An α-catenin déjà vu.

PubMed

Han, Siew-Ping; Yap, Alpha S

2013-03-01

α-Catenin exists as part of the cadherin-catenin adhesion complex as well as in a cytoplasmic pool. However, which of these pools is responsible for its biological impact remains controversial. A structure-function analysis in Drosophila melanogaster illuminates how the molecular properties of α-catenin translate into functional outcomes in an intact organism.

Lineage-specific genomics: Frequent birth and death in the human genome: The human genome contains many lineage-specific elements created by both sequence and functional turnover.

PubMed

Young, Robert S

2016-07-01

Frequent evolutionary birth and death events have created a large quantity of biologically important, lineage-specific DNA within mammalian genomes. The birth and death of DNA sequences is so frequent that the total number of these insertions and deletions in the human population remains unknown, although there are differences between these groups, e.g. transposable elements contribute predominantly to sequence insertion. Functional turnover - where the activity of a locus is specific to one lineage, but the underlying DNA remains conserved - can also drive birth and death. However, this does not appear to be a major driver of divergent transcriptional regulation. Both sequence and functional turnover have contributed to the birth and death of thousands of functional promoters in the human and mouse genomes. These findings reveal the pervasive nature of evolutionary birth and death and suggest that lineage-specific regions may play an important but previously underappreciated role in human biology and disease. © 2016 The Authors BioEssays Published by WILEY Periodicals, Inc.

Function and Biosynthesis of Cell Wall α-1,3-Glucan in Fungi.

PubMed

Yoshimi, Akira; Miyazawa, Ken; Abe, Keietsu

2017-11-18

Although α-1,3-glucan is a major cell wall polysaccharide in filamentous fungi, its biological functions remain unclear, except that it acts as a virulence factor in animal and plant pathogenic fungi: it conceals cell wall β-glucan on the fungal cell surface to circumvent recognition by hosts. However, cell wall α-1,3-glucan is also present in many of non-pathogenic fungi. Recently, the universal function of α-1,3-glucan as an aggregation factor has been demonstrated. Applications of fungi with modified cell wall α-1,3-glucan in the fermentation industry and of in vitro enzymatically-synthesized α-1,3-glucan in bio-plastics have been developed. This review focuses on the recent progress in our understanding of the biological functions and biosynthetic mechanism of cell wall α-1,3-glucan in fungi. We briefly consider the history of studies on α-1,3-glucan, overview its biological functions and biosynthesis, and finally consider the industrial applications of fungi deficient in α-1,3-glucan.

Massive-Scale Gene Co-Expression Network Construction and Robustness Testing Using Random Matrix Theory

PubMed Central

Isaacson, Sven; Luo, Feng; Feltus, Frank A.; Smith, Melissa C.

2013-01-01

The study of gene relationships and their effect on biological function and phenotype is a focal point in systems biology. Gene co-expression networks built using microarray expression profiles are one technique for discovering and interpreting gene relationships. A knowledge-independent thresholding technique, such as Random Matrix Theory (RMT), is useful for identifying meaningful relationships. Highly connected genes in the thresholded network are then grouped into modules that provide insight into their collective functionality. While it has been shown that co-expression networks are biologically relevant, it has not been determined to what extent any given network is functionally robust given perturbations in the input sample set. For such a test, hundreds of networks are needed and hence a tool to rapidly construct these networks. To examine functional robustness of networks with varying input, we enhanced an existing RMT implementation for improved scalability and tested functional robustness of human (Homo sapiens), rice (Oryza sativa) and budding yeast (Saccharomyces cerevisiae). We demonstrate dramatic decrease in network construction time and computational requirements and show that despite some variation in global properties between networks, functional similarity remains high. Moreover, the biological function captured by co-expression networks thresholded by RMT is highly robust. PMID:23409071

Associations of endothelial function and air temperature in diabetic subjects

EPA Science Inventory

Background and Objective: Epidemiological studies consistently show that air temperature is associated with changes in cardiovascular morbidity and mortality. However, the biological mechanisms underlying the association remain largely unknown. As one index of endothelial functio...

Bioinspired spring origami

NASA Astrophysics Data System (ADS)

Faber, Jakob A.; Arrieta, Andres F.; Studart, André R.

2018-03-01

Origami enables folding of objects into a variety of shapes in arts, engineering, and biological systems. In contrast to well-known paper-folded objects, the wing of the earwig has an exquisite natural folding system that cannot be sufficiently described by current origami models. Such an unusual biological system displays incompatible folding patterns, remains open by a bistable locking mechanism during flight, and self-folds rapidly without muscular actuation. We show that these notable functionalities arise from the protein-rich joints of the earwig wing, which work as extensional and rotational springs between facets. Inspired by this biological wing, we establish a spring origami model that broadens the folding design space of traditional origami and allows for the fabrication of precisely tunable, four-dimensional–printed objects with programmable bioinspired morphing functionalities.

Functional tissue engineering of tendon: Establishing biological success criteria for improving tendon repair.

PubMed

Breidenbach, Andrew P; Gilday, Steven D; Lalley, Andrea L; Dyment, Nathaniel A; Gooch, Cynthia; Shearn, Jason T; Butler, David L

2014-06-27

Improving tendon repair using Functional Tissue Engineering (FTE) principles has been the focus of our laboratory over the last decade. Although our primary goals were initially focused only on mechanical outcomes, we are now carefully assessing the biological properties of our tissue-engineered tendon repairs so as to link biological influences with mechanics. However, given the complexities of tendon development and healing, it remains challenging to determine which aspects of tendon biology are the most important to focus on in the context of tissue engineering. To address this problem, we have formalized a strategy to identify, prioritize, and evaluate potential biological success criteria for tendon repair. We have defined numerous biological properties of normal tendon relative to cellular phenotype, extracellular matrix and tissue ultra-structure that we would like to reproduce in our tissue-engineered repairs and prioritized these biological criteria by examining their relative importance during both normal development and natural tendon healing. Here, we propose three specific biological criteria which we believe are essential for normal tendon function: (1) scleraxis-expressing cells; (2) well-organized and axially-aligned collagen fibrils having bimodal diameter distribution; and (3) a specialized tendon-to-bone insertion site. Moving forward, these biological success criteria will be used in conjunction with our already established mechanical success criteria to evaluate the effectiveness of our tissue-engineered tendon repairs. © 2013 Published by Elsevier Ltd.

Quantifying uncertainty in partially specified biological models: how can optimal control theory help us?

PubMed

Adamson, M W; Morozov, A Y; Kuzenkov, O A

2016-09-01

Mathematical models in biology are highly simplified representations of a complex underlying reality and there is always a high degree of uncertainty with regards to model function specification. This uncertainty becomes critical for models in which the use of different functions fitting the same dataset can yield substantially different predictions-a property known as structural sensitivity. Thus, even if the model is purely deterministic, then the uncertainty in the model functions carries through into uncertainty in model predictions, and new frameworks are required to tackle this fundamental problem. Here, we consider a framework that uses partially specified models in which some functions are not represented by a specific form. The main idea is to project infinite dimensional function space into a low-dimensional space taking into account biological constraints. The key question of how to carry out this projection has so far remained a serious mathematical challenge and hindered the use of partially specified models. Here, we propose and demonstrate a potentially powerful technique to perform such a projection by using optimal control theory to construct functions with the specified global properties. This approach opens up the prospect of a flexible and easy to use method to fulfil uncertainty analysis of biological models.

Biology of Healthy Aging and Longevity.

PubMed

Carmona, Juan José; Michan, Shaday

2016-01-01

As human life expectancy is prolonged, age-related diseases are thriving. Aging is a complex multifactorial process of molecular and cellular decline that affects tissue function over time, rendering organisms frail and susceptible to disease and death. Over the last decades, a growing body of scientific literature across different biological models, ranging from yeast, worms, flies, and mice to primates, humans and other long-lived animals, has contributed greatly towards identifying conserved biological mechanisms that ward off structural and functional deterioration within living systems. Collectively, these data offer powerful insights into healthy aging and longevity. For example, molecular integrity of the genome, telomere length, epigenetic landscape stability, and protein homeostasis are all features linked to "youthful" states. These molecular hallmarks underlie cellular functions associated with aging like mitochondrial fitness, nutrient sensing, efficient intercellular communication, stem cell renewal, and regenerative capacity in tissues. At present, calorie restriction remains the most robust strategy for extending health and lifespan in most biological models tested. Thus, pathways that mediate the beneficial effects of calorie restriction by integrating metabolic signals to aging processes have received major attention, such as insulin/insulin growth factor-1, sirtuins, mammalian target of rapamycin, and 5' adenosine monophosphate-activated protein kinase. Consequently, small-molecule targets of these pathways have emerged in the impetuous search for calorie restriction mimetics, of which resveratrol, metformin, and rapamycin are the most extensively studied. A comprehensive understanding of the molecular and cellular mechanisms that underlie age-related deterioration and repair, and how these pathways interconnect, remains a major challenge for uncovering interventions to slow human aging while extending molecular and physiological youthfulness, vitality, and health. This review summarizes key molecular mechanisms underlying the biology of healthy aging and longevity.

A data mining paradigm for identifying key factors in biological processes using gene expression data.

PubMed

Li, Jin; Zheng, Le; Uchiyama, Akihiko; Bin, Lianghua; Mauro, Theodora M; Elias, Peter M; Pawelczyk, Tadeusz; Sakowicz-Burkiewicz, Monika; Trzeciak, Magdalena; Leung, Donald Y M; Morasso, Maria I; Yu, Peng

2018-06-13

A large volume of biological data is being generated for studying mechanisms of various biological processes. These precious data enable large-scale computational analyses to gain biological insights. However, it remains a challenge to mine the data efficiently for knowledge discovery. The heterogeneity of these data makes it difficult to consistently integrate them, slowing down the process of biological discovery. We introduce a data processing paradigm to identify key factors in biological processes via systematic collection of gene expression datasets, primary analysis of data, and evaluation of consistent signals. To demonstrate its effectiveness, our paradigm was applied to epidermal development and identified many genes that play a potential role in this process. Besides the known epidermal development genes, a substantial proportion of the identified genes are still not supported by gain- or loss-of-function studies, yielding many novel genes for future studies. Among them, we selected a top gene for loss-of-function experimental validation and confirmed its function in epidermal differentiation, proving the ability of this paradigm to identify new factors in biological processes. In addition, this paradigm revealed many key genes in cold-induced thermogenesis using data from cold-challenged tissues, demonstrating its generalizability. This paradigm can lead to fruitful results for studying molecular mechanisms in an era of explosive accumulation of publicly available biological data.

The α-Secretase-derived N-terminal Product of Cellular Prion, N1, Displays Neuroprotective Function in Vitro and in Vivo*

PubMed Central

Guillot-Sestier, Marie-Victoire; Sunyach, Claire; Druon, Charlotte; Scarzello, Sabine; Checler, Frédéric

2009-01-01

Cellular prion protein (PrPc) undergoes a disintegrin-mediated physiological cleavage, generating a soluble amino-terminal fragment (N1), the function of which remained unknown. Recombinant N1 inhibits staurosporine-induced caspase-3 activation by modulating p53 transcription and activity, whereas the PrPc-derived pathological fragment (N2) remains biologically inert. Furthermore, N1 protects retinal ganglion cells from hypoxia-induced apoptosis, reduces the number of terminal deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling-positive and p53-immunoreactive neurons in a pressure-induced ischemia model of the rat retina and triggers a partial recovery of b-waves but not a-waves of rat electroretinograms. Our work is the first demonstration that the α-secretase-derived PrPc fragment N1, but not N2, displays in vivo and in vitro neuroprotective function by modulating p53 pathway. It further demonstrates that distinct N-terminal cleavage products of PrPc harbor different biological activities underlying the various phenotypes linking PrPc to cell survival. PMID:19850936

Function and Biosynthesis of Cell Wall α-1,3-Glucan in Fungi

PubMed Central

Yoshimi, Akira; Miyazawa, Ken; Abe, Keietsu

2017-01-01

Although α-1,3-glucan is a major cell wall polysaccharide in filamentous fungi, its biological functions remain unclear, except that it acts as a virulence factor in animal and plant pathogenic fungi: it conceals cell wall β-glucan on the fungal cell surface to circumvent recognition by hosts. However, cell wall α-1,3-glucan is also present in many of non-pathogenic fungi. Recently, the universal function of α-1,3-glucan as an aggregation factor has been demonstrated. Applications of fungi with modified cell wall α-1,3-glucan in the fermentation industry and of in vitro enzymatically-synthesized α-1,3-glucan in bio-plastics have been developed. This review focuses on the recent progress in our understanding of the biological functions and biosynthetic mechanism of cell wall α-1,3-glucan in fungi. We briefly consider the history of studies on α-1,3-glucan, overview its biological functions and biosynthesis, and finally consider the industrial applications of fungi deficient in α-1,3-glucan. PMID:29371579

Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins.

PubMed

Hu, Pingzhao; Janga, Sarath Chandra; Babu, Mohan; Díaz-Mejía, J Javier; Butland, Gareth; Yang, Wenhong; Pogoutse, Oxana; Guo, Xinghua; Phanse, Sadhna; Wong, Peter; Chandran, Shamanta; Christopoulos, Constantine; Nazarians-Armavil, Anaies; Nasseri, Negin Karimi; Musso, Gabriel; Ali, Mehrab; Nazemof, Nazila; Eroukova, Veronika; Golshani, Ashkan; Paccanaro, Alberto; Greenblatt, Jack F; Moreno-Hagelsieb, Gabriel; Emili, Andrew

2009-04-28

One-third of the 4,225 protein-coding genes of Escherichia coli K-12 remain functionally unannotated (orphans). Many map to distant clades such as Archaea, suggesting involvement in basic prokaryotic traits, whereas others appear restricted to E. coli, including pathogenic strains. To elucidate the orphans' biological roles, we performed an extensive proteomic survey using affinity-tagged E. coli strains and generated comprehensive genomic context inferences to derive a high-confidence compendium for virtually the entire proteome consisting of 5,993 putative physical interactions and 74,776 putative functional associations, most of which are novel. Clustering of the respective probabilistic networks revealed putative orphan membership in discrete multiprotein complexes and functional modules together with annotated gene products, whereas a machine-learning strategy based on network integration implicated the orphans in specific biological processes. We provide additional experimental evidence supporting orphan participation in protein synthesis, amino acid metabolism, biofilm formation, motility, and assembly of the bacterial cell envelope. This resource provides a "systems-wide" functional blueprint of a model microbe, with insights into the biological and evolutionary significance of previously uncharacterized proteins.

