Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer.

Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.

Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion.

Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.

Transcriptional and Functional Analysis of CD1c+ Human Dendritic Cells Identifies a CD163+ Subset Priming CD8+CD103+ T Cells.

Dendritic cells (DCs) are antigen-presenting cells controlling T cell activation. In humans, the diversity, ontogeny, and functional capabilities of DC subsets are not fully understood. Here, we identified circulating CD88-CD1c+CD163+ DCs (called DC3s) as immediate precursors of inflammatory CD88-CD14+CD1c+CD163+FcεRI+ DCs. DC3s develop via a specific pathway activated by GM-CSF, independent of cDC-restricted (CDP) and monocyte-restricted (cMoP) progenitors. Like classical DCs but unlike monocytes, DC3s drove activation of naive T cells. In vitro, DC3s displayed a distinctive ability to prime CD8+ T cells expressing a tissue homing signature and the epithelial homing alpha-E integrin (CD103) through transforming growth factor ß (TGF-ß) signaling. In vivo, DC3s infiltrated luminal breast cancer primary tumors, and DC3 infiltration correlated positively with CD8+CD103+CD69+ tissue-resident memory T cells. Together, these findings define DC3s as a lineage of inflammatory DCs endowed with a strong potential to regulate tumor immunity.

Major environmental drivers determining life and death of cold-water corals through time.

Cold-water corals (CWCs) are the engineers of complex ecosystems forming unique biodiversity hotspots in the deep sea. They are expected to suffer dramatically from future environmental changes in the oceans such as ocean warming, food depletion, deoxygenation, and acidification. However, over the last decades of intense deep-sea research, no extinction event of a CWC ecosystem is documented, leaving quite some uncertainty on their sensitivity to these environmental parameters. Paleoceanographic reconstructions offer the opportunity to align the on- and offsets of CWC proliferation to environmental parameters. Here, we present the synthesis of 6 case studies from the North Atlantic Ocean and the Mediterranean Sea, revealing that food supply controlled by export production and turbulent hydrodynamics at the seabed exerted the strongest impact on coral vitality during the past 20,000 years, whereas locally low oxygen concentrations in the bottom water can act as an additional relevant stressor. The fate of CWCs in a changing ocean will largely depend on how these oceanographic processes will be modulated. Future ocean deoxygenation may be compensated regionally where the food delivery and food quality are optimal.

Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID-19 severity.

Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are several cyclins, cell division cycles, cyclin-dependent kinases, and mini-chromosome maintenance proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and natural killer cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention.

A systematic review of clinical trials for gene therapies for ß-hemoglobinopathy around the world.

BACKGROUND AIMS: Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for patients with transfusion-dependent ß-thalassemia (TDT) indicates the feasibility of gene therapy as curative for genetic hematologic disorders. This work analyzed the current-world scenario of clinical trials involving gene therapy for ß-hemoglobinopathies. METHODS: Eighteen trials for patients with sickle cell disease (SCD) and 24 for patients with TDT were analyzed. RESULTS: Most are phase 1 and 2 trials, funded by the industry and are currently recruiting volunteers. Treatment strategies for both diseases are fetal hemoglobin induction (52.4%); addition of wild-type or therapeutic ß-globin gene (38.1%) and correction of mutations (9,5%). Gene editing (52.4%) and gene addition (40.5%) are the two most used techniques. The United States and France are the countries with the greatest number of clinical trials centers for SCD, with 83.1% and 4.2%, respectively. The United States (41.1%), China (26%) and Italy (6.8%) lead TDT trials centers. CONCLUSIONS: Geographic trial concentration indicates the high costs of this technology, logistical issues and social challenges that need to be overcome for gene therapy to reach low- and middle-income countries where SCD and TDT are prevalent and where they most impact the patient's health.

Reproduction of Meloidogyne morocciensis (Tylenchida: Meloidogynidae) in weeds found in Brazil.

Weeds can be hosts of root-knot nematodes of the genus Meloidogyne. The importance of the species Meloidogyne morocciensis parasitizing many crops is recognized, but their reproductive capacity in weeds is not known. The present study hypothesizes the ability of M. morocciensis to parasitize and reproduce in different weed species found in Brazil. The objective was to evaluate the reproduction of M. morocciensis in 36 weed species. The plants were individually inoculated with 5,000 eggs and second stage juveniles and kept in greenhouse for 60 days. The experimental design was completely randomized with twelve replications. The root system of each plant was evaluated for gall index (GI), final nematode population (PF), number of nematode/g of root (NNGR) and reproduction factor (RF). It was verified that M. morocciensis has the capacity to parasite 36 weed species belonging to 16 different botanical families, confirming the hypothesis proposed. From the 36 species evaluated, 77.8% (28) were susceptible (FR ≥ 1.0) to M. morocciensis. The present study is the first to identify different weeds as hosts of M. morocciensis, evidencing its polyphagous habit, indicating species of plants with high capacity to multiply this nematode and that need more attention during the integrated management of these pathogen.

