Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC

DC Respond to Cognate T Cell Interaction in the Antigen-Challenged Lymph Node

Dendritic cells (DC) are unrivaled in their potential to prime naive T cells by presenting antigen and providing costimulation. DC are furthermore believed to decode antigen context by virtue of pattern recognition receptors and to polarize T cells through cytokine secretion toward distinct effector functions. Diverse polarized T helper (TH) cells have been explored in great detail. In contrast, studies of instructing DC have to date largely been restricted to in vitro settings or adoptively transferred DC. Here we report efforts to unravel the DC response to cognate T cell encounter in antigen-challenged lymph nodes (LN). Mice engrafted with antigen-specific T cells were immunized with nanoparticles (NP) entrapping adjuvants and absorbed with antigen to study the immediate DC response to T cell encounter using bulk and single cell RNA-seq profiling. NP induced robust antigen-specific TH1 cell responses with minimal bystander activation. Fluorescent-labeled NP allowed identification of antigen-carrying DC and focus on transcriptional changes in DC that encounter T cells. Our results support the existence of a bi-directional crosstalk between DC and T cells that promotes TH1 responses, including involvement of the ubiquitin-like molecule Isg15 that merits further study

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Summary Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans

A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim

GrassPlot - a database of multi-scale plant diversity in Palaearctic grasslands

GrassPlot is a collaborative vegetation-plot database organised by the Eurasian Dry Grassland Group (EDGG) and listed in the Global Index of Vegetation-Plot Databases (GIVD ID EU-00-003). GrassPlot collects plot records (releves) from grasslands and other open habitats of the Palaearctic biogeographic realm. It focuses on precisely delimited plots of eight standard grain sizes (0.0001; 0.001;... 1,000 m(2)) and on nested-plot series with at least four different grain sizes. The usage of GrassPlot is regulated through Bylaws that intend to balance the interests of data contributors and data users. The current version (v. 1.00) contains data for approximately 170,000 plots of different sizes and 2,800 nested-plot series. The key components are richness data and metadata. However, most included datasets also encompass compositional data. About 14,000 plots have near-complete records of terricolous bryophytes and lichens in addition to vascular plants. At present, GrassPlot contains data from 36 countries throughout the Palaearctic, spread across elevational gradients and major grassland types. GrassPlot with its multi-scale and multi-taxon focus complements the larger international vegetationplot databases, such as the European Vegetation Archive (EVA) and the global database " sPlot". Its main aim is to facilitate studies on the scale-and taxon-dependency of biodiversity patterns and drivers along macroecological gradients. GrassPlot is a dynamic database and will expand through new data collection coordinated by the elected Governing Board. We invite researchers with suitable data to join GrassPlot. Researchers with project ideas addressable with GrassPlot data are welcome to submit proposals to the Governing Board

Appendix S1

Appendix S1. Aligned sequences of ndhF (Matrix 1) and ITS (Matrix 2) genetic regions used to infer the phylogeny in Figure S1, including Genbank numbers. Sequences are in FASTA format

Tables S1-4

Table S1. A synthesis of taxa (species and genera) exhibiting ballistic–ant diplochory, collated from an exhaustive literature review. The list does not include plant genera for which we have only anecdotal reports. Table S2. Sampling information and dry mass of diaspore components for 90 Euphorbia species and Mercurialis annua (Euphorbiaceae). Table S3. Data of seed dispersal distance in ballochory and myrmecochory. Table S4. Data of seed dispersal distance and seed mass of diplochorous species

Figure S1

Figure S1. Phylogeny of the Euphorbia species used in this study for which sequence data are available

Trade-off or coordination? Correlations between ballochorous and myrmecochorous phases of diplochory

1.The combination of two dispersal syndromes (diplochory) brings additional benefits to seeds, yet the relative costs and benefits of the two phases are poorly understood. Our goal is to provide the first quantification to test the long-standing assumption that there are trade-offs between the two phases in ballistic–ant diplochory. 2.Dispersal investment data were empirically measured for 91 Euphorbiaceae species across different regions of the world. Dispersal distance data of ballochory (seed dispersal by explosion), myrmecochory (seed dispersal by ants) and diplochory were collated from the literature for 210 records (148 species from 44 families). The data were analysed using Model II regression, Kolmogorov–Smirnov test and t-test, complemented by phylogenetic comparative approaches. 3.Across diaspores of diplochorous species, the relative investment in myrmecochory increased more than that in ballochory. Fruit coat mass and elaiosome mass covaried in an allometric manner, regardless of seed mass. Diplochorous diaspores were significantly heavier than diaspores dispersed solely by ballochory. Dispersal distances of the two diplochorous phases were independent and comparable to that of sole ballochory or sole myrmecochory. 4.Our results do not support a trade-off, but a coordinated dispersal strategy between the two diplochorous phases. Large diaspores may evolve diplochory to overcome dispersal difficulties in term of dispersal distance. As the most comprehensive study of ballistic–ant diplochory, our findings advance the understanding of the relative importance of the two phases in diplochory. This article is protected by copyright. All rights reserved

Trade-off or coordination? Correlations between ballochorous and myrmecochorous phases of diplochory

1.The combination of two dispersal syndromes (diplochory) brings additional benefits to seeds, yet the relative costs and benefits of the two phases are poorly understood. Our goal is to provide the first quantification to test the long-standing assumption that there are trade-offs between the two phases in ballistic–ant diplochory. 2.Dispersal investment data were empirically measured for 91 Euphorbiaceae species across different regions of the world. Dispersal distance data of ballochory (seed dispersal by explosion), myrmecochory (seed dispersal by ants) and diplochory were collated from the literature for 210 records (148 species from 44 families). The data were analysed using Model II regression, Kolmogorov–Smirnov test and t-test, complemented by phylogenetic comparative approaches. 3.Across diaspores of diplochorous species, the relative investment in myrmecochory increased more than that in ballochory. Fruit coat mass and elaiosome mass covaried in an allometric manner, regardless of seed mass. Diplochorous diaspores were significantly heavier than diaspores dispersed solely by ballochory. Dispersal distances of the two diplochorous phases were independent and comparable to that of sole ballochory or sole myrmecochory. 4.Our results do not support a trade-off, but a coordinated dispersal strategy between the two diplochorous phases. Large diaspores may evolve diplochory to overcome dispersal difficulties in term of dispersal distance. As the most comprehensive study of ballistic–ant diplochory, our findings advance the understanding of the relative importance of the two phases in diplochory. This article is protected by copyright. All rights reserved