Cellular Engineering with Membrane Fusogenic Liposomes to Produce Functionalized Extracellular Vesicles.

PubMed

Lee, Junsung; Lee, Hyoungjin; Goh, Unbyeol; Kim, Jiyoung; Jeong, Moonkyoung; Lee, Jean; Park, Ji-Ho

2016-03-23

Engineering of extracellular vesicles (EVs) without affecting biological functions remains a challenge, limiting the broad applications of EVs in biomedicine. Here, we report a method to equip EVs with various functional agents, including fluorophores, drugs, lipids, and bio-orthogonal chemicals, in an efficient and controlled manner by engineering parental cells with membrane fusogenic liposomes, while keeping the EVs intact. As a demonstration of how this method can be applied, we prepared EVs containing azide-lipids, and conjugated them with targeting peptides using copper-free click chemistry to enhance targeting efficacy to cancer cells. We believe that this liposome-based cellular engineering method will find utility in studying the biological roles of EVs and delivering therapeutic agents through their innate pathway.

Principles of nanoparticle design for overcoming biological barriers to drug delivery

PubMed Central

Blanco, Elvin; Shen, Haifa; Ferrari, Mauro

2016-01-01

Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery. PMID:26348965

Social networks to biological networks: systems biology of Mycobacterium tuberculosis.

PubMed

Vashisht, Rohit; Bhardwaj, Anshu; Osdd Consortium; Brahmachari, Samir K

2013-07-01

Contextualizing relevant information to construct a network that represents a given biological process presents a fundamental challenge in the network science of biology. The quality of network for the organism of interest is critically dependent on the extent of functional annotation of its genome. Mostly the automated annotation pipelines do not account for unstructured information present in volumes of literature and hence large fraction of genome remains poorly annotated. However, if used, this information could substantially enhance the functional annotation of a genome, aiding the development of a more comprehensive network. Mining unstructured information buried in volumes of literature often requires manual intervention to a great extent and thus becomes a bottleneck for most of the automated pipelines. In this review, we discuss the potential of scientific social networking as a solution for systematic manual mining of data. Focusing on Mycobacterium tuberculosis, as a case study, we discuss our open innovative approach for the functional annotation of its genome. Furthermore, we highlight the strength of such collated structured data in the context of drug target prediction based on systems level analysis of pathogen.

The Default Mode Network Differentiates Biological From Non-Biological Motion

PubMed Central

Dayan, Eran; Sella, Irit; Mukovskiy, Albert; Douek, Yehonatan; Giese, Martin A.; Malach, Rafael; Flash, Tamar

2016-01-01

The default mode network (DMN) has been implicated in an array of social-cognitive functions, including self-referential processing, theory of mind, and mentalizing. Yet, the properties of the external stimuli that elicit DMN activity in relation to these domains remain unknown. Previous studies suggested that motion kinematics is utilized by the brain for social-cognitive processing. Here, we used functional MRI to examine whether the DMN is sensitive to parametric manipulations of observed motion kinematics. Preferential responses within core DMN structures differentiating non-biological from biological kinematics were observed for the motion of a realistically looking, human-like avatar, but not for an abstract object devoid of human form. Differences in connectivity patterns during the observation of biological versus non-biological kinematics were additionally observed. Finally, the results additionally suggest that the DMN is coupled more strongly with key nodes in the action observation network, namely the STS and the SMA, when the observed motion depicts human rather than abstract form. These findings are the first to implicate the DMN in the perception of biological motion. They may reflect the type of information used by the DMN in social-cognitive processing. PMID:25217472

Experiences of mobility for people living with rheumatoid arthritis who are receiving biologic drug therapy: implications for podiatry services.

PubMed

Sanders, Lucy; Donovan-Hall, Margaret; Borthwick, Alan; Bowen, Catherine J

2017-01-01

Despite significant advancements in new treatment modalities for rheumatoid arthritis with biological therapies, foot complications remain a disabling and common feature of the disease . In this study the aim was to explore and describe the personal experiences of people with rheumatoid arthritis in receipt of biologic treatments in a bid to understand the impact of this form of medication on their mobility. An interpretative phenomenological analysis (IPA) was undertaken to explore in depth the individual experience of rheumatoid disease through personal accounts of the patient journey spanning both 'before' and 'after' the instigation of biologic therapy. A purposive sampling strategy was adopted and in-depth semi structured interviews used to facilitate rich, detailed interview data exploring the lived experiences of individuals undertaking biological therapy and the changes to mobility experienced as a result. Thematic analysis was employed with an IPA framework to identify key meanings, and report patterns within the data. Five people with rheumatoid arthritis participated in the study. The mean disease duration was 20.2 years (range: 6 -32) and all were being treated with biologic therapies. Four key themes emerged from the data: 1) Life before biologic treatment, depicted in accounts as a negative experience characterised by painful and disabling symptoms and feelings of hopelessness. 2) Life with biologic treatment, often experienced as a life changing transition, restoring function and mobility and offering renewed hope. 3) Sense of self, in which the impact of rheumatoid disease and the subsequent changes arising from biologic therapy reveal a profound impact on feelings of personal identity both pre and post biologic therapy; an effect of footwear on self-image emerges as a dominant sub theme; 4) Unmet footcare needs were evident in the patient narrative, where the unrelenting if diminished impact of foot pain on mobility was viewed in the context of problematic access to foot health services. Whilst the findings from this study mirror those within the existing literature, which report improvements in physical function related to biological therapy, foot problems clearly remained an unremitting feature of life for patients with rheumatoid disease, even when in receipt of biologics.

Archaeal and eukaryotic homologs of Hfq

PubMed Central

Mura, Cameron; Randolph, Peter S.; Patterson, Jennifer; Cozen, Aaron E.

2013-01-01

Hfq and other Sm proteins are central in RNA metabolism, forming an evolutionarily conserved family that plays key roles in RNA processing in organisms ranging from archaea to bacteria to human. Sm-based cellular pathways vary in scope from eukaryotic mRNA splicing to bacterial quorum sensing, with at least one step in each of these pathways being mediated by an RNA-associated molecular assembly built upon Sm proteins. Though the first structures of Sm assemblies were from archaeal systems, the functions of Sm-like archaeal proteins (SmAPs) remain murky. Our ignorance about SmAP biology, particularly vis-à-vis the eukaryotic and bacterial Sm homologs, can be partly reduced by leveraging the homology between these lineages to make phylogenetic inferences about Sm functions in archaea. Nevertheless, whether SmAPs are more eukaryotic (RNP scaffold) or bacterial (RNA chaperone) in character remains unclear. Thus, the archaeal domain of life is a missing link, and an opportunity, in Sm-based RNA biology. PMID:23579284

Evolution and Biological Roles of Alternative 3'UTRs.

PubMed

Mayr, Christine

2016-03-01

More than half of human genes use alternative cleavage and polyadenylation to generate alternative 3' untranslated region (3'UTR) isoforms. Most efforts have focused on transcriptome-wide mapping of alternative 3'UTRs and on the question of how 3'UTR isoform ratios may be regulated. However, it remains less clear why alternative 3'UTRs have evolved and what biological roles they play. This review summarizes our current knowledge of the functional roles of alternative 3'UTRs, including mRNA localization, mRNA stability, and translational efficiency. Recent work suggests that alternative 3'UTRs may also enable the formation of protein-protein interactions to regulate protein localization or to diversify protein functions. These recent findings open an exciting research direction for the investigation of new biological roles of alternative 3'UTRs. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Mediator Complex and Lipid Metabolism.

PubMed

Zhang, Yi; Xiaoli; Zhao, Xiaoping; Yang, Fajun

2013-03-01

The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understanding on the biological functions of Mediator remains incomplete, research in the past decade has revealed an important role of Mediator in regulating lipid metabolism. Such function of Mediator is dependent on specific transcription factors, including peroxisome proliferator-activated receptor-gamma (PPARγ) and sterol regulatory element-binding proteins (SREBPs), which represent the master regulators of lipid metabolism. The medical significance of these findings is apparent, as aberrant lipid metabolism is intimately linked to major human diseases, such as type 2 diabetes and cardiovascular disease. Here, we briefly review the functions and molecular mechanisms of Mediator in regulation of lipid metabolism.

Paracrystalline Disorder from Phosphate Ion Orientation and Substitution in Synthetic Bone Mineral.

PubMed

Marisa, Mary E; Zhou, Shiliang; Melot, Brent C; Peaslee, Graham F; Neilson, James R

2016-12-05

Hydroxyapatite is an inorganic mineral closely resembling the mineral phase in bone. However, as a biological mineral, it is highly disordered, and its composition and atomistic structure remain poorly understood. Here, synchrotron X-ray total scattering and pair distribution function analysis methods provide insight into the nature of atomistic disorder in a synthetic bone mineral analogue, chemically substituted hydroxyapatite. By varying the effective hydrolysis rate and/or carbonate concentration during growth of the mineral, compounds with varied degrees of paracrystallinity are prepared. From advanced simulations constrained by the experimental pair distribution function and density functional theory, the paracrystalline disorder prevalent in these materials appears to result from accommodation of carbonate in the lattice through random displacement of the phosphate groups. Though many substitution modalities are likely to occur in concert, the most predominant substitution places carbonate into the mirror plane of an ideal phosphate site. Understanding the mineralogical imperfections of a biologically analogous hydroxyapatite is important not only to potential bone grafting applications but also to biological mineralization processes themselves.

Biased and unbiased strategies to identify biologically active small molecules.

PubMed

Abet, Valentina; Mariani, Angelica; Truscott, Fiona R; Britton, Sébastien; Rodriguez, Raphaël

2014-08-15

Small molecules are central players in chemical biology studies. They promote the perturbation of cellular processes underlying diseases and enable the identification of biological targets that can be validated for therapeutic intervention. Small molecules have been shown to accurately tune a single function of pluripotent proteins in a reversible manner with exceptional temporal resolution. The identification of molecular probes and drugs remains a worthy challenge that can be addressed by the use of biased and unbiased strategies. Hypothesis-driven methodologies employs a known biological target to synthesize complementary hits while discovery-driven strategies offer the additional means of identifying previously unanticipated biological targets. This review article provides a general overview of recent synthetic frameworks that gave rise to an impressive arsenal of biologically active small molecules with unprecedented cellular mechanisms. Copyright © 2014. Published by Elsevier Ltd.

Functional genomics approaches in parasitic helminths.

PubMed

Hagen, J; Lee, E F; Fairlie, W D; Kalinna, B H

2012-01-01

As research on parasitic helminths is moving into the post-genomic era, an enormous effort is directed towards deciphering gene function and to achieve gene annotation. The sequences that are available in public databases undoubtedly hold information that can be utilized for new interventions and control but the exploitation of these resources has until recently remained difficult. Only now, with the emergence of methods to genetically manipulate and transform parasitic worms will it be possible to gain a comprehensive understanding of the molecular mechanisms involved in nutrition, metabolism, developmental switches/maturation and interaction with the host immune system. This review focuses on functional genomics approaches in parasitic helminths that are currently used, to highlight potential applications of these technologies in the areas of cell biology, systems biology and immunobiology of parasitic helminths. © 2011 Blackwell Publishing Ltd.

The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that circadian clock within the cardiomyocyte plays a role in regulating myocardia...

The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that the circadian clock within the cardiomyocyte plays a role in regulating myo...

Computational discovery of small open reading frames in Bacillus lehensis

NASA Astrophysics Data System (ADS)

Zainuddin, Nurhafizhoh; Illias, Rosli Md.; Mahadi, Nor Muhammad; Firdaus-Raih, Mohd

2015-09-01

Bacillus lehensis is a Gram-positive and endospore-forming alkalitolerant bacterial strain. In recent years there has been increasing interest in alkaliphilic bacteria and their ability to grow under extreme conditions as well as their ability to serve various important functions in industrial biology especially enzyme production. Small open reading frames (sORFs) have emerged as important regulators in various biological roles such as tumor progression, hormone signalling and stress response. Over the past decade, many biocomputational tools have been developed to predict genes in bacterial genomes. In this study, three softwares were used to predict sORF (≤ 80 aa) in B. lehensis by using whole genome sequence. We used comparative analysis to identify the sORFs in B. lehensis that conserved across all other bacterial genomes. We extended the analysis by doing the homology analysis against protein database. This study established the sORFs in B. lehensis that are conserved across bacteria which might has important biological function which still remain elusive in biological field.

The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function.

PubMed

Grinberg-Bleyer, Yenkel; Caron, Rachel; Seeley, John J; De Silva, Nilushi S; Schindler, Christian W; Hayden, Matthew S; Klein, Ulf; Ghosh, Sankar

2018-04-01

CD4 + Foxp3 + regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-κB family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-κB pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2 , in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2 -deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-κB signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity. Copyright © 2018 by The American Association of Immunologists, Inc.

Nutritional Lipidomics: Molecular Metabolism, Analytics, and Diagnostics

PubMed Central

Smilowitz, Jennifer T.; Zivkovic, Angela M.; Wan, Yu-Jui Yvonne; Watkins, Steve M.; Nording, Malin L.; Hammock, Bruce D.; German, J. Bruce

2013-01-01

The field of lipidomics is providing nutritional science a more comprehensive view of lipid intermediates. Lipidomics research takes advantage of the increase in accuracy and sensitivity of mass detection of mass spectrometry with new bioinformatics toolsets to characterize the structures and abundances of complex lipids. Yet, translating lipidomics to practice via nutritional interventions is still in its infancy. No single instrumentation platform is able to solve the varying analytical challenges of the different molecular lipid species. Biochemical pathways of lipid metabolism remain incomplete and the tools to map lipid compositional data to pathways are still being assembled. Biology itself is dauntingly complex and simply separating biological structures remains a key challenge to lipidomics. Nonetheless, the strategy of combining tandem analytical methods to perform the sensitive, high-throughput, quantitative and comprehensive analysis of lipid metabolites of very large numbers of molecules is poised to drive the field forward rapidly. Among the next steps for nutrition to understand the changes in structures, compositions and function of lipid biomolecules in response to diet is to describe their distribution within discrete functional compartments-lipoproteins. Additionally, lipidomics must tackle the task of assigning the functions of lipids as signaling molecules, nutrient sensors, and intermediates of metabolic pathways. PMID:23818328

Biodiversity, ecosystem functioning, and classical biological control.

