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"systems biology"

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Fibroblasts stimulate macrophage migration in interconnected extracellular matrices through tunnel formation and fiber alignment.

Biomaterials. 2019 Apr 02;209:88-102

Authors: Ford AJ, Orbach SM, Rajagopalan P

Abstract
In vivo, macrophages and fibroblasts navigate through and remodel the three-dimensional (3D) extra-cellular matrix (ECM). The orientation of fibers, the porosity, and degree of cross-linking can change the interconnectivity of the ECM and affect cell migration. In turn, migrating cells can alter their microenvironment. To study the relationships between ECM interconnectivity and migration of cells, we assembled collagen hydrogels with dense (DCN) or with loosely interconnected networks (LCN). We find that in DCNs, RAW 264.7 macrophages in monocultures were virtually stationary. In DCN co-cultures, Balb/c 3T3 fibroblasts created tunnels that provided conduits for macrophage migration. In LCNs, fibroblasts aligned fibers up to a distance of 100 μm, which provided tracks for macrophages. Intra-cellular and extra-cellular fluorescent fragments of internalized and degraded collagen were detected inside both cell types as well as around their cell peripheries. Macrophages expressed higher levels of urokinase-type plasminogen activator receptor associated protein (uPARAP)/mannose receptor 1 (CD206) compared to α2β1 indicating that collagen internalization in these cells occurred primarily via integrin-independent mechanisms. Network remodeling indicated by higher Young's modulus was observed in fibroblast monocultures as a result of TGF-β secretion. This work unveils new roles for fibroblasts in forming tunnels in networked ECM to modulate macrophage migration.

PMID: 31030083 [PubMed - as supplied by publisher]

The role of coevolutionary signatures in protein interaction dynamics, complex inference, molecular recognition, and mutational landscapes.

Curr Opin Struct Biol. 2019 Apr 25;56:179-186

Authors: Morcos F, Onuchic JN

Abstract
Evolution imposes constraints at the interface of interacting biomolecules in order to preserve function or maintain fitness. This pressure may have a direct effect on the sequence composition of interacting biomolecules. As a result, statistical patterns of amino acid or nucleotide covariance that encode for physical and functional interactions are observed in sequences of extant organisms. In recent years, global pairwise models of amino acid and nucleotide coevolution from multiple sequence alignments have been developed and utilized to study molecular interactions in structural biology. In proteins, for which the energy landscape is funneled and minimally frustrated, a direct connection between the physical and sequence space landscapes can be established. Estimating coevolutionary information from sequences of interacting molecules has a broad impact in molecular biology. Applications include the accurate determination of 3D structures of molecular complexes, inference of protein interaction partners, models of protein-protein interaction specificity, the elucidation, and design of protein-nucleic acid recognition as well as the discovery of genome-wide epistatic effects. The current state of the art of coevolutionary analysis includes biomedical applications ranging from mutational landscapes and drug-design to vaccine development.

PMID: 31029927 [PubMed - as supplied by publisher]

Characterization of synovial fluid metabolomic phenotypes of cartilage morphological changes associated with osteoarthritis.

Osteoarthritis Cartilage. 2019 Apr 24;:

Authors: Carlson AK, Rawle RA, Wallace CW, Brooks EG, Adams E, Greenwood MC, Olmer M, Lotz MK, Bothner B, June RK

