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Hemocytes limit the capacity of mosquitoes to transmit human pathogens. Here we profile the transcriptomes of 8506 hemocytes of Anopheles gambiae and Aedes aegypti mosquito vectors. Our data reveal the functional diversity of hemocytes, with different subtypes of granulocytes expressing distinct and evolutionarily conserved subsets of effector genes. A previously unidentified cell type in An. gambiae , which we term "megacyte," is defined by a specific transmembrane protein marker (TM7318) and high expression of lipopolysaccharide-induced tumor necrosis factor-α transcription factor 3 (LL3). Knockdown experiments indicate that LL3 mediates hemocyte differentiation during immune priming. We identify and validate two main hemocyte lineages and find evidence of proliferating granulocyte populations. This atlas of medically relevant invertebrate immune cells at single-cell resolution identifies cellular events that underpin mosquito immunity to malaria infection., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Here, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas "immune" stromal cells are observed in early tumors, "contractile" cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR + macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune cells are characterized by diversity, specificity, plasticity, and adaptability-properties that enable them to contribute to homeostasis and respond specifically and dynamically to the many threats encountered by the body. Single-cell technologies, including the assessment of transcriptomics, genomics, and proteomics at the level of individual cells, are ideally suited to studying these properties of immune cells. In this review we discuss the benefits of adopting single-cell approaches in studying underappreciated qualities of immune cells and highlight examples where these technologies have been critical to advancing our understanding of the immune system in health and disease.

Cell-cell communication mediated by ligand-receptor complexes is critical to coordinating diverse biological processes, such as development, differentiation and inflammation. To investigate how the context-dependent crosstalk of different cell types enables physiological processes to proceed, we developed CellPhoneDB, a novel repository of ligands, receptors and their interactions. In contrast to other repositories, our database takes into account the subunit architecture of both ligands and receptors, representing heteromeric complexes accurately. We integrated our resource with a statistical framework that predicts enriched cellular interactions between two cell types from single-cell transcriptomics data. Here, we outline the structure and content of our repository, provide procedures for inferring cell-cell communication networks from single-cell RNA sequencing data and present a practical step-by-step guide to help implement the protocol. CellPhoneDB v.2.0 is an updated version of our resource that incorporates additional functionalities to enable users to introduce new interacting molecules and reduces the time and resources needed to interrogate large datasets. CellPhoneDB v.2.0 is publicly available, both as code and as a user-friendly web interface; it can be used by both experts and researchers with little experience in computational genomics. In our protocol, we demonstrate how to evaluate meaningful biological interactions with CellPhoneDB v.2.0 using published datasets. This protocol typically takes ~2 h to complete, from installation to statistical analysis and visualization, for a dataset of ~10 GB, 10,000 cells and 19 cell types, and using five threads.

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

In this work, magnetic and optical properties of magnetic nanoparticles were investigated, where the particles of iron oxide were prepared with a co-precipitation route and the component of gold was built up by reduction of AuCl 4- on the surface of iron oxide to assemble nanocomposite structures in the form of an electrostatic stabilized suspension. The size of the particles obtained with TEM increased from of 8.9 ± 2.7 to 16 ± 6 nm after the procedure of hybridisation. In order to distinguish the impact of the gold on the optical properties, UV-Vis and Raman spectroscopy techniques were used. Magnetic properties were studied in the temperature range of 5-300 K and the superparamagnetic state of MNPs at room temperature was confirmed for both systems.

Human lungs enable efficient gas exchange and form an interface with the environment, which depends on mucosal immunity for protection against infectious agents. Tightly controlled interactions between structural and immune cells are required to maintain lung homeostasis. Here, we use single-cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in healthy lungs, and lower airways in asthmatic lungs. We report location-dependent airway epithelial cell states and a novel subset of tissue-resident memory T cells. In the lower airways of patients with asthma, mucous cell hyperplasia is shown to stem from a novel mucous ciliated cell state, as well as goblet cell hyperplasia. We report the presence of pathogenic effector type 2 helper T cells (T H 2) in asthmatic lungs and find evidence for type 2 cytokines in maintaining the altered epithelial cell states. Unbiased analysis of cell-cell interactions identifies a shift from airway structural cell communication in healthy lungs to a T H 2-dominated interactome in asthmatic lungs.

During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.

Analyzing mouse tumor models in vivo, human T cells ex vivo, and human lung cancer samples, we provide direct evidence that NR2F6 acts as an immune checkpoint. Genetic ablation of Nr2f6, particularly in combination with established cancer immune checkpoint blockade, efficiently delays tumor progression and improves survival in experimental mouse models. The target genes deregulated in intratumoral T lymphocytes upon genetic ablation of Nr2f6 alone or together with PD-L1 blockade reveal multiple advantageous transcriptional alterations. Acute Nr2f6 silencing in both mouse and human T cells induces hyper-responsiveness that establishes a non-redundant T-cell-inhibitory function of NR2F6. NR2F6 protein expression in T-cell-infiltrating human NSCLC is upregulated in 54% of the cases (n = 303) and significantly correlates with PD-1 and CTLA-4 expression. Our data define NR2F6 as an intracellular immune checkpoint that suppresses adaptive anti-cancer immune responses and set the stage for clinical validation of targeting NR2F6 for next-generation immuno-oncological regimens.