PubMed

Evans, Edward W

Increasing concern over worldwide loss of biodiversity has led ecologists to focus intently on how ecosystem functioning may depend on diversity. In applied entomology, there is longstanding interest in the issue, especially as regards the importance of natural enemy diversity for pest control. Here I review parallels in interest, conceptual framework, and conclusions concerning biodiversity as it affects ecosystem functioning in general and classical biological control in particular. Whereas the former focuses on implications of loss of diversity, the latter focuses on implications of increase in diversity as additional species of natural enemies are introduced to novel communities in new geographic regions for insect pest and weed control. Many field studies now demonstrate that ecosystem functioning, e.g., as reflected in primary productivity, is enhanced and stabilized over time by high diversity as the community increases in its efficiency in exploiting available resources. Similarly, there is growing field support for the generalization that increasing species and functional diversity of natural enemies leads to increasing pest suppression. Nonetheless a central concern of classical biological control in particular, as it seeks to minimize non-target effects, remains as to whether one or a few species of natural enemies can provide sufficient pest control.

Functional Analogy in Human Metabolism: Enzymes with Different Biological Roles or Functional Redundancy?

PubMed Central

Piergiorge, Rafael Mina; de Miranda, Antonio Basílio; Catanho, Marcos

2017-01-01

Abstract Since enzymes catalyze almost all chemical reactions that occur in living organisms, it is crucial that genes encoding such activities are correctly identified and functionally characterized. Several studies suggest that the fraction of enzymatic activities in which multiple events of independent origin have taken place during evolution is substantial. However, this topic is still poorly explored, and a comprehensive investigation of the occurrence, distribution, and implications of these events has not been done so far. Fundamental questions, such as how analogous enzymes originate, why so many events of independent origin have apparently occurred during evolution, and what are the reasons for the coexistence in the same organism of distinct enzymatic forms catalyzing the same reaction, remain unanswered. Also, several isofunctional enzymes are still not recognized as nonhomologous, even with substantial evidence indicating different evolutionary histories. In this work, we begin to investigate the biological significance of the cooccurrence of nonhomologous isofunctional enzymes in human metabolism, characterizing functional analogous enzymes identified in metabolic pathways annotated in the human genome. Our hypothesis is that the coexistence of multiple enzymatic forms might not be interpreted as functional redundancy. Instead, these enzymatic forms may be implicated in distinct (and probably relevant) biological roles. PMID:28854631

Biological properties of extracellular vesicles and their physiological functions

PubMed Central

Yáñez-Mó, María; Siljander, Pia R.-M.; Andreu, Zoraida; Zavec, Apolonija Bedina; Borràs, Francesc E.; Buzas, Edit I.; Buzas, Krisztina; Casal, Enriqueta; Cappello, Francesco; Carvalho, Joana; Colás, Eva; Silva, Anabela Cordeiro-da; Fais, Stefano; Falcon-Perez, Juan M.; Ghobrial, Irene M.; Giebel, Bernd; Gimona, Mario; Graner, Michael; Gursel, Ihsan; Gursel, Mayda; Heegaard, Niels H. H.; Hendrix, An; Kierulf, Peter; Kokubun, Katsutoshi; Kosanovic, Maja; Kralj-Iglic, Veronika; Krämer-Albers, Eva-Maria; Laitinen, Saara; Lässer, Cecilia; Lener, Thomas; Ligeti, Erzsébet; Linē, Aija; Lipps, Georg; Llorente, Alicia; Lötvall, Jan; Manček-Keber, Mateja; Marcilla, Antonio; Mittelbrunn, Maria; Nazarenko, Irina; Hoen, Esther N.M. Nolte-‘t; Nyman, Tuula A.; O'Driscoll, Lorraine; Olivan, Mireia; Oliveira, Carla; Pállinger, Éva; del Portillo, Hernando A.; Reventós, Jaume; Rigau, Marina; Rohde, Eva; Sammar, Marei; Sánchez-Madrid, Francisco; Santarém, N.; Schallmoser, Katharina; Ostenfeld, Marie Stampe; Stoorvogel, Willem; Stukelj, Roman; Van der Grein, Susanne G.; Vasconcelos, M. Helena; Wauben, Marca H. M.; De Wever, Olivier

2015-01-01

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system. PMID:25979354

Biological properties of extracellular vesicles and their physiological functions.

PubMed

Yáñez-Mó, María; Siljander, Pia R-M; Andreu, Zoraida; Zavec, Apolonija Bedina; Borràs, Francesc E; Buzas, Edit I; Buzas, Krisztina; Casal, Enriqueta; Cappello, Francesco; Carvalho, Joana; Colás, Eva; Cordeiro-da Silva, Anabela; Fais, Stefano; Falcon-Perez, Juan M; Ghobrial, Irene M; Giebel, Bernd; Gimona, Mario; Graner, Michael; Gursel, Ihsan; Gursel, Mayda; Heegaard, Niels H H; Hendrix, An; Kierulf, Peter; Kokubun, Katsutoshi; Kosanovic, Maja; Kralj-Iglic, Veronika; Krämer-Albers, Eva-Maria; Laitinen, Saara; Lässer, Cecilia; Lener, Thomas; Ligeti, Erzsébet; Linē, Aija; Lipps, Georg; Llorente, Alicia; Lötvall, Jan; Manček-Keber, Mateja; Marcilla, Antonio; Mittelbrunn, Maria; Nazarenko, Irina; Nolte-'t Hoen, Esther N M; Nyman, Tuula A; O'Driscoll, Lorraine; Olivan, Mireia; Oliveira, Carla; Pállinger, Éva; Del Portillo, Hernando A; Reventós, Jaume; Rigau, Marina; Rohde, Eva; Sammar, Marei; Sánchez-Madrid, Francisco; Santarém, N; Schallmoser, Katharina; Ostenfeld, Marie Stampe; Stoorvogel, Willem; Stukelj, Roman; Van der Grein, Susanne G; Vasconcelos, M Helena; Wauben, Marca H M; De Wever, Olivier

2015-01-01

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

Mitochondrial Fitness, Gene Expression, and Hypoxic Stress in a Hybrid Population of the Killifish, Fundulus Heteroclitus

EPA Science Inventory

The physiological link between oxygen availability and mitochondrial function is well established. However, whether or not fitness variation is associated with mitochondrial genotypes in the field remains a contested topic in evolutionary biology. In this study we draw on a popul...

Quantitative determination of the conformational properties of partially folded and intrinsically disordered proteins using NMR dipolar couplings.

PubMed

Jensen, Malene Ringkjøbing; Markwick, Phineus R L; Meier, Sebastian; Griesinger, Christian; Zweckstetter, Markus; Grzesiek, Stephan; Bernadó, Pau; Blackledge, Martin

2009-09-09

Intrinsically disordered proteins (IDPs) inhabit a conformational landscape that is too complex to be described by classical structural biology, posing an entirely new set of questions concerning the molecular understanding of functional biology. The characterization of the conformational properties of IDPs, and the elucidation of the role they play in molecular function, is therefore one of the major challenges remaining for modern structural biology. NMR is the technique of choice for studying this class of proteins, providing information about structure, flexibility, and interactions at atomic resolution even in completely disordered states. In particular, residual dipolar couplings (RDCs) have been shown to be uniquely sensitive and powerful tools for characterizing local and long-range structural behavior in disordered proteins. In this review we describe recent applications of RDCs to quantitatively describe the level of local structure and transient long-range order in IDPs involved in viral replication, neurodegenerative disease, and cancer.

Bioinspired spring origami.

PubMed

Faber, Jakob A; Arrieta, Andres F; Studart, André R

2018-03-23

Origami enables folding of objects into a variety of shapes in arts, engineering, and biological systems. In contrast to well-known paper-folded objects, the wing of the earwig has an exquisite natural folding system that cannot be sufficiently described by current origami models. Such an unusual biological system displays incompatible folding patterns, remains open by a bistable locking mechanism during flight, and self-folds rapidly without muscular actuation. We show that these notable functionalities arise from the protein-rich joints of the earwig wing, which work as extensional and rotational springs between facets. Inspired by this biological wing, we establish a spring origami model that broadens the folding design space of traditional origami and allows for the fabrication of precisely tunable, four-dimensional-printed objects with programmable bioinspired morphing functionalities. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

The development of peptide-based interfacial biomaterials for generating biological functionality on the surface of bioinert materials.

PubMed

Meyers, Steven R; Khoo, Xiaojuan; Huang, Xin; Walsh, Elisabeth B; Grinstaff, Mark W; Kenan, Daniel J

2009-01-01

Biomaterials used in implants have traditionally been selected based on their mechanical properties, chemical stability, and biocompatibility. However, the durability and clinical efficacy of implantable biomedical devices remain limited in part due to the absence of appropriate biological interactions at the implant interface and the lack of integration into adjacent tissues. Herein, we describe a robust peptide-based coating technology capable of modifying the surface of existing biomaterials and medical devices through the non-covalent binding of modular biofunctional peptides. These peptides contain at least one material binding sequence and at least one biologically active sequence and thus are termed, "Interfacial Biomaterials" (IFBMs). IFBMs can simultaneously bind the biomaterial surface while endowing it with desired biological functionalities at the interface between the material and biological realms. We demonstrate the capabilities of model IFBMs to convert native polystyrene, a bioinert surface, into a bioactive surface that can support a range of cell activities. We further distinguish between simple cell attachment with insufficient integrin interactions, which in some cases can adversely impact downstream biology, versus biologically appropriate adhesion, cell spreading, and cell survival mediated by IFBMs. Moreover, we show that we can use the coating technology to create spatially resolved patterns of fluorophores and cells on substrates and that these patterns retain their borders in culture.

The Default Mode Network Differentiates Biological From Non-Biological Motion.

PubMed

Dayan, Eran; Sella, Irit; Mukovskiy, Albert; Douek, Yehonatan; Giese, Martin A; Malach, Rafael; Flash, Tamar

2016-01-01

The default mode network (DMN) has been implicated in an array of social-cognitive functions, including self-referential processing, theory of mind, and mentalizing. Yet, the properties of the external stimuli that elicit DMN activity in relation to these domains remain unknown. Previous studies suggested that motion kinematics is utilized by the brain for social-cognitive processing. Here, we used functional MRI to examine whether the DMN is sensitive to parametric manipulations of observed motion kinematics. Preferential responses within core DMN structures differentiating non-biological from biological kinematics were observed for the motion of a realistically looking, human-like avatar, but not for an abstract object devoid of human form. Differences in connectivity patterns during the observation of biological versus non-biological kinematics were additionally observed. Finally, the results additionally suggest that the DMN is coupled more strongly with key nodes in the action observation network, namely the STS and the SMA, when the observed motion depicts human rather than abstract form. These findings are the first to implicate the DMN in the perception of biological motion. They may reflect the type of information used by the DMN in social-cognitive processing. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Biocompatible and Biomimetic Self-Assembly of Functional Nanostructures

DTIC Science & Technology

2010-02-28

evaporation induced self-assembly of aqueous silica precursors with a biologically compatible surfactant, glycerol monooleate ( GMO ) via dip-coating...film is first deposited, it has a relatively low contact angle with water and remains in a semi-solid state. Upon exposure to UV/ozone, the GMO begins...Figure 8. A) Water contact angle of a GMO -templated silica film as a function of UV light and ozone exposure time, B) Localization of fluorescently

Realizing the Promise of Chemical Glycobiology.

PubMed

Wang, Lai-Xi; Davis, Benjamin G

2013-09-01

Chemical glycobiology is emerging as one of the most uniquely powerful sub-disciplines of chemical biology. The previous scarcity of chemical strategies and the unparalleled structural diversity have created a uniquely fertile ground that is both rich in challenges and potentially very profound in implications. Glycans (oligosaccharides, polysaccharides, and glycoconjugates) are everywhere in biological systems and yet remain disproportionately neglected - reviews highlighting this 'Cinderella status' abound. Yet, the last two decades have witnessed tremendous progress, notably in chemical and chemoenzymatic synthesis, 'sequencing' and arraying, metabolic engineering and imaging. These vital steps serve to highlight not only the great potential but just how much more remains to be done. The vast chemical and functional space of glycans remains to be truly explored. Top-down full-scale glycomic and glycoproteomic studies coupled with hypothesis-driven, bottom-up innovative chemical strategies will be required to properly realize the potential impact of glycoscience on human health, energy, and economy. In this review, we cherry-pick far-sighted advances and use these to identify possible challenges, opportunities and avenues in chemical glycobiology.

Alternative splicing in plant immunity.

PubMed

Yang, Shengming; Tang, Fang; Zhu, Hongyan

2014-06-10

Alternative splicing (AS) occurs widely in plants and can provide the main source of transcriptome and proteome diversity in an organism. AS functions in a range of physiological processes, including plant disease resistance, but its biological roles and functional mechanisms remain poorly understood. Many plant disease resistance (R) genes undergo AS, and several R genes require alternatively spliced transcripts to produce R proteins that can specifically recognize pathogen invasion. In the finely-tuned process of R protein activation, the truncated isoforms generated by AS may participate in plant disease resistance either by suppressing the negative regulation of initiation of immunity, or by directly engaging in effector-triggered signaling. Although emerging research has shown the functional significance of AS in plant biotic stress responses, many aspects of this topic remain to be understood. Several interesting issues surrounding the AS of R genes, especially regarding its functional roles and regulation, will require innovative techniques and additional research to unravel.

Alpha-Tocopherol modulates transcriptional activities that affect essential biological processes in Bovine Cells

USDA-ARS?s Scientific Manuscript database

Alpha-tocopherol is the major isoform of vitamin E. after nearly 100 years of research and countless publications, the physiological functions of vitamin E remain mysterious to a certain degree. Nevertheless, vitamin E is one of the most commonly used single nutrient supplements. Recent data has su...

A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors.

PubMed

Staal, Jerome A; Pei, Yanxin; Rood, Brian R

2016-10-19

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC -amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities.

Chemical regulators of plant hormones and their applications in basic research and agriculture.