Abstract
OBJECTIVE: Osteoarthritis (OA) is a multifactorial disease with etiological heterogeneity. The objective of this study was to classify OA subgroups by generating metabolomic phenotypes from human synovial fluid.
DESIGN: Post mortem synovial fluids (n=75) were analyzed by high performance-liquid chromatography mass spectrometry (LC-MS) to measure changes in the global metabolome. Comparisons of healthy (grade 0), early OA (grades I-II), and late OA (grades III-IV) donor populations were considered to reveal phenotypes throughout disease progression.
RESULTS: Global metabolomic profiles in synovial fluid were distinct between healthy, early OA, and late OA donors. Pathways differentially activated among these groups included structural deterioration, glycerophospholipid metabolism, inflammation, central energy metabolism, oxidative stress, and vitamin metabolism. Within disease states (early and late OA), subgroups of donors revealed distinct phenotypes. Synovial fluid metabolomic phenotypes exhibited increased inflammation (early and late OA), oxidative stress (late OA), or structural deterioration (early and late OA) in the synovial fluid.
CONCLUSION: These results revealed distinct metabolic phenotypes in human synovial fluid, provide insight into pathogenesis, represent novel biomarkers, and can move toward developing personalized interventions for subgroups of OA patients.

PMID: 31028882 [PubMed - as supplied by publisher]

Prologue to the special issue of JTB dedicated to the memory of René THOMAS (1928-2017): A journey through biological circuits, logical puzzles and complex dynamics.

J Theor Biol. 2019 Apr 24;:

Authors: Thieffry D, Kaufman M

PMID: 31028774 [PubMed - as supplied by publisher]

Shared signature dynamics tempered by local fluctuations enables fold adaptability and specificity.

Mol Biol Evol. 2019 Apr 27;:

Authors: Zhang S, Li H, Krieger JM, Bahar I

Abstract
Recent studies have drawn attention to the evolution of protein dynamics, in addition to sequence and structure, based on the premise structure-encodes-dynamics-encodes-function. Of interest is to understand how functional differentiation is accomplished while maintaining the fold, or how intrinsic dynamics plays out in the evolution of structural variations and functional specificity. We performed a systematic computational analysis of 26,899 proteins belonging to 116 CATH superfamilies. Characterising cooperative mechanisms and convergent/divergent features that underlie the shared/differentiated dynamics of family members required a methodology that lends itself to efficient analyses of large ensembles of proteins. We therefore introduced, SignDy, an integrated pipeline for evaluating the signature dynamics of families based on elastic network models. Our analysis confirmed that family members share conserved, highly cooperative (global) modes of motion. Importantly, our analysis discloses a subset of motions that sharply distinguishes subfamilies, which lie in a low-to-intermediate frequency (LTIF) regime of the mode spectrum. This regime has maximal impact on functional differentiation of families into subfamilies, while being evolutionarily conserved among subfamily members. Notably, the high frequency (HF) end of the spectrum also reveals evolutionary conserved features across and within subfamilies; but in sharp contrast to global motions, HF modes are minimally collective. Modulation of robust/conserved global dynamics by LTIF fluctuations thus emerges as a versatile mechanism ensuring the adaptability of selected folds and the specificity of their subfamilies. SignDy further allows for dynamics-based categorization as a new layer of information relevant to distinctive mechanisms of action of subfamilies, beyond sequence or structural classifications.

PMID: 31028708 [PubMed - as supplied by publisher]

Seq-Well: A Sample-Efficient, Portable Picowell Platform for Massively Parallel Single-Cell RNA Sequencing.

Methods Mol Biol. 2019;1979:111-132

Authors: Aicher TP, Carroll S, Raddi G, Gierahn T, Wadsworth MH, Hughes TK, Love C, Shalek AK

Abstract
Seq-Well is a low-cost picowell platform that can be used to simultaneously profile the transcriptomes of thousands of cells from diverse, low input clinical samples. In Seq-Well, uniquely barcoded mRNA capture beads and cells are co-confined in picowells that are sealed using a semipermeable membrane, enabling efficient cell lysis and mRNA capture. The beads are subsequently removed and processed in parallel for sequencing, with each transcript's cell of origin determined via the unique barcodes. Due to its simplicity and portability, Seq-Well can be performed almost anywhere.

PMID: 31028635 [PubMed - in process]

Single-Cell RNA Sequencing with Drop-Seq.