The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates immunoediting. The immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure.

Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape in solid cancers. We then discuss the importance of neoantigens for cancer immunotherapy using checkpoint blockers, vaccination, and adoptive T-cell transfer. Finally, we give an overview over emerging aspects in cancer immunity, including tumor heterogeneity and immunoediting, and give an outlook on future prospects.

The Cancer Genome Atlas revealed the genomic landscapes of human cancers. In parallel, immunotherapy is transforming the treatment of advanced cancers. Unfortunately, the majority of patients do not respond to immunotherapy, making the identification of predictive markers and the mechanisms of resistance an area of intense research. To increase our understanding of tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers and created The Cancer Immunome Atlas (https://tcia.at/). Cellular characterization of the immune infiltrates showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning, we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts. Our findings and this resource may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pepper & Nettle describe possible processes underlying what they call a behavioral constellation of deprivation (BCD). Although we are certain about the application of evolutionary models to our understanding of poverty, we are less certain about the utility of behavioral constellations. The empirical record on poverty-related behaviors is much more divergent and broad than such constellations suggest.

Objective: To study the capabilities of a procedure for sonotomography (STG) versus that of X-ray mammography (MG) in patients from different age groups who have different radiological types of the breast structure and to estimate the diagnostic possibilities of the STF and X-ray MG procedures in detecting cancer in patients its the X-ray dense background., Materials and Methods: The investigation enrolled 143 patients aged 38 to 77 years who had undergone STG after primary X-ray MG. Particular emphasis was placed on a methodological approach to optimizing STG in patients from different age groups with a varying radiological type of the breast structure in different physiological periods. The international breast imaging and reporting data system was used to standardize detected breast masses., Results: Out of the 143 patients, 102 persons, including 16 patients with verified breast cancer (BC), were found to have space-occupying lesions. During the performed investigation, computed processing of 3D scans at the working station confirmed the entire quadrant-by-consentaneity of the glandular structure of the breast at STG and X-ray MG. There were a higher proportion of abnormal breast masses with increased percentage ratio of glandular tissue in the breast. Emphasis was laid on the role of STG as an additional examination technique in patients from all age groups with the radiologically dense breast in order to detect cancer due to a high sensitivity of 100% and a specificity of 96%., Conclusion: The procedure of STG versus that of X-ray MS showed a high degree of compatibility of opinions as to the type of the breast structure in the patients. Due to the fact that standard-projection STG scans can be compared, during mammography the procedure of STG must hold a firm place in the examination algorithm of the breast in women with its X-ray dense structure.

The possibility of remotely inducing a defined effect on NPs by means of electromagnetic radiation appears attractive. From a practical point of view, this effect opens horizons for remote control of drug release systems, as well as modulation of biochemical functions in cells. Gold-coated magnetite nanoparticles are perfect candidates for such application. Herein, we have successfully synthesized core-shell NPs having magnetite cores and gold shells modified with various sulphur containing ligands and developed a new, simple and robust procedure for the purification of the resulting nanoparticles. The carboxylic groups displayed at the surface of the NPs were utilized for NP conjugation with a model enzyme (ChT). In the present study, we report the effect of the low-frequency AC magnetic field on the catalytic activity of the immobilized ChT. We show that the enzyme activity decreases upon exposure of the NPs to the field., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Recent advances in genome sequencing technologies provide unprecedented opportunities to characterize individual genomic landscapes and identify mutations relevant for diagnosis and therapy. Specifically, whole-exome sequencing using next-generation sequencing (NGS) technologies is gaining popularity in the human genetics community due to the moderate costs, manageable data amounts and straightforward interpretation of analysis results. While whole-exome and, in the near future, whole-genome sequencing are becoming commodities, data analysis still poses significant challenges and led to the development of a plethora of tools supporting specific parts of the analysis workflow or providing a complete solution. Here, we surveyed 205 tools for whole-genome/whole-exome sequencing data analysis supporting five distinct analytical steps: quality assessment, alignment, variant identification, variant annotation and visualization. We report an overview of the functionality, features and specific requirements of the individual tools. We then selected 32 programs for variant identification, variant annotation and visualization, which were subjected to hands-on evaluation using four data sets: one set of exome data from two patients with a rare disease for testing identification of germline mutations, two cancer data sets for testing variant callers for somatic mutations, copy number variations and structural variations, and one semi-synthetic data set for testing identification of copy number variations. Our comprehensive survey and evaluation of NGS tools provides a valuable guideline for human geneticists working on Mendelian disorders, complex diseases and cancers.

