language), FPGA technology allows testing of several controller topologies and/or parameters without the need of any physical change at hardware. This feature allows a much faster development cycle of either commercial products or academic experiments. Besides the reconfigurability of the FPGA, the STEMlab board also offers the advantage of several peripheral already available, which includes, among others, high speed analog-to-digital and digital-to-analog converters, Ethernet communication and a dual-core ARM processor capable of running a Linux operating system. In this paper, a didactic method of use of this board is presented, from getting started to a complete academic and industrial application: detection of early damage on an induction motor using frequency response analysis.

This paper presents the detailed project of a modular educational kit to be used in research and teaching activities in the area of power electronics - with emphasis on applications in medium voltage multilevel converters. The half bridge topology has been chosen for the submodules, as they can be arranged together in a multitude of other topologies. A system composed by a mother board and daughter cards is presented. A DSP control card and a FPGA System-On-Module are inserted in the mother board in order to control the half bridge submodules. The targets of this project are applications in medium voltage - hence, the communication between the submodules and the FPGA/DSP is performed through optical fibers. Also a self power system is presented for the submodules, in order for them to operate at floating potentials. Experimental results have been presented for the most usual topologies of converters, including a Modular Multilevel Converter operating at 2000V.

Abstract Background Resistance to chemotherapy is the most common cause of treatment failure in acute myeloid leukemia (AML) and the drug efflux pump ABCB1 is a critical mediator. Recent studies have identified promoter translocations as common drivers of high ABCB1 expression in recurrent, chemotherapy-treated high-grade serous ovarian cancer (HGSC) and breast cancer. These fusions place ABCB1 under the control of a strong promoter while leaving its open reading frame intact. The mechanisms controlling high ABCB1 expression in AML are largely unknown. We therefore established an experimental system and analysis pipeline to determine whether promoter translocations account for high ABCB1 expression in cases of relapsed human AML. Methods The human AML cell line THP-1 was used to create a model of chemotherapy resistance in which ABCB1 expression was driven by a promoter fusion. The THP-1 model was used to establish a targeted nanopore long-read sequencing approach that was then applied to cases of ABCB1 high HGSC and AML. H3K27Ac ChIP sequencing was used to assess the activity of native promoters in cases of ABCB1 high AML. Results Prolonged in vitro daunorubicin exposure induced activating ABCB1 promoter translocations in human THP-1 AML cells, similar to those recently described in recurrent high-grade serous ovarian and breast cancers. Targeted nanopore sequencing proved an efficient method for identifying ABCB1 structural variants in THP-1 AML cells and HGSC; the promoter translocations identified in HGSC were both previously described and novel. In contrast, activating ABCB1 promoter translocations were not identified in ABCB1 high AML; instead H3K27Ac ChIP sequencing demonstrated active native promoters in all cases studied. Conclusions Despite frequent high level expression of ABCB1 in relapsed primary AML we found no evidence of ABCB1 translocations and instead confirmed high-level activity of native ABCB1 promoters, consistent with endogenous regulation.

This study shows that cerebellar molecular layer interneurons (MLIs) develop responses encoding for identity of the stimulus in an associative learning task. Chemogenetic inhibition of MLIs decreased the ability of mice to discriminate stimuli suggesting that MLIs encode for stimulus valence.