PubMed

Jiang, Kai; Asami, Tadao

2018-04-20

Plant hormones are small molecules that play versatile roles in regulating plant growth, development, and responses to the environment. Classic methodologies, including genetics, analytic chemistry, biochemistry, and molecular biology, have contributed to the progress in plant hormone studies. In addition, chemical regulators of plant hormone functions have been important in such studies. Today, synthetic chemicals, including plant growth regulators, are used to study and manipulate biological systems, collectively referred to as chemical biology. Here, we summarize the available chemical regulators and their contributions to plant hormone studies. We also pose questions that remain to be addressed in plant hormone studies and that might be solved with the help of chemical regulators.

Impact of a in situ laboratory on physician expectancy.

PubMed

Brulé, Romain; Sarazin, Marianne; Tayeb, Nicole; Roubille, Martine; Szymanowicz, Anton

2018-01-01

Biological examinations are essential for clinicians' medical care. The aim of this study is to assess clinicians' expectations in healthcare facilities and their perception of medical biology in different types of organization. We performed a prospective transversal study by electronic questionnaire conducted among 242 practitioners in four healthcare facilities. The aspects explored were as follows: quality, reliability, rendering time of examination results and biology platform support. Analyses were conducted after rectification of the sample by weight. Sixty one clinicians responded (25.2% [19.7-30.7]). The rendering time of examination is the main criterion mentioned with a requirement of less than one hour in case of emergency (81.5% [71.8-91.2] of the answers) to less than 72 hours for specialized examinations (81.5% [71.8-91.2] of the answers). Better collaboration with biologists is expected by clinicians (54.7% [50.9-58.5]). Satisfaction with the biology platform support and rendering time of emergency cases results was significantly (p <0.005) lower in facilities without an on-site laboratory. In conclusion, although medical biology performance is generally satisfactory within medical facilities, it remains nonetheless affected when the laboratory is not on site. The rendering time of examination, depending on the biology platform support functions and the proximity of the laboratory, remains the main criterion. Clinician-biologist collaboration, which increases of the medico-economic efficiency of patient's healthcare, appears as an essential criterion in a structural conception of medical biology.

Hierarchical Feedback Modules and Reaction Hubs in Cell Signaling Networks

PubMed Central

Xu, Jianfeng; Lan, Yueheng

2015-01-01

Despite much effort, identification of modular structures and study of their organizing and functional roles remain a formidable challenge in molecular systems biology, which, however, is essential in reaching a systematic understanding of large-scale cell regulation networks and hence gaining capacity of exerting effective interference to cell activity. Combining graph theoretic methods with available dynamics information, we successfully retrieved multiple feedback modules of three important signaling networks. These feedbacks are structurally arranged in a hierarchical way and dynamically produce layered temporal profiles of output signals. We found that global and local feedbacks act in very different ways and on distinct features of the information flow conveyed by signal transduction but work highly coordinately to implement specific biological functions. The redundancy embodied with multiple signal-relaying channels and feedback controls bestow great robustness and the reaction hubs seated at junctions of different paths announce their paramount importance through exquisite parameter management. The current investigation reveals intriguing general features of the organization of cell signaling networks and their relevance to biological function, which may find interesting applications in analysis, design and control of bio-networks. PMID:25951347

Paracrystalline Disorder from Phosphate Ion Orientation and Substitution in Synthetic Bone Mineral

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marisa, Mary E.; Zhou, Shiliang; Melot, Brent C.

Hydroxyapatite is an inorganic mineral closely resembling the mineral phase in bone. However, as a biological mineral, it is highly disordered, and its composition and atomistic structure remain poorly understood. Here, synchrotron X-ray total scattering and pair distribution function analysis methods provide insight into the nature of atomistic disorder in a synthetic bone mineral analogue, chemically substituted hydroxyapatite. By varying the effective hydrolysis rate and/or carbonate concentration during growth of the mineral, compounds with varied degrees of paracrystallinity are prepared. From advanced simulations constrained by the experimental pair distribution function and density functional theory, the paracrystalline disorder prevalent in thesemore » materials appears to result from accommodation of carbonate in the lattice through random displacement of the phosphate groups. Though many substitution modalities are likely to occur in concert, the most predominant substitution places carbonate into the mirror plane of an ideal phosphate site. Understanding the mineralogical imperfections of a biologically analogous hydroxyapatite is important not only to potential bone grafting applications but also to biological mineralization processes themselves.« less

Mathematical and Computational Modeling in Complex Biological Systems

PubMed Central

Li, Wenyang; Zhu, Xiaoliang

2017-01-01

The biological process and molecular functions involved in the cancer progression remain difficult to understand for biologists and clinical doctors. Recent developments in high-throughput technologies urge the systems biology to achieve more precise models for complex diseases. Computational and mathematical models are gradually being used to help us understand the omics data produced by high-throughput experimental techniques. The use of computational models in systems biology allows us to explore the pathogenesis of complex diseases, improve our understanding of the latent molecular mechanisms, and promote treatment strategy optimization and new drug discovery. Currently, it is urgent to bridge the gap between the developments of high-throughput technologies and systemic modeling of the biological process in cancer research. In this review, we firstly studied several typical mathematical modeling approaches of biological systems in different scales and deeply analyzed their characteristics, advantages, applications, and limitations. Next, three potential research directions in systems modeling were summarized. To conclude, this review provides an update of important solutions using computational modeling approaches in systems biology. PMID:28386558

Mathematical and Computational Modeling in Complex Biological Systems.

PubMed

Ji, Zhiwei; Yan, Ke; Li, Wenyang; Hu, Haigen; Zhu, Xiaoliang

2017-01-01

The biological process and molecular functions involved in the cancer progression remain difficult to understand for biologists and clinical doctors. Recent developments in high-throughput technologies urge the systems biology to achieve more precise models for complex diseases. Computational and mathematical models are gradually being used to help us understand the omics data produced by high-throughput experimental techniques. The use of computational models in systems biology allows us to explore the pathogenesis of complex diseases, improve our understanding of the latent molecular mechanisms, and promote treatment strategy optimization and new drug discovery. Currently, it is urgent to bridge the gap between the developments of high-throughput technologies and systemic modeling of the biological process in cancer research. In this review, we firstly studied several typical mathematical modeling approaches of biological systems in different scales and deeply analyzed their characteristics, advantages, applications, and limitations. Next, three potential research directions in systems modeling were summarized. To conclude, this review provides an update of important solutions using computational modeling approaches in systems biology.

Surface functionalization of thin-film diamond for highly stable and selective biological interfaces

PubMed Central

Stavis, Courtney; Clare, Tami Lasseter; Butler, James E.; Radadia, Adarsh D.; Carr, Rogan; Zeng, Hongjun; King, William P.; Carlisle, John A.; Aksimentiev, Aleksei; Bashir, Rashid; Hamers, Robert J.

2011-01-01

Carbon is an extremely versatile family of materials with a wide range of mechanical, optical, and mechanical properties, but many similarities in surface chemistry. As one of the most chemically stable materials known, carbon provides an outstanding platform for the development of highly tunable molecular and biomolecular interfaces. Photochemical grafting of alkenes has emerged as an attractive method for functionalizing surfaces of diamond, but many aspects of the surface chemistry and impact on biological recognition processes remain unexplored. Here we report investigations of the interaction of functionalized diamond surfaces with proteins and biological cells using X-ray photoelectron spectroscopy (XPS), atomic force microscopy, and fluorescence methods. XPS data show that functionalization of diamond with short ethylene glycol oligomers reduces the nonspecific binding of fibrinogen below the detection limit of XPS, estimated as > 97% reduction over H-terminated diamond. Measurements of different forms of diamond with different roughness are used to explore the influence of roughness on nonspecific binding onto H-terminated and ethylene glycol (EG)-terminated surfaces. Finally, we use XPS to characterize the chemical stability of Escherichia coli K12 antibodies on the surfaces of diamond and amine-functionalized glass. Our results show that antibody-modified diamond surfaces exhibit increased stability in XPS and that this is accompanied by retention of biological activity in cell-capture measurements. Our results demonstrate that surface chemistry on diamond and other carbon-based materials provides an excellent platform for biomolecular interfaces with high stability and high selectivity. PMID:20884854

Mutual information estimation reveals global associations between stimuli and biological processes

PubMed Central

Suzuki, Taiji; Sugiyama, Masashi; Kanamori, Takafumi; Sese, Jun

2009-01-01

Background Although microarray gene expression analysis has become popular, it remains difficult to interpret the biological changes caused by stimuli or variation of conditions. Clustering of genes and associating each group with biological functions are often used methods. However, such methods only detect partial changes within cell processes. Herein, we propose a method for discovering global changes within a cell by associating observed conditions of gene expression with gene functions. Results To elucidate the association, we introduce a novel feature selection method called Least-Squares Mutual Information (LSMI), which computes mutual information without density estimaion, and therefore LSMI can detect nonlinear associations within a cell. We demonstrate the effectiveness of LSMI through comparison with existing methods. The results of the application to yeast microarray datasets reveal that non-natural stimuli affect various biological processes, whereas others are no significant relation to specific cell processes. Furthermore, we discover that biological processes can be categorized into four types according to the responses of various stimuli: DNA/RNA metabolism, gene expression, protein metabolism, and protein localization. Conclusion We proposed a novel feature selection method called LSMI, and applied LSMI to mining the association between conditions of yeast and biological processes through microarray datasets. In fact, LSMI allows us to elucidate the global organization of cellular process control. PMID:19208155

Biosimilars: biologics that meet patients' needs and healthcare economics.

PubMed

McCamish, Mark; Yoon, William; McKay, James

2016-09-01

Biologics have revolutionized medical care, yet uniform access to these effective medicines remains difficult due to the increasing costs of healthcare. As patent exclusivity on the early biologics wanes, regulatory and legal systems are adapting to bring competition to the field in the form of biosimilars. Biosimilars are biologics that offer the same clinical benefit in one or more of the same indications as the reference biologic drug and bring competition to the biologics space. Legislation creating a pathway resulting in the first US approvals of biosimilars has been in place since 2010, but the regulatory methodology and science of evaluating the sameness of two biologics has been in use for decades. The demonstration of biosimilarity is based on the "totality of the evidence" concept, in which all structural, functional, nonclinical, and clinical data for a biosimilar product are evaluated to show high similarity to the reference product. Clinical trials for biosimilars, therefore, are designed to confirm similarity, or discover clinically relevant differences between the reference product and the biosimilar, should differences exist. It is hoped that competition from biosimilars will drive biologic innovation and increase patient access to biologics.

Chemical Foundations of Hydrogen Sulfide Biology

PubMed Central

Li, Qian; Lancaster, Jack R.

2013-01-01

Following nitric oxide (nitrogen monoxide) and carbon monoxide, hydrogen sulfide (or its newer systematic name sulfane, H2S) became the third small molecule that can be both toxic and beneficial depending on the concentration. In spite of its impressive therapeutic potential, the underlying mechanisms for its beneficial effects remain unclear. Any novel mechanism has to obey fundamental chemical principles. H2S chemistry was studied long before its biological relevance was discovered, however, with a few exceptions, these past works have received relatively little attention in the path of exploring the mechanistic conundrum of H2S biological functions. This review calls attention to the basic physical and chemical properties of H2S, focuses on the chemistry between H2S and its three potential biological targets: oxidants, metals and thiol derivatives, discusses the applications of these basics into H2S biology and methodology, and introduces the standard terminology to this youthful field. PMID:23850631

Cell and molecular mechanics of biological materials

NASA Astrophysics Data System (ADS)

Bao, G.; Suresh, S.

2003-11-01

Living cells can sense mechanical forces and convert them into biological responses. Similarly, biological and biochemical signals are known to influence the abilities of cells to sense, generate and bear mechanical forces. Studies into the mechanics of single cells, subcellular components and biological molecules have rapidly evolved during the past decade with significant implications for biotechnology and human health. This progress has been facilitated by new capabilities for measuring forces and displacements with piconewton and nanometre resolutions, respectively, and by improvements in bio-imaging. Details of mechanical, chemical and biological interactions in cells remain elusive. However, the mechanical deformation of proteins and nucleic acids may provide key insights for understanding the changes in cellular structure, response and function under force, and offer new opportunities for the diagnosis and treatment of disease. This review discusses some basic features of the deformation of single cells and biomolecules, and examines opportunities for further research.

RNA circularization strategies in vivo and in vitro

PubMed Central

Petkovic, Sonja; Müller, Sabine

2015-01-01

In the plenitude of naturally occurring RNAs, circular RNAs (circRNAs) and their biological role were underestimated for years. However, circRNAs are ubiquitous in all domains of life, including eukaryotes, archaea, bacteria and viruses, where they can fulfill diverse biological functions. Some of those functions, as for example playing a role in the life cycle of viral and viroid genomes or in the maturation of tRNA genes, have been elucidated; other putative functions still remain elusive. Due to the resistance to exonucleases, circRNAs are promising tools for in vivo application as aptamers, trans-cleaving ribozymes or siRNAs. How are circRNAs generated in vivo and what approaches do exist to produce ring-shaped RNAs in vitro? In this review we illustrate the occurrence and mechanisms of RNA circularization in vivo, survey methods for the generation of circRNA in vitro and provide appropriate protocols. PMID:25662225

Unicellular eukaryotes as models in cell and molecular biology: critical appraisal of their past and future value.

PubMed

Simon, Martin; Plattner, Helmut

2014-01-01

Unicellular eukaryotes have been appreciated as model systems for the analysis of crucial questions in cell and molecular biology. This includes Dictyostelium (chemotaxis, amoeboid movement, phagocytosis), Tetrahymena (telomere structure, telomerase function), Paramecium (variant surface antigens, exocytosis, phagocytosis cycle) or both ciliates (ciliary beat regulation, surface pattern formation), Chlamydomonas (flagellar biogenesis and beat), and yeast (S. cerevisiae) for innumerable aspects. Nowadays many problems may be tackled with "higher" eukaryotic/metazoan cells for which full genomic information as well as domain databases, etc., were available long before protozoa. Established molecular tools, commercial antibodies, and established pharmacology are additional advantages available for higher eukaryotic cells. Moreover, an increasing number of inherited genetic disturbances in humans have become elucidated and can serve as new models. Among lower eukaryotes, yeast will remain a standard model because of its peculiarities, including its reduced genome and availability in the haploid form. But do protists still have a future as models? This touches not only the basic understanding of biology but also practical aspects of research, such as fund raising. As we try to scrutinize, due to specific advantages some protozoa should and will remain favorable models for analyzing novel genes or specific aspects of cell structure and function. Outstanding examples are epigenetic phenomena-a field of rising interest. © 2014 Elsevier Inc. All rights reserved.