In the context of translational and clinical oncology, mathematical models can provide novel insights into tumor-related processes and can support clinical oncologists in the design of the treatment regime, dosage, schedule, toxicity and drug-sensitivity. In this review we present an overview of mathematical models in this field beginning with carcinogenesis and proceeding to the different cancer treatments. By doing so we intended to highlight recent developments and emphasize the power of such theoretical work.We first highlight mathematical models for translational oncology comprising epidemiologic and statistical models, mechanistic models for carcinogenesis and tumor growth, as well as evolutionary dynamics models which can help to describe and overcome a major problem in the clinic: therapy resistance. Next we review models for clinical oncology with a special emphasis on therapy including chemotherapy, targeted therapy, radiotherapy, immunotherapy and interaction of cancer cells with the immune system.As evident from the published studies, mathematical modeling and computational simulation provided valuable insights into the molecular mechanisms of cancer, and can help to improve diagnosis and prognosis of the disease, and pinpoint novel therapeutic targets.

Recent mechanistic insights obtained from preclinical studies and the approval of the first immunotherapies has motivated increasing number of academic investigators and pharmaceutical/biotech companies to further elucidate the role of immunity in tumor pathogenesis and to reconsider the role of immunotherapy. Additionally, technological advances (e.g., next-generation sequencing) are providing unprecedented opportunities to draw a comprehensive picture of the tumor genomics landscape and ultimately enable individualized treatment. However, the increasing complexity of the generated data and the plethora of bioinformatics methods and tools pose considerable challenges to both tumor immunologists and clinical oncologists. In this review, we describe current concepts and future challenges for the management and analysis of data for cancer immunology and immunotherapy. We first highlight publicly available databases with specific focus on cancer immunology including databases for somatic mutations and epitope databases. We then give an overview of the bioinformatics methods for the analysis of next-generation sequencing data (whole-genome and exome sequencing), epitope prediction tools as well as methods for integrative data analysis and network modeling. Mathematical models are powerful tools that can predict and explain important patterns in the genetic and clinical progression of cancer. Therefore, a survey of mathematical models for tumor evolution and tumor-immune cell interaction is included. Finally, we discuss future challenges for individualized immunotherapy and suggest how a combined computational/experimental approaches can lead to new insights into the molecular mechanisms of cancer, improved diagnosis, and prognosis of the disease and pinpoint novel therapeutic targets.

Equilibrium model is based on the hypothesis of sorptive mechanisms of absorption of chemical elements in the soil solid phase-soil solution-plant system. The characteristics of the model are in the line with basic experimental relationships: dependence of concentrations of radionuclides or heavy metals in plant on: a) concentration of radionuclides or heavy metals in soil; b) sorptive capacity of plant; c) concentration of macro element-analogue in soil; d) soil fertility. The accumulation of elements by plants depends on ratio of cation capacities of plant and soil as well as the ratio of sorption-desorption of an element in the soil solid phase (plant)-soil solution system.

54 patients, 24 men and 30 women, (mean age 27 years) were examined. Two types of obsessive-phobic disorders with the phenomena of mysophobia were distinguished: obsession of the external (extracorporal) threat and obsession of contamination. Disorders of the first type (25 cases) were observed in psychopathic-like schizophrenia. They were characterized by a fear of possible contacts with different pathogenic agents--toxic substances, sharp small subjects, bacteria. Obsessions presented with a system of actions preventing phobic situations (rituals). With progression of the disease there was a decrease of both the degree and affective saturation of phobic disorders together with preserving rituals. Negative disorders presented with rough psychopathic-like changes with features of the "verschroben" defect. The disorders of the second type (29 patients) were observed in neurosis-like schizophrenia. Mysophobia manifested with both the repeated control and the fear of contamination accomplished. Ritual behavior presented with repeated actions and repeated control of the "sterility" of the own body and the surrounding subjects. Dynamics of these disorders was characterized by a tendency to more severe rituals of the control and persisting anxiety. Deficit disorders manifested with mental infantilism with psychopathic-like disorders of schizo-anancastic sphere. The above types of the obsessive-phobic disorders have a differential-diagnostic significance in respect of clinical variations of schizophrenia and determination of the state acuity with possible reversibility of the disorders (in neurosis-like schizophrenia).

The interaction between analogous elements K and 134Cs in the system "peat-soil-plant" was investigated. The values of some parameters of sorption model for uptake of radionuclides by plants from soil were determined. An attempt to interpret the processes going on in the studied system under pot experiment from the viewpoint of soil chemistry was done. Two intervals of potassium concentration in peat-soil were displayed, with different effect on 134Cs uptake by plants.

The three-chamber model of radionuclides uptake from soil was proposed. This model permit to analyse the transfer factors as the function of the some properties of the radionuclides, macroelement-analogs, soil and plants. The field experiment results (Novozybkov District) was analysed. In this experiment the uptake 137Cs in Bromopsis inermis L. from peat soil under increasing K- and N-fertilizer doses was investigated.