Edaphic fauna in soil profile after three decades of different soil management and cover crops in a subtropical region.

This research evaluated the effects of long-term (30 years) winter cover crops under conventional farming system and no-tillage system on edaphic fauna in a Rhodic Hapludox soil, from Paraná State, Brazil. We used three winter cover crops (black oat, hairy vetch and fallow), and as a reference a fragment of natural forest. Soil monoliths were collected at two times, one during the flowering of maize (April 2013) and the other during the flowering of soybean (January 2014). The extraction of the monoliths was carried out in three layers in the soil profile (0-10, 10-20 and 20-30 cm). Seventeen taxonomic groups were sampled. The density of the edaphic fauna is inversely related to soil depth. The winter crops associated with the no-tillage system in long-term resulted in fauna densities similar to the natural environment, with a higher density (density increase of 2.2x) at a depth of 10-20 cm in areas with black oat. At 0-10 cm depth, black oat and vetch under no-tillage systems resulted in an increase of 62% and 69% (April 2013) and 46 and 44% (January 2014), respectively, in the density of soil fauna, when compared to the same winter crops in conventional farming system.

Reproduction of Meloidogyne javanica in soybean genotypes.

Meloidogyne javanica is among the most important nematodes that damage soybean, and although genetic resistance is the ideal control measure, there are few cultivars described as resistant among those recommended for southern Brazil. The objective of this work was to evaluate the reaction of soybean cultivars to M. javanica. The inoculum of nematodes (Est. J3) was obtained from soybean plants and inoculated into tomato plants cultivar "Santa Cruz". Thirty-seven soybean cultivars widely used in the South, Southeast and Midwest of Brazil were used in the experiment. For each plant a suspension of 5,000 eggs + juveniles of second stage of M. javanica was inoculated into a sterile soil hole in 2-liter pots with six replications. The evaluation of root weight, number of galls, number of nematodes was 60 days after M. javanica inoculation. The results were subjected to analysis of variance, and the averages of each treatment were compared to each other by the Scott-Knott cluster test at 5% probability. Even though M. javanica presented RF> 1.00 in all soybean genotypes tested, different levels of susceptibility were observed. Thus, the lowest reproduction of the root-knot nematode was observed in M ​​5947 IPRO, HO AMAMBAY IPRO, BMX GARRA IPRO and FPS ATALANTA.

Distribution and invasion risk assessments of Chrysodeixis includens (Walker, [1858]) (Lepidoptera: Noctuidae) using CLIMEX.

Chrysodeixis includens is a polyphagous pest restricted to the American continent. The occurrence of C. includens is allied, among other factors, by favorable conditions such as temperature, humidity, presence of hosts, and migratory behavior. In this work, we built spatiotemporal species distribution models at continental and global levels for the distribution of C. includens using CLIMEX to determine times and regions favorable for year-round survival and migration of this species and in case of invasion on other continents to apply timely and right phytosanitary measures. Our models estimated high climate suitability for C. includens in Central and large proportions of South America throughout the year. Moreover, there is suitability for C. includens growth in all months of the year in Central and northern part of South America. In the northern hemisphere, these conditions range from April to October, while in mid-southern parts of South America, favorable periods comprise October through June. The countries with the highest suitability for C. includens outside the American continent are located on the African and Asian continents. Our results show variable climate suitability for C. includens during the year that help to understand likely migration pattern in North America. This information would direct efforts for appropriate C. includens management during warm and moist periods of the year. Furthermore, our models notify the need for the development of strategies for the inspection and interception of C. includens especially in central Africa, India, South and Southeast Asia, and Northeast Australia.

Non-invasive setup for grape maturation classification using deep learning.