Abstract Background Hand function is often impaired after stroke, strongly affecting the ability to perform daily activities. Upper limb robotic devices have been developed to complement rehabilitation therapy offered to persons who suffered a stroke, but they rarely focus on the training of hand sensorimotor function. The primary goal of this study was to evaluate whether robot-assisted therapy of hand function following a neurocognitive approach (i.e., combining motor training with somatosensory and cognitive tasks) produces an equivalent decrease in upper limb motor impairment compared to dose-matched conventional neurocognitive therapy, when embedded in the rehabilitation program of inpatients in the subacute stage after stroke. Methods A parallel-group, randomized controlled trial was conducted on subjects with subacute stroke receiving either conventional or robot-assisted neurocognitive hand therapy using a haptic device. Therapy was provided for 15, 45-min sessions over four weeks, nested within the standard therapy program. Primary outcome was the change from baseline in the upper extremity part of the Fugl-Meyer Assessment (FMA-UE) after the intervention, which was compared between groups using equivalence testing. Secondary outcome measures included upper limb motor, sensory and cognitive assessments, delivered therapy dose, as well as questionnaires on user technology acceptance. Results Thirty-three participants with stroke were enrolled. 14 subjects in the robot-assisted and 13 subjects in the conventional therapy group completed the study. At the end of intervention, week 8 and week 32, the robot-assisted/conventional therapy group improved by 7.14/6.85, 7.79/7.31, and 8.64/8.08 points on the FMA-UE, respectively, establishing that motor recovery in the robot-assisted group is non-inferior to that in the control group. Conclusions Neurocognitive robot-assisted therapy of hand function allows for a non-inferior motor recovery compared to conventional dose-matched neurocognitive therapy when performed during inpatient rehabilitation in the subacute stage. This allows the early familiarization of subjects with stroke to the use of such technologies, as a first step towards minimal therapist supervision in the clinic, or directly at home after hospital discharge, to help increase the dose of hand therapy for persons with stroke. Trial registration EUDAMED database (CIV-13-02-009921), clinicaltrials.gov (NCT02096445). Registered 26 March 2014 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02096445

Este artigo tem como objetivo refletir sobre a questão da moradia entre imigrantes bolivianos em São Paulo, buscando investigar até que ponto existe uma correlação entre a “ilusão do provisório” – inerente à condição do imigrante (Sayad, 1998) – e as formas precárias de habitar na cidade. Tais formas podem ser definidas como moradias da pobreza e (ou) “nomadismo urbano” (Véras, 2003b; 2016a). A pesquisa, utilizando-se da combinação de método qualitativo, pelas entrevistas com bolivianos (nos bairros do Brás e Grajaú), e o quantitativo, por meio de levantamento dos dados de Censos Demográficos do IBGE, indica uma interdependência entre as formas precárias de habitar dos bolivianos e a ideia de provisoriedade que eles têm de sua permanência no país.

Machine learning (ML) is largely used to develop automatic predictors in migraine classification but automatic predictors for medication overuse (MO) in migraine are still in their infancy. Thus, to understand the benefits of ML in MO prediction, we explored an automated predictor to estimate MO risk in migraine. To achieve this objective, a study was designed to analyze the performance of a customized ML-based decision support system that combines support vector machines and Random Optimization (RO-MO). We used RO-MO to extract prognostic information from demographic, clinical and biochemical data. Using a dataset of 777 consecutive migraine patients we derived a set of predictors with discriminatory power for MO higher than that observed for baseline SVM. The best four were incorporated into the final RO-MO decision support system and risk evaluation on a five-level stratification was performed. ROC analysis resulted in a c-statistic of 0.83 with a sensitivity and specificity of 0.69 and 0.87, respectively, and an accuracy of 0.87 when MO was predicted by at least three RO-MO models. Logistic regression analysis confirmed that the derived RO-MO system could effectively predict MO with ORs of 5.7 and 21.0 for patients classified as probably (3 predictors positive), or definitely at risk of MO (4 predictors positive), respectively. In conclusion, a combination of ML and RO – taking into consideration clinical/biochemical features, drug exposure and lifestyle – might represent a valuable approach to MO prediction in migraine and holds the potential for improving model precision through weighting the relative importance of attributes.

The discrete Fourier transform (DFT) is widely employed for multi-beam digital beamforming. The DFT can be efficiently implemented through the use of fast Fourier transform (FFT) algorithms, thus reducing chip area, power consumption, processing time, and consumption of other hardware resources. This paper proposes three new hybrid DFT 1024-point DFT approximations and their respective fast algorithms. These approximate DFT (ADFT) algorithms have significantly reduced circuit complexity and power consumption compared to traditional FFT approaches while trading off a subtle loss in computational precision which is acceptable for digital beamforming applications in RF antenna implementations. ADFT algorithms have not been introduced for beamforming beyond N = 32, but this paper anticipates the need for massively large adaptive arrays for future 5G and 6G systems. Digital CMOS circuit designs for the ADFTs show the resulting improvements in both circuit complexity and power consumption metrics. Simulation results show similar or lower critical path delay with up to 48.5% lower chip area compared to a standard Cooley-Tukey FFT. The time-area and dynamic power metrics are reduced up to 66.0%. The 1024-point ADFT beamformers produce signal-to-noise ratio (SNR) gains between 29.2-30.1 dB, which is a loss of ≤ 0.9 dB SNR gain compared to exact 1024-point DFT beamformers (worst case) realizable at using an FFT.