Urinary long noncoding RNAs in nonmuscle-invasive bladder cancer: new architects in cancer prognostic biomarkers.

PubMed

Terracciano, Daniela; Ferro, Matteo; Terreri, Sara; Lucarelli, Giuseppe; D'Elia, Carolina; Musi, Gennaro; de Cobelli, Ottavio; Mirone, Vincenzo; Cimmino, Amelia

2017-06-01

Several reports over the last 10 years provided evidence that long noncoding RNAs (lncRNAs) are often altered in bladder cancers. lncRNAs are longer than 200 nucleotides and function as important regulators of gene expression, interacting with the major pathways of cell growth, proliferation, differentiation, and survival. A large number of lncRNAs has oncogenic function and is more expressed in tumor compared with normal tissues. Their overexpression may be associated with tumor formation, progression, and metastasis in a variety of tumors including bladder cancer. Although lncRNAs have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle-invasive bladder cancer remain largely unknown. Nevertheless, a growing body of evidence suggests that several lncRNAs expression profiles in bladder malignancies are associated with poor prognosis, and they can be detected in biological fluids, such as urines. Here, we review current progress in the biology and the implication of lncRNAs associated with bladder cancer, and we discuss their potential use as diagnosis and prognosis biomarkers in bladder malignancies with a focus on their role in high-risk nonmuscle-invasive tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

Microbial ecology of denitrification in biological wastewater treatment.

PubMed

Lu, Huijie; Chandran, Kartik; Stensel, David

2014-11-01

Globally, denitrification is commonly employed in biological nitrogen removal processes to enhance water quality. However, substantial knowledge gaps remain concerning the overall community structure, population dynamics and metabolism of different organic carbon sources. This systematic review provides a summary of current findings pertaining to the microbial ecology of denitrification in biological wastewater treatment processes. DNA fingerprinting-based analysis has revealed a high level of microbial diversity in denitrification reactors and highlighted the impacts of carbon sources in determining overall denitrifying community composition. Stable isotope probing, fluorescence in situ hybridization, microarrays and meta-omics further link community structure with function by identifying the functional populations and their gene regulatory patterns at the transcriptional and translational levels. This review stresses the need to integrate microbial ecology information into conventional denitrification design and operation at full-scale. Some emerging questions, from physiological mechanisms to practical solutions, for example, eliminating nitrous oxide emissions and supplementing more sustainable carbon sources than methanol, are also discussed. A combination of high-throughput approaches is next in line for thorough assessment of wastewater denitrifying community structure and function. Though denitrification is used as an example here, this synergy between microbial ecology and process engineering is applicable to other biological wastewater treatment processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

The development of peptide-based interfacial biomaterials for generating biological functionality on the surface of bioinert materials

PubMed Central

Meyers, Steven R.; Khoo, Xiaojuan; Huang, Xin; Walsh, Elisabeth B.; Grinstaff, Mark W.; Kenan, Daniel J.

2013-01-01

Biomaterials used in implants have traditionally been selected based on their mechanical properties, chemical stability, and biocompatibility. However, the durability and clinical efficacy of implantable biomedical devices remains limited in part due to the absence of appropriate biological interactions at the implant interface and the lack of integration into adjacent tissues. Herein, we describe a robust peptide-based coating technology capable of modifying the surface of existing biomaterials and medical devices through the non-covalent binding of modular biofunctional peptides. These peptides contain at least one material binding sequence and at least one biologically active sequence and thus are termed, “Interfacial Biomaterials” (IFBMs). IFBMs can simultaneously bind the biomaterial surface while endowing it with desired biological functionalities at the interface between the material and biological realms. We demonstrate the capabilities of model IFBMs to convert native polystyrene, a bioinert surface, into a bioactive surface that can support a range of cell activities. We further distinguish between simple cell attachment with insufficient integrin interactions, which in some cases can adversely impact downstream biology, versus biologically appropriate adhesion, cell spreading, and cell survival mediated by IFBMs. Moreover, we show that we can use the coating technology to create spatially resolved patterns of fluorophores and cells on substrates and that these patterns retain their borders in culture. PMID:18929406

PTSD and Sexual Dysfunction in Men and Women.

PubMed

Yehuda, Rachel; Lehrner, Amy; Rosenbaum, Talli Y

2015-05-01

Difficulties in sexual desire and function often occur in persons with posttraumatic stress disorder (PTSD), but many questions remain regarding the mechanisms underlying the occurrence of sexual problems in PTSD. The aim of this review was to present a model of sexual dysfunction in PTSD underpinned by an inability to regulate and redirect the physiological arousal needed for healthy sexual function away from aversive hyperarousal and intrusive memories. A literature review pertaining to PTSD and sexual function was conducted. Evidence for the comorbidity of sexual dysfunction and PTSD is presented, and biological and psychological mechanisms that may underlie this co-occurrence are proposed. This manuscript presents evidence of sexual dysfunction in conjunction with PTSD, and of the neurobiology and neuroendocrinology of PTSD and sexual function. Sexual dysfunction following trauma exposure may be mediated by PTSD-related biological, cognitive, and affective processes. The treatment of PTSD must include attention to sexual dysfunction and vice versa. © 2015 International Society for Sexual Medicine.

Lipid Rafts in Mast Cell Biology

PubMed Central

Silveira e Souza, Adriana Maria Mariano; Mazucato, Vivian Marino; Jamur, Maria Célia; Oliver, Constance

2011-01-01

Mast cells have long been recognized to have a direct and critical role in allergic and inflammatory reactions. In allergic diseases, these cells exert both local and systemic responses, including allergic rhinitis and anaphylaxis. Mast cell mediators are also related to many chronic inflammatory conditions. Besides the roles in pathological conditions, the biological functions of mast cells include roles in innate immunity, involvement in host defense mechanisms against parasites, immunomodulation of the immune system, tissue repair, and angiogenesis. Despite their growing significance in physiological and pathological conditions, much still remains to be learned about mast cell biology. This paper presents evidence that lipid rafts or raft components modulate many of the biological processes in mast cells, such as degranulation and endocytosis, play a role in mast cell development and recruitment, and contribute to the overall preservation of mast cell structure and organization. PMID:21490812

Cell biology of the Koji mold Aspergillus oryzae.

PubMed

Kitamoto, Katsuhiko

2015-01-01

Koji mold, Aspergillus oryzae, has been used for the production of sake, miso, and soy sauce for more than one thousand years in Japan. Due to the importance, A. oryzae has been designated as the national micro-organism of Japan (Koku-kin). A. oryzae has been intensively studied in the past century, with most investigations focusing on breeding techniques and developing methods for Koji making for sake brewing. However, the understanding of fundamental biology of A. oryzae remains relatively limited compared with the yeast Saccharomyces cerevisiae. Therefore, we have focused on studying the cell biology including live cell imaging of organelles, protein vesicular trafficking, autophagy, and Woronin body functions using the available genomic information. In this review, I describe essential findings of cell biology of A. oryzae obtained in our study for a quarter of century. Understanding of the basic biology will be critical for not its biotechnological application, but also for an understanding of the fundamental biology of other filamentous fungi.

The Use of Functional Genomics in Conjunction with Metabolomics for Mycobacterium tuberculosis Research

PubMed Central

Swanepoel, Conrad C.

2014-01-01

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a fatal infectious disease, resulting in 1.4 million deaths globally per annum. Over the past three decades, genomic studies have been conducted in an attempt to elucidate the functionality of the genome of the pathogen. However, many aspects of this complex genome remain largely unexplored, as approaches like genomics, proteomics, and transcriptomics have failed to characterize them successfully. In turn, metabolomics, which is relatively new to the “omics” revolution, has shown great potential for investigating biological systems or their modifications. Furthermore, when these data are interpreted in combination with previously acquired genomics, proteomics and transcriptomics data, using what is termed a systems biology approach, a more holistic understanding of these systems can be achieved. In this review we discuss how metabolomics has contributed so far to characterizing TB, with emphasis on the resulting improved elucidation of M. tuberculosis in terms of (1) metabolism, (2) growth and replication, (3) pathogenicity, and (4) drug resistance, from the perspective of systems biology. PMID:24771957

Next-generation libraries for robust RNA interference-based genome-wide screens

PubMed Central

Kampmann, Martin; Horlbeck, Max A.; Chen, Yuwen; Tsai, Jordan C.; Bassik, Michael C.; Gilbert, Luke A.; Villalta, Jacqueline E.; Kwon, S. Chul; Chang, Hyeshik; Kim, V. Narry; Weissman, Jonathan S.

2015-01-01

Genetic screening based on loss-of-function phenotypes is a powerful discovery tool in biology. Although the recent development of clustered regularly interspaced short palindromic repeats (CRISPR)-based screening approaches in mammalian cell culture has enormous potential, RNA interference (RNAi)-based screening remains the method of choice in several biological contexts. We previously demonstrated that ultracomplex pooled short-hairpin RNA (shRNA) libraries can largely overcome the problem of RNAi off-target effects in genome-wide screens. Here, we systematically optimize several aspects of our shRNA library, including the promoter and microRNA context for shRNA expression, selection of guide strands, and features relevant for postscreen sample preparation for deep sequencing. We present next-generation high-complexity libraries targeting human and mouse protein-coding genes, which we grouped into 12 sublibraries based on biological function. A pilot screen suggests that our next-generation RNAi library performs comparably to current CRISPR interference (CRISPRi)-based approaches and can yield complementary results with high sensitivity and high specificity. PMID:26080438

Fluorescein isothiocyanate-labeled human plasma fibronectin in extracellular matrix remodeling.

PubMed

Hoffmann, Celine; Leroy-Dudal, Johanne; Patel, Salima; Gallet, Olivier; Pauthe, Emmanuel

2008-01-01

Fluorescein isothiocyanate (FITC) is a well-known probe for labeling biologically relevant proteins. However, the impact of the labeling procedure on protein structure and biological activities remains unclear. In this work, FITC-labeled human plasma fibronectin (Fn) was developed to gain insight into the dynamic relationship between cells and Fn. The similarities and differences concerning the structure and function between Fn-FITC and standard Fn were evaluated using biochemical as well as cellular approaches. By varying the FITC/Fn ratio, we demonstrated that overlabeling (>10 FITC molecules/Fn molecule) induces probe fluorescence quenching, protein aggregation, and cell growth modifications. A correct balance between reliable fluorescence for detection and no significant modifications to structure and biological function compared with standard Fn was obtained with a final ratio of 3 FITC molecules per Fn molecule (Fn-FITC3). Fn-FITC3, similar to standard Fn, is correctly recruited into the cell matrix network. Also, Fn-FITC3 is proposed to be a powerful molecular tool to investigate Fn organization and cellular behavior concomitantly.

Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS)

PubMed Central

Maninger, Nicole; Wolkowitz, Owen M.; Reus, Victor I.; Epel, Elissa S.; Mellon, Synthia H.

2009-01-01

DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed. PMID:19063914

Structural disorder within sendai virus nucleoprotein and phosphoprotein: insight into the structural basis of molecular recognition.

PubMed

Jensen, Malene Ringkjøbing; Bernadó, Pau; Houben, Klaartje; Blanchard, Laurence; Marion, Dominque; Ruigrok, Rob W H; Blackledge, Martin

2010-08-01

Intrinsically disordered regions of significant length are present throughout eukaryotic genomes, and are particularly prevalent in viral proteins. Due to their inherent flexibility, these proteins inhabit a conformational landscape that is too complex to be described by classical structural biology. The elucidation of the role that conformational flexibility plays in molecular function will redefine our understanding of the molecular basis of biological function, and the development of appropriate technology to achieve this aim remains one of the major challenges for the future of structural biology. NMR is the technique of choice for studying intrinsically disordered proteins, providing information about structure, flexibility and interactions at atomic resolution even in completely disordered proteins. In particular residual dipolar couplings (RDCs) are sensitive and powerful tools for determining local and long-range structural behaviour in flexible proteins. Here we describe recent applications of the use of RDCs to quantitatively describe the level of local structure in intrinsically disordered proteins involved in replication and transcription in Sendai virus.

Redox Regulation of Endothelial Cell Fate

PubMed Central

Song, Ping; Zou, Ming-Hui

2014-01-01

Endothelial cells (ECs) are present throughout blood vessels and have variable roles in both physiological and pathological settings. EC fate is altered and regulated by several key factors in physiological or pathological conditions. Reactive nitrogen species and reactive oxygen species derived from NAD(P)H oxidases, mitochondria, or nitric oxide-producing enzymes are not only cytotoxic but also compose a signaling network in the redox system. The formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. We review the identities, sources, and biological actions of oxidants and reductants produced during EC function or dysfunction. Further, we discuss how ECs shape key redox sensors and examine the biological functions, transcriptional responses, and post-translational modifications evoked by the redox system in ECs. We summarize recent findings regarding the mechanisms by which redox signals regulate the fate of ECs and address the outcome of altered EC fate in health and disease. Future studies will examine if the redox biology of ECs can be targeted in pathophysiological conditions. PMID:24633153

Emerging roles for the BAI1 protein family in the regulation of phagocytosis, synaptogenesis, neurovasculature, and tumor development

PubMed Central

Cork, Sarah M.

2011-01-01

While G-protein-coupled receptors (GPCRs) have received considerable attention for their biological activity in a diversity of physiological functions and have become targets for therapeutic intervention in many diseases, the function of the cell adhesion subfamily of GPCRs remains poorly understood. Within this group, the family of brain angiogenesis inhibitor molecules (BAI1-3) has become increasingly appreciated for their diverse roles in biology and disease. In particular, recent findings suggest emerging roles for BAI1 in the regulation of phenomena including phagocytosis, synaptogenesis, and the inhibition of tumor growth and angiogenesis via the processing of its extracellular domain into secreted vasculostatins. Here we summarize the known biological features of the BAI proteins, including their structure, proteolysis events, and interacting partners, and their recently identified ability to regulate certain signaling pathways. Finally, we discuss the potential of the BAIs as therapeutics or targets for diseases as varied as cancer, stroke, and schizophrenia. PMID:21509575

Chemical methods for encoding and decoding of posttranslational modifications

PubMed Central

Chuh, Kelly N.; Batt, Anna R.; Pratt, Matthew R.