BACKGROUND: The San Francisco Valley region from Brazil is known worldwide for its fruit production and exportation, especially grapes and wines. The grapes have high quality not only due to the excellent morphological characteristics, but also to the pleasant taste of their fruits. Such features are obtained because of the climatic conditions present in the region. In addition to the favorable climate for grape cultivation, harvesting at the right time interferes with fruit properties. RESULTS: This work aims to define grape maturation stage of Syrah and Cabernet Sauvignon cultivars with the aid of deep-learning models. The idea of working with these algorithms came from the fact that the techniques commonly used to find the ideal harvesting point are invasive, expensive, and take a long time to get their results. In this work, convolutional neural networks were used in an image classification system, in which grape images were acquired, preprocessed, and classified based on their maturation stage. Images were acquired with varying illuminants that were considered as parameters of the classification models, as well as the different post-harvesting weeks. The best models achieved maturation classification accuracy of 93.41% and 72.66% for Syrah and Cabernet Sauvignon respectively. CONCLUSIONS: It was possible to correctly classify wine grapes using computational intelligent algorithms with high accuracy, regarding the harvesting time, corroborating chemometric results. © 2020 Society of Chemical Industry.

Host status of morning-glory (Ipomoea spp.) to Meloidogyne species.

Weeds can be hosting and alternative multipliers of root-knot nematodes (Meloidogyne spp.). Among the main weeds, species of the genus Ipomoea stands out for their cosmopolitan presence and the negative impact on crops. In addition, they can behave as hosts and promote the reproduction of pests, diseases, and nematodes. However, the ability of Meloidogyne nematodes to infect morning-glory (Ipomoea spp.) is little understood. In this context, the objective was to evaluate the reproduction of M. arenaria, M. enterolobii, M. ethiopica, M. hapla, M. incognita, M. javanica, M. luci, and M. morocciensis in I. grandifolia, I. hederifolia, I. nil, I. purpurea, and I. quamoclit. Plants were individually inoculated with 5,000 eggs and second-stage juveniles and kept in a greenhouse for 60 days. The design was completely randomized with six repetitions. After this period, the root system of each plant was evaluated to gall index (IG) and reproduction factor (RF). It was verified that the eight species of Melodoigyne have the capacity to parasitize I. grandifolia, I. hederifolia, I. nil, I. purpurea, and I. quamoclit, showing the susceptibility of these weeds to the plant-parasitic nematodes. The highest RF were observed for M. enterolobii with values of 12.5 and 12.9 for I. quamoclit and I. hederifolia, respectively. While M. arenaria obtained the lowest values, with RF ≤ 4.0 for all species of Ipomoea. Thus, weed species of the Ipomoea genus are potential hosts and multipliers of root-knot nematodes, making it important to be considered in integrated management strategies for these plant-parasitic nematodes.

Mapping of the Steneotarsonemus spinki invasion risk in suitable areas for rice (Oryza sativa) cultivation using MaxEnt.

Rice is one of the most important socioeconomic crops in the world. The tarsonemid mite Steneotarsonemus spinki is one of the most destructive pests for this crop and is restricted to some regions of Asia and America. The aim of this work was to map the risk of S. spinki invasion in rice-growing areas in the world. Presence data of Oryza sativa and S. spinki obtained from the literature and bioclimatic parameters from WorldClim were analyzed in the MaxEnt program to generate suitability indices and distribution maps for each species and for the two species together. High annual mean temperature associated with low temperature annual range were the most important environmental variables for the occurrence of O. sativa and S. spinki, and low rainfall favoring S. spinki. The model indicates that there are climatic conditions for the establishment of S. spinki in important rice-producing regions, such as western and central Africa, Oceania, Asia, and North, Central, and South America. Our results are useful for the efficient establishment of phytosanitary measures to prevent the dispersal of S. spinki to new rice-producing areas.

Climate model for seasonal variation in Bemisia tabaci using CLIMEX in tomato crops.

The whitefly, Bemisia tabaci, is considered one of the most important pests for tomato Solanum lycopersicum. The population density of this pest varies throughout the year in response to seasonal variation. Studies of seasonality are important to understand the ecological dynamics and insect population in crops and help to identify which seasons have the best climatic conditions for the growth and development of this insect species. In this research, we used CLIMEX to estimate the seasonal abundance of a species in relation to climate over time and species geographical distribution. Therefore, this research is designed to infer the mechanisms affecting population processes, rather than simply provide an empirical description of field observations based on matching patterns of meteorological data. In this research, we identified monthly suitability for Bemisia tabaci, with the climate models, for 12 commercial tomato crop locations through CLIMEX (version 4.0). We observed that B. tabaci displays seasonality with increased abundance in tomato crops during March, April, May, June, October and November (first year) and during March, April, May, September and October (second year) in all monitored areas. During this period, our model demonstrated a strong agreement between B. tabaci density and CLIMEX weekly growth index (GIw), which indicates significant reliability of our model results. Our results may be useful to design sampling and control strategies, in periods and locations when there is high suitability for B. tabaci.