Over 50% of the world population is at risk of mosquito-borne diseases. Female Ae. aegypti mosquito species transmit Zika, Dengue, and Chikungunya. The spread of these diseases correlate positively with the vector population, and this population depends on biotic and abiotic environmental factors including temperature, vegetation condition, humidity and precipitation. To combat virus outbreaks, information about vector population is required. To this aim, Earth observation (EO) data provide fast, efficient and economically viable means to estimate environmental features of interest. In this work, we present a temporal distribution model for adult female Ae. aegypti mosquitoes based on the joint use of the Normalized Difference Vegetation Index, the Normalized Difference Water Index, the Land Surface Temperature (both at day and night time), along with the precipitation information, extracted from EO data. The model was applied separately to data obtained during three different vector control and field data collection condition regimes, and used to explain the differences in environmental variable contributions across these regimes. To this aim, a random forest (RF) regression technique and its nonlinear features importance ranking based on mean decrease impurity (MDI) were implemented. To prove the robustness of the proposed model, other machine learning techniques, including support vector regression, decision trees and k-nearest neighbor regression, as well as artificial neural networks, and statistical models such as the linear regression model and generalized linear model were also considered. Our results show that machine learning techniques perform better than linear statistical models for the task at hand, and RF performs best. By ranking the importance of all features based on MDI in RF and selecting the subset comprising the most informative ones, a more parsimonious but equally effective and explainable model can be obtained. Moreover, the results can be empirically interpreted for use in vector control activities.

Specific microRNAs expressions may accurately characterize different stages of canine myxomatous mitral valve disease. This preliminary pilot study aimed to (1) describe the clinical and echocardiographic parameters of Cavalier King Charles Spaniels affected by myxomatous mitral valve disease at different American College of Veterinary Internal Medicine (ACVIM) stages (B1, B2 and C) and healthy control group (ACVIM A), comparing the parameters collected during the first examination (T0) and the end of the follow-up (T1); (2) assess the association between the values of echocardiographic parameters at T1 and the expression profile of miR-30b-5p at T0. Thirty-five Cavalier King Charles Spaniels (median age 4.29 years and median weight 9 Kg) in different ACVIM stages were included (7 A, 19 B1, 6 B2 and 3 C). Inverse probability weighting analysis was performed to estimate the association of the exposure variable (miR-30b-5p) with the outcome variables (clinical and echocardiographic variables). Time was included as variable. The results pointed out that high levels of plasma miR-30b-5p corresponded to lower values of left ventricular end-diastolic diameter normalized for body weight, end-diastolic and end-systolic volumes indexed for body weight, and left atrium-to aortic root ratio. Hence, higher miR-30b-5p expressions were associated with milder forms of mitral valve disease in our study population. In contrast, the results obtained for the intensity of heart murmur, the mitral regurgitation severity, and the Mitral INsufficiency Echocardiographic score) were not statistically significant. A relationship between high abundance of miR-30b-5p and myxomatous mitral valve disease that appear echocardiographically more stable over time has been demonstrated. In conclusion, Cavalier King Charles Spaniels affected by myxomatous mitral valve disease that at the first cardiologic evaluation showed an upregulation of miR-30b-5p are expected to experience lesser variations on their echocardiographic examination between T0 and T1.