2016-01-01

A large array of posttranslational modifications can dramatically change the properties of proteins and influence different aspects of their biological function such as enzymatic activity, binding interactions, and proteostasis. Despite the significant knowledge that has been gained about the function of posttranslational modifications using traditional biological techniques, the analysis of the site-specific effects of a particular modification, the identification of the full compliment of modified proteins in the proteome, and the detection of new types of modifications remains challenging. Over the years, chemical methods have contributed significantly in both of these areas of research. This review highlights several posttranslational modifications where chemistry-based approaches have made significant contributions to our ability to both prepare homogeneously modified proteins and identify and characterize particular modifications in complex biological settings. As the number and chemical diversity of documented posttranslational modifications continues to rise, we believe that chemical strategies will be essential to advance the field in years to come. PMID:26933738

Recent Progress in the Development of Metabolome Databases for Plant Systems Biology

PubMed Central

Fukushima, Atsushi; Kusano, Miyako

2013-01-01

Metabolomics has grown greatly as a functional genomics tool, and has become an invaluable diagnostic tool for biochemical phenotyping of biological systems. Over the past decades, a number of databases involving information related to mass spectra, compound names and structures, statistical/mathematical models and metabolic pathways, and metabolite profile data have been developed. Such databases complement each other and support efficient growth in this area, although the data resources remain scattered across the World Wide Web. Here, we review available metabolome databases and summarize the present status of development of related tools, particularly focusing on the plant metabolome. Data sharing discussed here will pave way for the robust interpretation of metabolomic data and advances in plant systems biology. PMID:23577015

Regulatory RNA in Mycobacterium tuberculosis, back to basics.

PubMed

Schwenk, Stefan; Arnvig, Kristine B

2018-06-01

Since the turn of the millenium, RNA-based control of gene expression has added an extra dimension to the central dogma of molecular biology. Still, the roles of Mycobacterium tuberculosis regulatory RNAs and the proteins that facilitate their functions remain elusive, although there can be no doubt that RNA biology plays a central role in the baterium's adaptation to its many host environments. In this review, we have presented examples from model organisms and from M. tuberculosis to showcase the abundance and versatility of regulatory RNA, in order to emphasise the importance of these 'fine-tuners' of gene expression.

Developmental biology of gut-probiotic interaction

PubMed Central

Patel, Ravi Mangal

2010-01-01

While our current knowledge of probiotic interaction in the developing gut remains poorly understood, emerging science is providing greater biological insight into their mechanism of action and therapeutic potential for human disease. Given their beneficial effects, probiotics remain promising agents in neonatal gastrointestinal disorders. Probiotics may restore or supply essential bacterial strains needed for gut maturation and homeostasis, particularly in hosts where this process has been disrupted. Here we highlight the unique characteristics of developing intestinal epithelia with a focus on gut development and colonization as well as the inflammatory propensity of immature epithelia. Additionally, we review potential mechanisms of beneficial probiotic interaction with immature intestinal epithelia including immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis and maintenance of barrier function. Improved knowledge of gut-probiotic interaction in developing epithelia will allow for a better understanding of how probiotics exert their beneficial effects and help guide their therapeutic use. PMID:21327024

Functional Proteomic Analysis of Human NucleolusD⃞

PubMed Central

Scherl, Alexander; Couté, Yohann; Déon, Catherine; Callé, Aleth; Kindbeiter, Karine; Sanchez, Jean-Charles; Greco, Anna; Hochstrasser, Denis; Diaz, Jean-Jacques

2002-01-01

The notion of a “plurifunctional” nucleolus is now well established. However, molecular mechanisms underlying the biological processes occurring within this nuclear domain remain only partially understood. As a first step in elucidating these mechanisms we have carried out a proteomic analysis to draw up a list of proteins present within nucleoli of HeLa cells. This analysis allowed the identification of 213 different nucleolar proteins. This catalog complements that of the 271 proteins obtained recently by others, giving a total of ∼350 different nucleolar proteins. Functional classification of these proteins allowed outlining several biological processes taking place within nucleoli. Bioinformatic analyses permitted the assignment of hypothetical functions for 43 proteins for which no functional information is available. Notably, a role in ribosome biogenesis was proposed for 31 proteins. More generally, this functional classification reinforces the plurifunctional nature of nucleoli and provides convincing evidence that nucleoli may play a central role in the control of gene expression. Finally, this analysis supports the recent demonstration of a coupling of transcription and translation in higher eukaryotes. PMID:12429849

Do geographically isolated wetlands influence landscape functions?

USGS Publications Warehouse

Cohen, Matthew J.; Creed, Irena F.; Alexander, Laurie C.; Basu, Nandita; Calhoun, Aram J.K.; Craft, Christopher; D’Amico, Ellen; DeKeyser, Edward S.; Fowler, Laurie; Golden, Heather E.; Jawitz, James W.; Kalla, Peter; Kirkman, L. Katherine; Lane, Charles R.; Lang, Megan; Leibowitz, Scott G.; Lewis, David Bruce; Marton, John; McLaughlin, Daniel L.; Mushet, David M.; Raanan-Kiperwas, Hadas; Rains, Mark C.; Smith, Lora; Walls, Susan C.

2015-01-01

Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs.

Do geographically isolated wetlands influence landscape functions?

PubMed Central

Cohen, Matthew J.; Creed, Irena F.; Alexander, Laurie; Basu, Nandita B.; Calhoun, Aram J. K.; Craft, Christopher; D’Amico, Ellen; DeKeyser, Edward; Fowler, Laurie; Golden, Heather E.; Jawitz, James W.; Kalla, Peter; Kirkman, L. Katherine; Lane, Charles R.; Lang, Megan; Leibowitz, Scott G.; Lewis, David Bruce; Marton, John; McLaughlin, Daniel L.; Mushet, David M.; Raanan-Kiperwas, Hadas; Rains, Mark C.; Smith, Lora; Walls, Susan C.

2016-01-01

Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs. PMID:26858425

Paradoxical roles of dual oxidases in cancer biology.

PubMed

Little, Andrew C; Sulovari, Arvis; Danyal, Karamatullah; Heppner, David E; Seward, David J; van der Vliet, Albert

2017-09-01

Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities. Copyright © 2017 Elsevier Inc. All rights reserved.

Knowledge Gaps in Rodent Pancreas Biology: Taking Human Pluripotent Stem Cell-Derived Pancreatic Beta Cells into Our Own Hands

PubMed Central

Santosa, Munirah Mohamad; Low, Blaise Su Jun; Pek, Nicole Min Qian; Teo, Adrian Kee Keong

2016-01-01

In the field of stem cell biology and diabetes, we and others seek to derive mature and functional human pancreatic β cells for disease modeling and cell replacement therapy. Traditionally, knowledge gathered from rodents is extended to human pancreas developmental biology research involving human pluripotent stem cells (hPSCs). While much has been learnt from rodent pancreas biology in the early steps toward Pdx1+ pancreatic progenitors, much less is known about the transition toward Ngn3+ pancreatic endocrine progenitors. Essentially, the later steps of pancreatic β cell development and maturation remain elusive to date. As a result, the most recent advances in the stem cell and diabetes field have relied upon combinatorial testing of numerous growth factors and chemical compounds in an arbitrary trial-and-error fashion to derive mature and functional human pancreatic β cells from hPSCs. Although this hit-or-miss approach appears to have made some headway in maturing human pancreatic β cells in vitro, its underlying biology is vaguely understood. Therefore, in this mini-review, we discuss some of these late-stage signaling pathways that are involved in human pancreatic β cell differentiation and highlight our current understanding of their relevance in rodent pancreas biology. Our efforts here unravel several novel signaling pathways that can be further studied to shed light on unexplored aspects of rodent pancreas biology. New investigations into these signaling pathways are expected to advance our knowledge in human pancreas developmental biology and to aid in the translation of stem cell biology in the context of diabetes treatments. PMID:26834702

Knowledge Gaps in Rodent Pancreas Biology: Taking Human Pluripotent Stem Cell-Derived Pancreatic Beta Cells into Our Own Hands.

PubMed

Santosa, Munirah Mohamad; Low, Blaise Su Jun; Pek, Nicole Min Qian; Teo, Adrian Kee Keong

2015-01-01

In the field of stem cell biology and diabetes, we and others seek to derive mature and functional human pancreatic β cells for disease modeling and cell replacement therapy. Traditionally, knowledge gathered from rodents is extended to human pancreas developmental biology research involving human pluripotent stem cells (hPSCs). While much has been learnt from rodent pancreas biology in the early steps toward Pdx1(+) pancreatic progenitors, much less is known about the transition toward Ngn3(+) pancreatic endocrine progenitors. Essentially, the later steps of pancreatic β cell development and maturation remain elusive to date. As a result, the most recent advances in the stem cell and diabetes field have relied upon combinatorial testing of numerous growth factors and chemical compounds in an arbitrary trial-and-error fashion to derive mature and functional human pancreatic β cells from hPSCs. Although this hit-or-miss approach appears to have made some headway in maturing human pancreatic β cells in vitro, its underlying biology is vaguely understood. Therefore, in this mini-review, we discuss some of these late-stage signaling pathways that are involved in human pancreatic β cell differentiation and highlight our current understanding of their relevance in rodent pancreas biology. Our efforts here unravel several novel signaling pathways that can be further studied to shed light on unexplored aspects of rodent pancreas biology. New investigations into these signaling pathways are expected to advance our knowledge in human pancreas developmental biology and to aid in the translation of stem cell biology in the context of diabetes treatments.

A biomimetic colorimetric logic gate system based on multi-functional peptide-mediated gold nanoparticle assembly

NASA Astrophysics Data System (ADS)

Li, Yong; Li, Wang; He, Kai-Yu; Li, Pei; Huang, Yan; Nie, Zhou; Yao, Shou-Zhuo

2016-04-01

In natural biological systems, proteins exploit various functional peptide motifs to exert target response and activity switch, providing a functional and logic basis for complex cellular activities. Building biomimetic peptide-based bio-logic systems is highly intriguing but remains relatively unexplored due to limited logic recognition elements and complex signal outputs. In this proof-of-principle work, we attempted to address these problems by utilizing multi-functional peptide probes and the peptide-mediated nanoparticle assembly system. Here, the rationally designed peptide probes function as the dual-target responsive element specifically responsive to metal ions and enzymes as well as the mediator regulating the assembly of gold nanoparticles (AuNPs). Taking advantage of Zn2+ ions and chymotrypsin as the model inputs of metal ions and enzymes, respectively, we constructed the peptide logic system computed by the multi-functional peptide probes and outputted by the readable colour change of AuNPs. In this way, the representative binary basic logic gates (AND, OR, INHIBIT, NAND, IMPLICATION) have been achieved by delicately coding the peptide sequence, demonstrating the versatility of our logic system. Additionally, we demonstrated that the three-input combinational logic gate (INHIBIT-OR) could also be successfully integrated and applied as a multi-tasking biosensor for colorimetric detection of dual targets. This nanoparticle-based peptide logic system presents a valid strategy to illustrate peptide information processing and provides a practical platform for executing peptide computing or peptide-related multiplexing sensing, implying that the controllable nanomaterial assembly is a promising and potent methodology for the advancement of biomimetic bio-logic computation.In natural biological systems, proteins exploit various functional peptide motifs to exert target response and activity switch, providing a functional and logic basis for complex cellular activities. Building biomimetic peptide-based bio-logic systems is highly intriguing but remains relatively unexplored due to limited logic recognition elements and complex signal outputs. In this proof-of-principle work, we attempted to address these problems by utilizing multi-functional peptide probes and the peptide-mediated nanoparticle assembly system. Here, the rationally designed peptide probes function as the dual-target responsive element specifically responsive to metal ions and enzymes as well as the mediator regulating the assembly of gold nanoparticles (AuNPs). Taking advantage of Zn2+ ions and chymotrypsin as the model inputs of metal ions and enzymes, respectively, we constructed the peptide logic system computed by the multi-functional peptide probes and outputted by the readable colour change of AuNPs. In this way, the representative binary basic logic gates (AND, OR, INHIBIT, NAND, IMPLICATION) have been achieved by delicately coding the peptide sequence, demonstrating the versatility of our logic system. Additionally, we demonstrated that the three-input combinational logic gate (INHIBIT-OR) could also be successfully integrated and applied as a multi-tasking biosensor for colorimetric detection of dual targets. This nanoparticle-based peptide logic system presents a valid strategy to illustrate peptide information processing and provides a practical platform for executing peptide computing or peptide-related multiplexing sensing, implying that the controllable nanomaterial assembly is a promising and potent methodology for the advancement of biomimetic bio-logic computation. Electronic supplementary information (ESI) available: Additional figures (Tables S1-S3 and Fig. S1-S6). See DOI: 10.1039/c6nr01072e

Reality Check: What Science Has to Tell Us about Psychiatric Drugs and Their Long-Term Effects

ERIC Educational Resources Information Center

Whitaker, Robert B.

2007-01-01

Three decades of research into the "chemical imbalance" theory of mental disorders failed to pan out. The biological causes of most mental disorders remain unknown. However, it is now well understood that psychiatric drugs work by perturbing neurotransmitter systems, and that the brain, in response to this blocking of normal function, undergoes a…

Combining animal personalities with transcriptomics resolves individual variation within a wild-type zebrafish population and identifies underpinning molecular differences in brain function.

PubMed

Rey, S; Boltana, S; Vargas, R; Roher, N; Mackenzie, S

2013-12-01

Resolving phenotype variation within a population in response to environmental perturbation is central to understanding biological adaptation. Relating meaningful adaptive changes at the level of the transcriptome requires the identification of processes that have a functional significance for the individual. This remains a major objective towards understanding the complex interactions between environmental demand and an individual's capacity to respond to such demands. The interpretation of such interactions and the significance of biological variation between individuals from the same or different populations remain a difficult and under-addressed question. Here, we provide evidence that variation in gene expression between individuals in a zebrafish population can be partially resolved by a priori screening for animal personality and accounts for >9% of observed variation in the brain transcriptome. Proactive and reactive individuals within a wild-type population exhibit consistent behavioural responses over time and context that relates to underlying differences in regulated gene networks and predicted protein-protein interactions. These differences can be mapped to distinct regions of the brain and provide a foundation towards understanding the coordination of underpinning adaptive molecular events within populations. © 2013 John Wiley & Sons Ltd.

Remaining Mysteries of Molecular Biology: The Role of Polyamines in the Cell.