Methods Mol Biol. 2019;1979:73-85

Authors: Bageritz J, Raddi G

Abstract
Drop-Seq is a low-cost, high-throughput platform to profile thousands of cells by encapsualting them into individual droplets. Uniquely barcoded mRNA capture microparticles and cells are coconfined through a microfluidic device within the droplets where they undergo cell lysis and RNA hybridiztion. After breaking the droplets and pooling the hybridized particles, reverse transcription, PCR, and sequencing in single reactions allow to generate data from thousands of single-cell transcriptomes while maintaining information on the cellular origin of each transcript.

PMID: 31028633 [PubMed - in process]

Adaptive Evolution within Gut Microbiomes of Healthy People.

Cell Host Microbe. 2019 Apr 16;:

Authors: Zhao S, Lieberman TD, Poyet M, Kauffman KM, Gibbons SM, Groussin M, Xavier RJ, Alm EJ

Abstract
Natural selection shapes bacterial evolution in all environments. However, the extent to which commensal bacteria diversify and adapt within the human gut remains unclear. Here, we combine culture-based population genomics and metagenomics to investigate the within-microbiome evolution of Bacteroides fragilis. We find that intra-individual B. fragilis populations contain substantial de novo nucleotide and mobile element diversity, preserving years of within-person history. This history reveals multiple signatures of within-person adaptation, including parallel evolution in sixteen genes. Many of these genes are implicated in cell-envelope biosynthesis and polysaccharide utilization. Tracking evolutionary trajectories using near-daily metagenomic sampling, we find evidence for years-long coexistence in one subject despite adaptive dynamics. We used public metagenomes to investigate one adaptive mutation common in our cohort and found that it emerges frequently in Western, but not Chinese, microbiomes. Collectively, these results demonstrate that B. fragilis adapts within individual microbiomes, pointing to factors that promote long-term gut colonization.

PMID: 31028005 [PubMed - as supplied by publisher]

Natural Genetic Variation Reveals Key Features of Epigenetic and Transcriptional Memory in Virus-Specific CD8 T Cells.

Immunity. 2019 Apr 16;:

Authors: van der Veeken J, Zhong Y, Sharma R, Mazutis L, Dao P, Pe'er D, Leslie CS, Rudensky AY

Abstract
Stable changes in chromatin states and gene expression in cells of the immune system form the basis for memory of infections and other challenges. Here, we used naturally occurring cis-regulatory variation in wild-derived inbred mouse strains to explore the mechanisms underlying long-lasting versus transient gene regulation in CD8 T cells responding to acute viral infection. Stably responsive DNA elements were characterized by dramatic and congruent chromatin remodeling events affecting multiple neighboring sites and required distinct transcription factor (TF) binding motifs for their accessibility. Specifically, we found that cooperative recruitment of T-box and Runx family transcription factors to shared targets mediated stable chromatin remodeling upon T cell activation. Our observations provide insights into the molecular mechanisms driving virus-specific CD8 T cell responses and suggest a general mechanism for the formation of transcriptional and epigenetic memory applicable to other immune and non-immune cells.

PMID: 31027997 [PubMed - as supplied by publisher]

A Review on Viruses Infecting Taro (Colocasia esculenta (L.) Schott).

Pathogens. 2019 Apr 25;8(2):

Authors: Yusop MSM, Saad MFM, Talip N, Baharum SN, Bunawan H

Abstract
Taro is an important crop in parts of the world, especially in the Pacific Islands. Like all plants, it is also susceptible to virus infections that could result in diseases, which negatively affects the source of food and trade revenue. Understanding the biology of taro viruses could improve current knowledge regarding the relationship between viruses and taro, thus allowing for a better approach towards the management of the diseases that are associated with them. By compiling and discussing the research on taro and its four major viruses (Dasheen mosaic virus, Taro bacilliform virus, Colocasia bobone disease virus, and Taro vein chlorosis virus) and a relatively new one (Taro bacilliform CH virus), this paper explores the details of each virus by examining their characteristics and highlighting information that could be used to mitigate taro infections and disease management.

PMID: 31027164 [PubMed]