First report of Meloidogyne javanica (Nematoda: Meloidogynidae) infecting Scoparia dulcis, a medicinal plant in Brazil.

Medicinal plants Scoparia dulcis showing symptoms caused by root-knot nematodes were detected in the municipality of Cachoeira do Sul, Rio Grande do Sul State, Brazil. Based on the morphological, esterase phenotypes, and molecular analyses of the mitochondrial DNA region between the cytochome oxidase subunit II and 16S rRNA genes (mtDNA) and species-specific sequence characterized amplified region (SCAR), the causal agent of the observed symptoms was identified as Meloidogyne javanica. Pathogenicity was confirmed by fulfilling a modified version of Koch's postulates. To our knowledge, this is the first report of M. javanica infecting S. dulcis in Brazil.

Mechanisms of Resistance to Immune Checkpoint Antibodies.

Immunotherapy using checkpoint inhibitors has changed the way we treat several aggressive cancers such as melanoma, non-small cell lung and head & neck cancers, among others, with durable responses achieved in the metastatic setting. However, unfortunately, the vast majority of patients do not respond to checkpoint inhibition therapy and a minority of patients, who do respond to treatment, develop secondary resistance and experience relapse by mechanisms still inadequately understood. Emerging evidence shows that alterations in multiple signaling pathways are involved in primary and/or secondary resistance to checkpoint inhibition. In this review we discuss how selected cancer-cell autonomous cues may influence the outcome of cancer immunotherapy, particularly immune checkpoint inhibition.

Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ.

BACKGROUND: CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. OBJECTIVES: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. METHODS: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. RESULTS: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. CONCLUSION: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.

Integrated innate mechanisms involved in airway allergic inflammation to the serine protease subtilisin.

Proteases are recognized environmental allergens, but little is known about the mechanisms responsible for sensing enzyme activity and initiating the development of allergic inflammation. Because usage of the serine protease subtilisin in the detergent industry resulted in an outbreak of occupational asthma in workers, we sought to develop an experimental model of allergic lung inflammation to subtilisin and to determine the immunological mechanisms involved in type 2 responses. By using a mouse model of allergic airway disease, we have defined in this study that s.c. or intranasal sensitization followed by airway challenge to subtilisin induces prototypic allergic lung inflammation, characterized by airway eosinophilia, type 2 cytokine release, mucus production, high levels of serum IgE, and airway reactivity. These allergic responses were dependent on subtilisin protease activity, protease-activated receptor-2, IL-33R ST2, and MyD88 signaling. Also, subtilisin stimulated the expression of the proallergic cytokines IL-1α, IL-33, thymic stromal lymphopoietin, and the growth factor amphiregulin in a human bronchial epithelial cell line. Notably, acute administration of subtilisin into the airways increased lung IL-5-producing type 2 innate lymphoid cells, which required protease-activated receptor-2 expression. Finally, subtilisin activity acted as a Th2 adjuvant to an unrelated airborne Ag-promoting allergic inflammation to inhaled OVA. Therefore, we established a murine model of occupational asthma to a serine protease and characterized the main molecular pathways involved in allergic sensitization to subtilisin that potentially contribute to initiate allergic airway disease.

Toxicity of new pyrethroid in pest insects Asciamonuste and Diaphania hyalinata, predator Solenopsis saevissima and stingless bee Tetragonisca angustula.

There is increasing demand for new products for vegetable pest management. Thus, the aim of this study was to assess the toxicity of pyrethroids with acid moiety modifications to measure the insecticidal activity of these compounds on the lepidopteran vegetable pests Diaphania hyalinata (L.) (Lepidoptera: Pyralidae) and Asciamonuste (Latreille) (Lepidoptera: Pieridae) and evaluate their selectivity for the predatory ant Solenopsis saevissima (F. Smith) (Hymenoptera: Formicidae) and pollinator Tetragonisca angustula (Latreille) (Hymenoptera: Apidae: Meliponinae). Racemic mixtures of five new pyrethroids (30 µg molecule mg-1 insect body weight) resulted in high (100%) and rapid (stable LD50 after 12 h) mortality in D. hyalinata and A. monuste. In A. monuste, the trans-pyrethroid [12] isomer showed similar toxicity to permethrin. For D. hyalinata, the trans-pyrethroid [9] isomer and cis-pyrethroid [10] isomer were as toxic as permethrin. Due to their low selectivity, these new pyrethroids should be applied on the basis of ecological selectivity principles to minimize impacts on nontarget organisms S. saevissima and T. angustula.