PubMed

Miller-Fleming, Leonor; Olin-Sandoval, Viridiana; Campbell, Kate; Ralser, Markus

2015-10-23

The polyamines (PAs) spermidine, spermine, putrescine and cadaverine are an essential class of metabolites found throughout all kingdoms of life. In this comprehensive review, we discuss their metabolism, their various intracellular functions and their unusual and conserved regulatory features. These include the regulation of translation via upstream open reading frames, the over-reading of stop codons via ribosomal frameshifting, the existence of an antizyme and an antizyme inhibitor, ubiquitin-independent proteasomal degradation, a complex bi-directional membrane transport system and a unique posttranslational modification-hypusination-that is believed to occur on a single protein only (eIF-5A). Many of these features are broadly conserved indicating that PA metabolism is both concentration critical and evolutionary ancient. When PA metabolism is disrupted, a plethora of cellular processes are affected, including transcription, translation, gene expression regulation, autophagy and stress resistance. As a result, the role of PAs has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer. Despite comprehensive studies addressing PAs, a unifying concept to interpret their molecular role is missing. The precise biochemical function of polyamines is thus one of the remaining mysteries of molecular cell biology. Copyright © 2015. Published by Elsevier Ltd.

Rational Diversification of a Promoter Providing Fine-Tuned Expression and Orthogonal Regulation for Synthetic Biology

PubMed Central

Blount, Benjamin A.; Weenink, Tim; Vasylechko, Serge; Ellis, Tom

2012-01-01

Yeast is an ideal organism for the development and application of synthetic biology, yet there remain relatively few well-characterised biological parts suitable for precise engineering of this chassis. In order to address this current need, we present here a strategy that takes a single biological part, a promoter, and re-engineers it to produce a fine-graded output range promoter library and new regulated promoters desirable for orthogonal synthetic biology applications. A highly constitutive Saccharomyces cerevisiae promoter, PFY1p, was identified by bioinformatic approaches, characterised in vivo and diversified at its core sequence to create a 36-member promoter library. TetR regulation was introduced into PFY1p to create a synthetic inducible promoter (iPFY1p) that functions in an inverter device. Orthogonal and scalable regulation of synthetic promoters was then demonstrated for the first time using customisable Transcription Activator-Like Effectors (TALEs) modified and designed to act as orthogonal repressors for specific PFY1-based promoters. The ability to diversify a promoter at its core sequences and then independently target Transcription Activator-Like Orthogonal Repressors (TALORs) to virtually any of these sequences shows great promise toward the design and construction of future synthetic gene networks that encode complex “multi-wire” logic functions. PMID:22442681

B. F. Skinner and G. H. Mead: on biological science and social science.

PubMed Central

Blackman, D E

1991-01-01

Skinner's contributions to psychology provide a unique bridge between psychology conceptualized as a biological science and psychology conceptualized as a social science. Skinner focused on behavior as a naturally occurring biological phenomenon of interest in its own right, functionally related to surrounding events and, in particular (like phylogenesis), subject to selection by its consequences. This essentially biological orientation was further enhanced by Skinner's emphasis on the empirical foundations provided by laboratory-based experimental analyses of behavior, often with nonhuman subjects. Skinner's theoretical writings, however, also have affinity with the traditions of constructionist social science. The verbal behavior of humans is said to be subject, like other behavior, to functional analyses in terms of its environment, in this case its social context. Verbal behavior in turn makes it possible for us to relate to private events, a process that ultimately allows for the development of consciousness, which is thus said to be a social product. Such ideas make contact with aspects of G. H. Mead's social behaviorism and, perhaps of more contemporary impact in psychology, L. Vygotsky's general genetic law of cultural development. Failure to articulate both the biological and the social science aspects of Skinner's theoretical approach to psychology does a disservice to his unique contribution to a discipline that remains fragmented between two intellectual traditions. PMID:2037828

Rational diversification of a promoter providing fine-tuned expression and orthogonal regulation for synthetic biology.

PubMed

Blount, Benjamin A; Weenink, Tim; Vasylechko, Serge; Ellis, Tom

2012-01-01

Yeast is an ideal organism for the development and application of synthetic biology, yet there remain relatively few well-characterised biological parts suitable for precise engineering of this chassis. In order to address this current need, we present here a strategy that takes a single biological part, a promoter, and re-engineers it to produce a fine-graded output range promoter library and new regulated promoters desirable for orthogonal synthetic biology applications. A highly constitutive Saccharomyces cerevisiae promoter, PFY1p, was identified by bioinformatic approaches, characterised in vivo and diversified at its core sequence to create a 36-member promoter library. TetR regulation was introduced into PFY1p to create a synthetic inducible promoter (iPFY1p) that functions in an inverter device. Orthogonal and scalable regulation of synthetic promoters was then demonstrated for the first time using customisable Transcription Activator-Like Effectors (TALEs) modified and designed to act as orthogonal repressors for specific PFY1-based promoters. The ability to diversify a promoter at its core sequences and then independently target Transcription Activator-Like Orthogonal Repressors (TALORs) to virtually any of these sequences shows great promise toward the design and construction of future synthetic gene networks that encode complex "multi-wire" logic functions.

Origin and Functional Prediction of Pollen Allergens in Plants1[OPEN

PubMed Central

Chen, Miaolin; Xu, Jie; Ren, Kang; Searle, Iain

2016-01-01

Pollen allergies have long been a major pandemic health problem for human. However, the evolutionary events and biological function of pollen allergens in plants remain largely unknown. Here, we report the genome-wide prediction of pollen allergens and their biological function in the dicotyledonous model plant Arabidopsis (Arabidopsis thaliana) and the monocotyledonous model plant rice (Oryza sativa). In total, 145 and 107 pollen allergens were predicted from rice and Arabidopsis, respectively. These pollen allergens are putatively involved in stress responses and metabolic processes such as cell wall metabolism during pollen development. Interestingly, these putative pollen allergen genes were derived from large gene families and became diversified during evolution. Sequence analysis across 25 plant species from green alga to angiosperms suggest that about 40% of putative pollen allergenic proteins existed in both lower and higher plants, while other allergens emerged during evolution. Although a high proportion of gene duplication has been observed among allergen-coding genes, our data show that these genes might have undergone purifying selection during evolution. We also observed that epitopes of an allergen might have a biological function, as revealed by comprehensive analysis of two known allergens, expansin and profilin. This implies a crucial role of conserved amino acid residues in both in planta biological function and allergenicity. Finally, a model explaining how pollen allergens were generated and maintained in plants is proposed. Prediction and systematic analysis of pollen allergens in model plants suggest that pollen allergens were evolved by gene duplication and then functional specification. This study provides insight into the phylogenetic and evolutionary scenario of pollen allergens that will be helpful to future characterization and epitope screening of pollen allergens. PMID:27436829

Origin and Functional Prediction of Pollen Allergens in Plants.

PubMed

Chen, Miaolin; Xu, Jie; Devis, Deborah; Shi, Jianxin; Ren, Kang; Searle, Iain; Zhang, Dabing

2016-09-01

Pollen allergies have long been a major pandemic health problem for human. However, the evolutionary events and biological function of pollen allergens in plants remain largely unknown. Here, we report the genome-wide prediction of pollen allergens and their biological function in the dicotyledonous model plant Arabidopsis (Arabidopsis thaliana) and the monocotyledonous model plant rice (Oryza sativa). In total, 145 and 107 pollen allergens were predicted from rice and Arabidopsis, respectively. These pollen allergens are putatively involved in stress responses and metabolic processes such as cell wall metabolism during pollen development. Interestingly, these putative pollen allergen genes were derived from large gene families and became diversified during evolution. Sequence analysis across 25 plant species from green alga to angiosperms suggest that about 40% of putative pollen allergenic proteins existed in both lower and higher plants, while other allergens emerged during evolution. Although a high proportion of gene duplication has been observed among allergen-coding genes, our data show that these genes might have undergone purifying selection during evolution. We also observed that epitopes of an allergen might have a biological function, as revealed by comprehensive analysis of two known allergens, expansin and profilin. This implies a crucial role of conserved amino acid residues in both in planta biological function and allergenicity. Finally, a model explaining how pollen allergens were generated and maintained in plants is proposed. Prediction and systematic analysis of pollen allergens in model plants suggest that pollen allergens were evolved by gene duplication and then functional specification. This study provides insight into the phylogenetic and evolutionary scenario of pollen allergens that will be helpful to future characterization and epitope screening of pollen allergens. © 2016 American Society of Plant Biologists. All rights reserved.

Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

PubMed Central

Weisberg, Sarah J.; Lyakhovetsky, Roman; Werdiger, Ayelet-chen; Gitler, Aaron D.; Soen, Yoav; Kaganovich, Daniel

2012-01-01

Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability. PMID:22967507

Biology of bone and how it orchestrates the form and function of the skeleton

NASA Technical Reports Server (NTRS)

Sommerfeldt, D. W.; Rubin, C. T.

2001-01-01

The principal role of the skeleton is to provide structural support for the body. While the skeleton also serves as the body's mineral reservoir, the mineralized structure is the very basis of posture, opposes muscular contraction resulting in motion, withstands functional load bearing, and protects internal organs. Although the mass and morphology of the skeleton is defined, to some extent, by genetic determinants, it is the tissue's ability to remodel--the local resorption and formation of bone--which is responsible for achieving this intricate balance between competing responsibilities. The aim of this review is to address bone's form-function relationship, beginning with extensive research in the musculoskeletal disciplines, and focusing on several recent cellular and molecular discoveries which help understand the complex interdependence of bone cells, growth factors, physical stimuli, metabolic demands, and structural responsibilities. With a clinical and spine-oriented audience in mind, the principles of bone cell and molecular biology and physiology are presented, and an attempt has been made to incorporate epidemiologic data and therapeutic implications. Bone research remains interdisciplinary by nature, and a deeper understanding of bone biology will ultimately lead to advances in the treatment of diseases and injuries to bone itself.

Selection platforms for directed evolution in synthetic biology.

PubMed

Tizei, Pedro A G; Csibra, Eszter; Torres, Leticia; Pinheiro, Vitor B

2016-08-15

Life on Earth is incredibly diverse. Yet, underneath that diversity, there are a number of constants and highly conserved processes: all life is based on DNA and RNA; the genetic code is universal; biology is limited to a small subset of potential chemistries. A vast amount of knowledge has been accrued through describing and characterizing enzymes, biological processes and organisms. Nevertheless, much remains to be understood about the natural world. One of the goals in Synthetic Biology is to recapitulate biological complexity from simple systems made from biological molecules-gaining a deeper understanding of life in the process. Directed evolution is a powerful tool in Synthetic Biology, able to bypass gaps in knowledge and capable of engineering even the most highly conserved biological processes. It encompasses a range of methodologies to create variation in a population and to select individual variants with the desired function-be it a ligand, enzyme, pathway or even whole organisms. Here, we present some of the basic frameworks that underpin all evolution platforms and review some of the recent contributions from directed evolution to synthetic biology, in particular methods that have been used to engineer the Central Dogma and the genetic code. © 2016 The Author(s).

Biological roles of glycans

PubMed Central

Varki, Ajit

2017-01-01

Abstract Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences. PMID:27558841

A dedicated database system for handling multi-level data in systems biology.

PubMed

Pornputtapong, Natapol; Wanichthanarak, Kwanjeera; Nilsson, Avlant; Nookaew, Intawat; Nielsen, Jens

2014-01-01

Advances in high-throughput technologies have enabled extensive generation of multi-level omics data. These data are crucial for systems biology research, though they are complex, heterogeneous, highly dynamic, incomplete and distributed among public databases. This leads to difficulties in data accessibility and often results in errors when data are merged and integrated from varied resources. Therefore, integration and management of systems biological data remain very challenging. To overcome this, we designed and developed a dedicated database system that can serve and solve the vital issues in data management and hereby facilitate data integration, modeling and analysis in systems biology within a sole database. In addition, a yeast data repository was implemented as an integrated database environment which is operated by the database system. Two applications were implemented to demonstrate extensibility and utilization of the system. Both illustrate how the user can access the database via the web query function and implemented scripts. These scripts are specific for two sample cases: 1) Detecting the pheromone pathway in protein interaction networks; and 2) Finding metabolic reactions regulated by Snf1 kinase. In this study we present the design of database system which offers an extensible environment to efficiently capture the majority of biological entities and relations encountered in systems biology. Critical functions and control processes were designed and implemented to ensure consistent, efficient, secure and reliable transactions. The two sample cases on the yeast integrated data clearly demonstrate the value of a sole database environment for systems biology research.

Structured Water Layers Adjacent to Biological Membranes

PubMed Central

Higgins, Michael J.; Polcik, Martin; Fukuma, Takeshi; Sader, John E.; Nakayama, Yoshikazu; Jarvis, Suzanne P.

2006-01-01

Water amid the restricted space of crowded biological macromolecules and at membrane interfaces is essential for cell function, though the structure and function of this “biological water” itself remains poorly defined. The force required to remove strongly bound water is referred to as the hydration force and due to its widespread importance, it has been studied in numerous systems. Here, by using a highly sensitive dynamic atomic force microscope technique in conjunction with a carbon nanotube probe, we reveal a hydration force with an oscillatory profile that reflects the removal of up to five structured water layers from between the probe and biological membrane surface. Further, we find that the hydration force can be modified by changing the membrane fluidity. For 1,2-dipalmitoyl-sn-glycero-3-phosphocholine gel (Lβ) phase bilayers, each oscillation in the force profile indicates the force required to displace a single layer of water molecules from between the probe and bilayer. In contrast, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine fluid (Lα) phase bilayers at 60°C and 1,2-dioleoyl-sn-glycero-3-phosphocholine fluid (Lα) phase bilayers at 24°C seriously disrupt the molecular ordering of the water and result predominantly in a monotonic force profile. PMID:16798815

Embryological development of pacemaker hierarchy and membrane currents related to the function of the adult sinus node: implications for autonomic modulation of biopacemakers.

PubMed

Opthof, Tobias

2007-02-01

The sinus node is an inhomogeneous structure. In the embryonic heart all myocytes have sinus node type pacemaker channels (I (f)) in their sarcolemma. Shortly before birth, these channels disappear from the ventricular myocytes. The response of the adult sinus node to changes in the interstitium, in particular to (neuro)transmitters, results from the interplay between the responses of all of its constituent cells. The response of the whole sinus node cannot be simply deduced from these cellular responses, because all cells have different responses to specific agonists. A biological pacemaker will be more homogeneous. Therefore it can be anticipated that tuning of cycle length may be problematic. It is discussed that efforts to create a biological pacemaker responsive to vagal stimulation, may be counterproductive, because it may have the potential risk of 'standstill' of the biological pacemaker. A normal sinus node remains spontaneously active at high concentrations of acetylcholine, because it has areas that are unresponsive to acetylcholine. The same is pertinent to other substances with a negative chronotropic effect. Such functional inhomogeneity is lacking in biological pacemakers.