Major Depressive Disorder (MDD) is a disabling illness affecting more than 5% of the elderly population. Higher female prevalence and sex-specific symptomatology have been observed, suggesting that biologically-determined dimensions might affect the disease onset and outcome. Rumination and executive dysfunction characterize adult-onset MDD, but sex differences in these domains and in the related brain mechanisms are still largely unexplored. The present pilot study aimed to explore any interactions between adult-onset MDD and sex on brain morphology and brain function during a Go/No-Go paradigm. We hypothesized to detect diagnosis by sex effects on brain regions involved in self-referential processes and cognitive control. Twenty-four subjects, 12 healthy (HC) (mean age 68.7 y, 7 females and 5 males) and 12 affected by adult-onset MDD (mean age 66.5 y, 5 females and 7 males), underwent clinical evaluations and a 3T magnetic resonance imaging (MRI) session. Diagnosis and diagnosis by sex effects were assessed on regional gray matter (GM) volumes and task-related functional MRI (fMRI) activations. The GM volume analyses showed diagnosis effects in left mid frontal cortex (p < 0.01), and diagnosis by sex effects in orbitofrontal, olfactory, and calcarine regions (p < 0.05). The Go/No-Go fMRI analyses showed MDD effects on fMRI activations in left precuneus and right lingual gyrus, and diagnosis by sex effects on fMRI activations in right parahippocampal gyrus and right calcarine cortex (p < 0.001, ≥ 40 voxels). Our exploratory results suggest the presence of sex-specific brain correlates of adult-onset MDD–especially in regions involved in attention processing and in the brain default mode–potentially supporting cognitive and symptom differences between sexes.

Psychosomatic syndromes have emerged as an important source of comorbidity in cardiac patients and have been associated with increased risk for adverse outcomes in patients with heart failure (HF). Understanding of the mechanisms underlying this connection is limited, however immune activity represents a possible pathway. While there have been numerous studies connecting immune activity to psychosomatic psychopathology, there is a lack of research on patients with HF. We examined forty-one consecutive outpatients affected by HF. We assessed psychosomatic psychopathology using the Diagnostic Criteria for Psychosomatic Research (DCPR) and the Patient Health Questionnaire-15 (PHQ-15). The Psychosocial Index (PSI) was used for assessing stress and psychosocial dimensions. Depression was evaluated with Beck Depression Inventory-II (BDI-II). Circulating levels of proinflammatory cytokines IL-6 and TNF-alpha were ascertained. Univariate and multivariable regression models were used to test for associations between inflammatory cytokines and psychosomatic psychopathology (i.e., DCPR syndromes, PHQ-15) and psychological dimensions (i.e., BDI-II, PSI). A significant positive correlation was found between IL-6 levels and psychosomatic psychopathology even when controlling for any confounding variables (i.e., Body-mass index (BMI), New York Heart Association (NYHA) class, smoking habits, alcohol consumption, statin use, aspirin use, beta blockers use, age, and gender). In contrast, the associations between TNF-alpha levels were non-significant. These findings can contribute to research in support of a psychoneuroimmune connection between psychosomatic psychopathology and HF. Findings also suggest the possibility that elevated IL-6 levels are more relevant for the pathogenesis of psychosomatic syndromes than for depression in patients with HF.

Transposable elements (TEs) constitute a considerable fraction of eukaryote genomes representing a major source of genetic variability. We describe two DNA sequences isolated in the lizard Zootoca vivipara, here named Zv516 and Zv817. Both sequences are single-copy nuclear sequences, including a truncation of two transposable elements (TEs), SINE Squam1 in Zv516 and a Tc1/Mariner-like DNA transposon in Zv817. FISH analyses with Zv516 showed the occurrence of interspersed signals of the SINE Squam1 sequence on all chromosomes of Z. vivipara and quantitative dot blot indicated that this TE is present with about 4700 copies in the Z. vivipara genome. FISH and dot blot with Zv817 did not produce clear hybridization signals. Bioinformatic analysis showed the presence of active SINE Squam 1 copies in the genome of different lacertids, in different mRNAs, and intronic and coding regions of various genes. The Tc1/Mariner-like DNA transposon occurs in all reptiles, excluding Sphenodon and Archosauria. Zv817 includes a trait of 284 bp, representing an amniote ultra-conserved element (UCE). Using amniote UCE homologous sequences from available whole genome sequences of major amniote taxonomic groups, we performed a phylogenetic analysis which retrieved Prototheria as the sister group of Metatheria and Eutheria. Within diapsids, Testudines are the sister group to Aves + Crocodylia (Archosauria), and Sphenodon is the sister group to Squamata. Furthermore, large trait regions flanking the UCE are conserved at family level.

