Semaphorin 6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs.

Regulated neural-metabolic-inflammatory responses are essential for maintaining physiological homeostasis. However, the molecular machinery that coordinates neural, metabolic, and inflammatory responses is largely unknown. Here, we show that semaphorin 6D (SEMA6D) coordinates anxiogenic, metabolic, and inflammatory outputs from the amygdala by maintaining synaptic homeostasis.

Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng.

Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1-NK cells in vivo, reducing tumor growth dependent on IFN-γ.

Regnase-1 D141N mutation induces CD4+ T cell-mediated lung granuloma formation via upregulation of Pim2.

Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases.

A universal tool for predicting differentially active features in single-cell and spatial genomics data.

With the growing complexity of single-cell and spatial genomics data, there is an increasing importance of unbiased and efficient exploratory data analysis tools. One common exploratory data analysis step is the prediction of genes with different levels of activity in a subset of cells or locations inside a tissue. We previously developed singleCellHaystack, a method for predicting differentially expressed genes from single-cell transcriptome data, without relying on comparisons between clusters of cells.

Intercellular crosstalk in adult dental pulp is mediated by heparin-binding growth factors Pleiotrophin and Midkine.

Background: In-depth knowledge of the cellular and molecular composition of dental pulp (DP) and the crosstalk between DP cells that drive tissue homeostasis are not well understood. To address these questions, we performed a comparative analysis of publicly available single-cell transcriptomes of healthy adult human DP to 5 other reference tissues: peripheral blood mononuclear cells, bone marrow, adipose tissue, lung, and skin.

Results: Our analysis revealed that DP resident cells have a unique gene expression profile when compared to the reference tissues, and that DP fibroblasts are the main cell type contributing to this expression profile.

Thyroid hormone regulators in human cerebral cortex development.

Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood-brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan-Herndon-Dudley syndrome, with altered thyroid hormone concentrations in the blood and profound neurological impairment and intellectual deficit.

Unbiased integration of single cell transcriptome replicates.

Single cell transcriptomic approaches are becoming mainstream, with replicate experiments commonly performed with the same single cell technology. Methods that enable integration of these datasets by removing batch effects while preserving biological information are required for unbiased data interpretation. Here, we introduce Canek for this purpose.

Single-Cell Transcriptome Profiling of Thyroid Hormone Effectors in the Human Fetal Neocortex: Expression of , , and in Specific Cell Types.

Thyroid hormones are crucial for brain development, acting through the thyroid hormone nuclear receptors (TR)α1 and β to control gene expression. Triiodothyronine (T3), the receptor-ligand, is transported into the brain from the blood by the monocarboxylate transporter 8 (MCT8). Another source of brain T3 is from the local deiodination of thyroxine (T4) by type 2 deiodinase (DIO2).

A clustering-independent method for finding differentially expressed genes in single-cell transcriptome data.

A common analysis of single-cell sequencing data includes clustering of cells and identifying differentially expressed genes (DEGs). How cell clusters are defined has important consequences for downstream analyses and the interpretation of results, but is often not straightforward. To address this difficulty, we present singleCellHaystack, a method that enables the prediction of DEGs without relying on explicit clustering of cells.

Methods for sequence and structural analysis of B and T cell receptor repertoires.

B cell receptors (BCRs) and T cell receptors (TCRs) make up an essential network of defense molecules that, collectively, can distinguish self from non-self and facilitate destruction of antigen-bearing cells such as pathogens or tumors. The analysis of BCR and TCR repertoires plays an important role in both basic immunology as well as in biotechnology. Because the repertoires are highly diverse, specialized software methods are needed to extract meaningful information from BCR and TCR sequence data.

Quality of life, functional impairment and social factors as determinants of nutritional status in older adults: The VERISAÚDE study.

Background & Aims: Malnutrition is an important and growing health problem in elderly people. The main aim of this research was to examine the relationship between socio-demographic factors, social resources, functional status and quality of life and malnutrition or risk of malnutrition in elders.

Methods: A cross-sectional study was conducted with a representative sample of 749 community-dwelling elders aged 65 years and over.

Effects of Degree of Urbanization and Lifetime Longest-Held Occupation on Cognitive Impairment Prevalence in an Older Spanish Population.

Our aim was to estimate the prevalence of cognitive impairment in rural and urban elderly populations and to examine the relationship between lifetime occupation and general cognitive performance. A cross-sectional study was carried out covering a representative sample ( = 749) of adults aged ≥65 years. Two categories were created to define the degree of urbanization using a criterion of geographical contiguity in combination with a minimum population threshold: densely populated (urban) areas and intermediate-thinly populated (rural) areas.

Mapping circulating serum miRNAs to their immune-related target mRNAs.

Purpose: Evidence suggests that circulating serum microRNAs (miRNAs) might preferentially target immune-related mRNAs. If this were the case, we hypothesized that immune-related mRNAs would have more predicted serum miRNA binding sites than other mRNAs and, reciprocally, that serum miRNAs would have more immune-related mRNA targets than non-serum miRNAs.

Materials And Methods: We developed a consensus target predictor using the random forest framework and calculated the number of predicted miRNA-mRNA interactions in various subsets of miRNAs (serum, non-serum) and mRNAs (immune related, nonimmune related).

Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies.

RAS proteins are the founding members of the RAS superfamily of GTPases. They are involved in key signaling pathways regulating essential cellular functions such as cell growth and differentiation. As a result, their deregulation by inactivating mutations often results in aberrant cell proliferation and cancer.

A novel affinity-based method for the isolation of highly purified extracellular vesicles.

Extracellular vesicles (EVs) such as exosomes and microvesicles serve as messengers of intercellular network, allowing exchange of cellular components between cells. EVs carry lipids, proteins, and RNAs derived from their producing cells, and have potential as biomarkers specific to cell types and even cellular states. However, conventional methods (such as ultracentrifugation or polymeric precipitation) for isolating EVs have disadvantages regarding purity and feasibility.

Health determinants of nutritional status in community-dwelling older population: the VERISAÚDE study.

Objective: Malnutrition is a common and relevant syndrome in elderly people due to its influence on quality of life. The main aim of the present study was to identify health determinants of malnutrition or risk of malnutrition.

Design: Cross-sectional study collecting information on sociodemographic and health factors (co-morbidity, cognitive or affective problems, prescription medication use, frailty status, self-rated health) as determinants of nutritional status, assessed by the short form of the Mini Nutritional Assessment.

Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia.

Selective elimination of synaptic connections is a common phenomenon which occurs during both developmental and pathological conditions. Glial cells have a central role in the pruning of synapses by specifically engulfing the degenerating neurites of inappropriate connections, but its regulatory mechanisms have been largely unknown. To identify mediators of this process, we established an in vitro cell culture assay for the synapse elimination.

Network analysis in the investigation of chronic respiratory diseases. From basics to application.

Chronic respiratory diseases are complex multifactorial disorders whose pathogenesis depends on the interplay between host and environmental factors. To fully understand them and to identify novel treatments, a holistic approach that integrates multiple types and levels of clinical and biological data is necessary. Toward this end, the application of systems biology-based strategies, in particular, network analysis, offers great potential.

Genomic and computational approaches to dissect the mechanisms of STAT3's universal and cell type-specific functions.

STAT3 is the quintessential pleiotropic transcription factor with many biological roles throughout development as well as in multiple adult tissues. Its functional heterogeneity is encoded in the range of genome-wide binding patterns that specify different regulatory networks in distinct cell types. However, STAT3 does not display remarkable DNA binding preferences that may help correlate specific motifs with individual biological functions or cell types.

Systematic identification of transcriptional regulatory modules from protein-protein interaction networks.

Transcription factors (TFs) combine with co-factors to form transcriptional regulatory modules (TRMs) that regulate gene expression programs with spatiotemporal specificity. Here we present a novel and generic method (rTRM) for the reconstruction of TRMs that integrates genomic information from TF binding, cell type-specific gene expression and protein-protein interactions. rTRM was applied to reconstruct the TRMs specific for embryonic stem cells (ESC) and hematopoietic stem cells (HSC), neural progenitor cells, trophoblast stem cells and distinct types of terminally differentiated CD4(+) T cells.

The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges.

Inflammation is a fundamental response of the immune system whose successful termination involves the elimination of the invading pathogens, the resolution of inflammation and the repair of the local damaged tissue. In this context, the interleukin 10 (IL-10)-mediated anti-inflammatory response (AIR) represents an essential homeostatic mechanism that controls the degree and duration of inflammation. Here, we review recent work on the mechanistic characterization of the IL-10-mediated AIR on multiple levels: from the cataloguing of the in vivo genomic targets of STAT3 (the transcription factor downstream of IL-10) to the identification of specific co-factors that endow STAT3 with genomic-binding specificity, and how genomic and computational methods are being used to elucidate the regulatory mechanisms of this essential physiological response in macrophages.

The repertoires of ubiquitinating and deubiquitinating enzymes in eukaryotic genomes.

Reversible protein ubiquitination regulates virtually all known cellular activities. Here, we present a quantitatively evaluated and broadly applicable method to predict eukaryotic ubiquitinating enzymes (UBE) and deubiquitinating enzymes (DUB) and its application to 50 distinct genomes belonging to four of the five major phylogenetic supergroups of eukaryotes: unikonts (including metazoans, fungi, choanozoa, and amoebozoa), excavates, chromalveolates, and plants. Our method relies on a collection of profile hidden Markov models, and we demonstrate its superior performance (coverage and classification accuracy >99%) by identifying approximately 25% and approximately 35% additional UBE and DUB genes in yeast and human, which had not been reported before.

Distinct transcriptional regulatory modules underlie STAT3's cell type-independent and cell type-specific functions.

Transcription factors (TFs) regulate gene expression by binding to short DNA sequence motifs, yet their binding specificities alone cannot explain how certain TFs drive a diversity of biological processes. In order to investigate the factors that control the functions of the pleiotropic TF STAT3, we studied its genome-wide binding patterns in four different cell types: embryonic stem cells, CD4(+) T cells, macrophages and AtT-20 cells. We describe for the first time two distinct modes of STAT3 binding.

Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics.

Background: Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response.