Quantum gravity effects in effective models of loop quantum gravity, such as loop quantum cosmology, are encoded in the choice of so-called polymerisation schemes. Physical viability of the models, such as an onset of quantum effects at curvature scales near the Planck curvature, severely restricts the possible choices. An alternative point of view on the choice of polymerisation scheme is to choose adapted variables so that the scheme is the simplest possible one, known as μ0-scheme in loop quantum cosmology. There, physically viable models with μ0-scheme polymerise the Hubble rate b that is directly related to the Ricci scalar and the matter energy density on-shell. Consequently, the onset of quantum effects depends precisely on those parameters. In this letter, we construct similar variables for black to white hole transitions modelled using the description of the Schwarzschild interior as a Kantowski-Sachs cosmology. The resulting model uses the μ0-scheme and features sensible physics for a broad range of initial conditions (= choices of black and white hole masses) and favours symmetric transitions upon invoking additional qualitative arguments. The resulting Hamiltonian is very simple and at most quadratic in its arguments, allowing for a straightforward quantisation.

The irrigation management practices by the producers of industrial tomatoes have been done in an empirical way, which can harm the crop yield and the water resources. Thus, this study aimed to analyze water use, comparing the irrigation management that the producer uses with what should be carried out in the cycle of industrial tomatoes in Goiás. For this purpose, fourteen industrial tomato production areas were monitored during the 2018, 2019, and 2020 harvest. The applied irrigation depths were recorded using rain gauges installed in the cultivation areas. The water demands were estimated from the crop coefficients recommended by Embrapa and by the reference evapotranspiration according to the Penman-Monteith Model, obtained from meteorological data from stations installed in loco. The results showed that water demands ranged from 269.2 to 422.6 mm between 109 and 131 days of the cycle. The diagnosis revealed that there were errors in the irrigation management in all evaluated areas when analyzing the total water applied in the cycle. The average error was 83.3 mm for excess (57% of areas) and 31.1 mm for deficit (43% of areas). The phenological cycle of the crop was divided into four phases. On average, there was excess in two phases, error for the deficit in one phase, and correct irrigation in other. In phase I, there was 35.7% correct irrigation, 50% (35.0 mm) of error for excess, and 14.3% (17.9 mm) of error for the deficit. In phase II, 14.3% of correct irrigation were observed, 85.7% (46.9 mm) of error for excess. In phase III, there was 7.1% of correct irrigation, 14.3% (44.7 mm) of error for excess, and 78.6% (38.2 mm) of error for the deficit. There was 21.4% correct irrigation in phase IV, 42.9% (44.8 mm) of error for excess, and 35.7% (22.1 mm) of error for the deficit.

Group 2 innate lymphoid cells (ILC2s) are tissue resident in the lung and activated by inhaled allergens via epithelial-derived alarmins including IL-33. Activated ILC2s proliferate, produce IL-5 and IL-13, and induce eosinophilic inflammation. Here, we report that intranasal IL-33 or the protease allergen papain administration resulted in increased numbers of ILC2s not only in the lung but also in peripheral blood and liver. Analyses of IL-33 treated parabiosis mice showed that the increase in lung ILC2s was due to proliferation of lung resident ILC2s, whereas the increase in liver ILC2s was due to the migration of activated lung ILC2s. Lung-derived ILC2s induced eosinophilic hepatitis and expression of fibrosis-related genes. Intranasal IL-33 pre-treatment also attenuated concanavalin A-induced acute hepatitis and cirrhosis. These results suggest that activated lung resident ILC2s emigrate from the lung, circulate, settle in the liver and promote type 2 inflammation and attenuate type 1 inflammation.