Organic core-sheath nanowire artificial synapses with femtojoule energy consumption.

PubMed

Xu, Wentao; Min, Sung-Yong; Hwang, Hyunsang; Lee, Tae-Woo

2016-06-01

Emulation of biological synapses is an important step toward construction of large-scale brain-inspired electronics. Despite remarkable progress in emulating synaptic functions, current synaptic devices still consume energy that is orders of magnitude greater than do biological synapses (~10 fJ per synaptic event). Reduction of energy consumption of artificial synapses remains a difficult challenge. We report organic nanowire (ONW) synaptic transistors (STs) that emulate the important working principles of a biological synapse. The ONWs emulate the morphology of nerve fibers. With a core-sheath-structured ONW active channel and a well-confined 300-nm channel length obtained using ONW lithography, ~1.23 fJ per synaptic event for individual ONW was attained, which rivals that of biological synapses. The ONW STs provide a significant step toward realizing low-energy-consuming artificial intelligent electronics and open new approaches to assembling soft neuromorphic systems with nanometer feature size.

Hierarchical chirality transfer in the growth of Towel Gourd tendrils

PubMed Central

Wang, Jian-Shan; Wang, Gang; Feng, Xi-Qiao; Kitamura, Takayuki; Kang, Yi-Lan; Yu, Shou-Wen; Qin, Qing-Hua

2013-01-01

Chirality plays a significant role in the physical properties and biological functions of many biological materials, e.g., climbing tendrils and twisted leaves, which exhibit chiral growth. However, the mechanisms underlying the chiral growth of biological materials remain unclear. In this paper, we investigate how the Towel Gourd tendrils achieve their chiral growth. Our experiments reveal that the tendrils have a hierarchy of chirality, which transfers from the lower levels to the higher. The change in the helical angle of cellulose fibrils at the subcellular level induces an intrinsic torsion of tendrils, leading to the formation of the helical morphology of tendril filaments. A chirality transfer model is presented to elucidate the chiral growth of tendrils. This present study may help understand various chiral phenomena observed in biological materials. It also suggests that chirality transfer can be utilized in the development of hierarchically chiral materials having unique properties. PMID:24173107

Inverse statistical physics of protein sequences: a key issues review.

PubMed

Cocco, Simona; Feinauer, Christoph; Figliuzzi, Matteo; Monasson, Rémi; Weigt, Martin

2018-03-01

In the course of evolution, proteins undergo important changes in their amino acid sequences, while their three-dimensional folded structure and their biological function remain remarkably conserved. Thanks to modern sequencing techniques, sequence data accumulate at unprecedented pace. This provides large sets of so-called homologous, i.e. evolutionarily related protein sequences, to which methods of inverse statistical physics can be applied. Using sequence data as the basis for the inference of Boltzmann distributions from samples of microscopic configurations or observables, it is possible to extract information about evolutionary constraints and thus protein function and structure. Here we give an overview over some biologically important questions, and how statistical-mechanics inspired modeling approaches can help to answer them. Finally, we discuss some open questions, which we expect to be addressed over the next years.

Inverse statistical physics of protein sequences: a key issues review

NASA Astrophysics Data System (ADS)

Cocco, Simona; Feinauer, Christoph; Figliuzzi, Matteo; Monasson, Rémi; Weigt, Martin

2018-03-01

In the course of evolution, proteins undergo important changes in their amino acid sequences, while their three-dimensional folded structure and their biological function remain remarkably conserved. Thanks to modern sequencing techniques, sequence data accumulate at unprecedented pace. This provides large sets of so-called homologous, i.e. evolutionarily related protein sequences, to which methods of inverse statistical physics can be applied. Using sequence data as the basis for the inference of Boltzmann distributions from samples of microscopic configurations or observables, it is possible to extract information about evolutionary constraints and thus protein function and structure. Here we give an overview over some biologically important questions, and how statistical-mechanics inspired modeling approaches can help to answer them. Finally, we discuss some open questions, which we expect to be addressed over the next years.

Bile salts as semiochemicals in fish

USGS Publications Warehouse

Buchinger, Tyler J.; Li, Weiming; Johnson, Nicholas S.

2014-01-01

Bile salts are potent olfactory stimuli in fishes; however the biological functions driving such sensitivity remain poorly understood. We provide an integrative review of bile salts as semiochemicals in fish. First, we present characteristics of bile salt structure, metabolism, and function that are particularly relevant to chemical communication. Bile salts display a systematic pattern of structural variation across taxa, are efficiently synthesized, and are stable in the environment. Bile salts are released into the water via the intestine, urinary tract, or gills, and are highly water soluble. Second, we consider the potential role of bile salts as semiochemicals in the contexts of detecting nearby fish, foraging, assessing risk, migrating, and spawning. Lastly, we suggest future studies on bile salts as semiochemicals further characterize release into the environment, behavioral responses by receivers, and directly test the biological contexts underlying olfactory sensitivity.

Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases.

PubMed

Fragoulis, George E; Siebert, Stefan; McInnes, Iain B

2016-01-01

The discovery of the biological functions of the interleukin-23/-17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated diseases. Therapeutic agents targeting these cytokines and/or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.

Resource recovery from wastewater: application of meta-omics to phosphorus and carbon management.

PubMed

Sales, Christopher M; Lee, Patrick K H

2015-06-01

A growing trend at wastewater treatment plants is the recovery of resources and energy from wastewater. Enhanced biological phosphorus removal and anaerobic digestion are two established biotechnology approaches for the recovery of phosphorus and carbon, respectively. Meta-omics approaches (meta-genomics, transcriptomics, proteomics, and metabolomics) are providing novel biological insights into these complex biological systems. In particular, genome-centric metagenomics analyses are revealing the function and physiology of individual community members. Querying transcripts, proteins and metabolites are emerging techniques that can inform the cellular responses under different conditions. Overall, meta-omics approaches are shedding light into complex microbial communities once regarded as 'blackboxes', but challenges remain to integrate information from meta-omics into engineering design and operation guidelines. Copyright © 2015 Elsevier Ltd. All rights reserved.

78 FR 50094 - Notice of Inventory Completion: Maxey Museum, Walla Walla, WA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-16

... of the Maxey Museum, Walla Walla, WA. The human remains were removed from the Whitman College Biology... the Biology Department at Whitman College, in Walla Walla County, WA, the Biology Department asked the Maxey Museum at Whitman College to determine whether any of the human remains in the Biology Department...

A New Approach to Dissect Nuclear Organization: TALE-Mediated Genome Visualization (TGV).

PubMed

Miyanari, Yusuke

2016-01-01

Spatiotemporal organization of chromatin within the nucleus has so far remained elusive. Live visualization of nuclear remodeling could be a promising approach to understand its functional relevance in genome functions and mechanisms regulating genome architecture. Recent technological advances in live imaging of chromosomes begun to explore the biological roles of the movement of the chromatin within the nucleus. Here I describe a new technique, called TALE-mediated genome visualization (TGV), which allows us to visualize endogenous repetitive sequence including centromeric, pericentromeric, and telomeric repeats in living cells.

In Silico Analysis for the Study of Botulinum Toxin Structure

NASA Astrophysics Data System (ADS)

Suzuki, Tomonori; Miyazaki, Satoru

2010-01-01

Protein-protein interactions play many important roles in biological function. Knowledge of protein-protein complex structure is required for understanding the function. The determination of protein-protein complex structure by experimental studies remains difficult, therefore computational prediction of protein structures by structure modeling and docking studies is valuable method. In addition, MD simulation is also one of the most popular methods for protein structure modeling and characteristics. Here, we attempt to predict protein-protein complex structure and property using some of bioinformatic methods, and we focus botulinum toxin complex as target structure.

Uncovering the etiology of conversion disorder: insights from functional neuroimaging

PubMed Central

Ejareh dar, Maryam; Kanaan, Richard AA

2016-01-01

Conversion disorder (CD) is a syndrome of neurological symptoms arising without organic cause, arguably in response to emotional stress, but the exact neural substrates of these symptoms and the underlying mechanisms remain poorly understood with the hunt for a biological basis afoot for centuries. In the past 15 years, novel insights have been gained with the advent of functional neuroimaging studies in patients suffering from CDs in both motor and nonmotor domains. This review summarizes recent functional neuroimaging studies including functional magnetic resonance imaging (fMRI), single photon emission computerized tomography (SPECT), and positron emission tomography (PET) to see whether they bring us closer to understanding the etiology of CD. Convergent functional neuroimaging findings suggest alterations in brain circuits that could point to different mechanisms for manifesting functional neurological symptoms, in contrast with feigning or healthy controls. Abnormalities in emotion processing and in emotion-motor processing suggest a diathesis, while differential reactions to certain stressors implicate a specific response to trauma. No comprehensive theory emerges from these clues, and all results remain preliminary, but functional neuroimaging has at least given grounds for hope that a model for CD may soon be found. PMID:26834476

Determinants of the rate of protein sequence evolution

PubMed Central

Zhang, Jianzhi; Yang, Jian-Rong

2015-01-01

The rate and mechanism of protein sequence evolution have been central questions in evolutionary biology since the 1960s. Although the rate of protein sequence evolution depends primarily on the level of functional constraint, exactly what constitutes functional constraint has remained unclear. The increasing availability of genomic data has allowed for much needed empirical examinations on the nature of functional constraint. These studies found that the evolutionary rate of a protein is predominantly influenced by its expression level rather than functional importance. A combination of theoretical and empirical analyses have identified multiple mechanisms behind these observations and demonstrated a prominent role that selection against errors in molecular and cellular processes plays in protein evolution. PMID:26055156

Process-based network decomposition reveals backbone motif structure

PubMed Central

Wang, Guanyu; Du, Chenghang; Chen, Hao; Simha, Rahul; Rong, Yongwu; Xiao, Yi; Zeng, Chen

2010-01-01

A central challenge in systems biology today is to understand the network of interactions among biomolecules and, especially, the organizing principles underlying such networks. Recent analysis of known networks has identified small motifs that occur ubiquitously, suggesting that larger networks might be constructed in the manner of electronic circuits by assembling groups of these smaller modules. Using a unique process-based approach to analyzing such networks, we show for two cell-cycle networks that each of these networks contains a giant backbone motif spanning all the network nodes that provides the main functional response. The backbone is in fact the smallest network capable of providing the desired functionality. Furthermore, the remaining edges in the network form smaller motifs whose role is to confer stability properties rather than provide function. The process-based approach used in the above analysis has additional benefits: It is scalable, analytic (resulting in a single analyzable expression that describes the behavior), and computationally efficient (all possible minimal networks for a biological process can be identified and enumerated). PMID:20498084

Developing PFC representations using reinforcement learning

PubMed Central

Reynolds, Jeremy R.; O'Reilly, Randall C.

2009-01-01

From both functional and biological considerations, it is widely believed that action production, planning, and goal-oriented behaviors supported by the frontal cortex are organized hierarchically (Fuster, 1990, Koechlin, Ody, & Kouneiher, 2003, & Miller, Galanter, & Pribram, 1960) However, the nature of the different levels of the hierarchy remains unclear, and little attention has been paid to the origins of such a hierarchy. We address these issues through biologically-inspired computational models that develop representations through reinforcement learning. We explore several different factors in these models that might plausibly give rise to a hierarchical organization of representations within the PFC, including an initial connectivity hierarchy within PFC, a hierarchical set of connections between PFC and subcortical structures controlling it, and differential synaptic plasticity schedules. Simulation results indicate that architectural constraints contribute to the segregation of different types of representations, and that this segregation facilitates learning. These findings are consistent with the idea that there is a functional hierarchy in PFC, as captured in our earlier computational models of PFC function and a growing body of empirical data. PMID:19591977

Lactosamine-Based Derivatives as Tools to Delineate the Biological Functions of Galectins: Application to Skin Tissue Repair.

PubMed

Dion, Johann; Deshayes, Frédérique; Storozhylova, Nataliya; Advedissian, Tamara; Lambert, Annie; Viguier, Mireille; Tellier, Charles; Dussouy, Christophe; Poirier, Françoise; Grandjean, Cyrille

2017-04-18

Galectins have been recognized as potential novel therapeutic targets for the numerous fundamental biological processes in which they are involved. Galectins are key players in homeostasis, and as such their expression and function are finely tuned in vivo. Thus, their modes of action are complex and remain largely unexplored, partly because of the lack of dedicated tools. We thus designed galectin inhibitors from a lactosamine core, functionalized at key C2 and C3' positions by aromatic substituents to ensure both high affinity and selectivity, and equipped with a spacer that can be modified on demand to further modulate their physico-chemical properties. As a proof-of-concept, galectin-3 was selectively targeted. The efficacy of the synthesized di-aromatic lactosamine tools was shown in cellular assays to modulate collective epithelial cell migration and to interfere with actin/cortactin localization. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel approaches to determine contractile function of the isolated adult zebrafish ventricular cardiac myocyte.

PubMed

Dvornikov, Alexey V; Dewan, Sukriti; Alekhina, Olga V; Pickett, F Bryan; de Tombe, Pieter P

2014-05-01

The zebrafish (Danio rerio) has been used extensively in cardiovascular biology, but mainly in the study of heart development. The relative ease of its genetic manipulation may indicate the suitability of this species as a cost-effective model system for the study of cardiac contractile biology. However, whether the zebrafish heart is an appropriate model system for investigations pertaining to mammalian cardiac contractile structure-function relationships remains to be resolved. Myocytes were isolated from adult zebrafish hearts by enzymatic digestion, attached to carbon rods, and twitch force and intracellular Ca(2+) were measured. We observed the modulation of twitch force, but not of intracellular Ca(2+), by both extracellular [Ca(2+)] and sarcomere length. In permeabilized cells/myofibrils, we found robust myofilament length-dependent activation. Moreover, modulation of myofilament activation-relaxation and force redevelopment kinetics by varied Ca(2+) activation levels resembled that found previously in mammalian myofilaments. We conclude that the zebrafish is a valid model system for the study of cardiac contractile structure-function relationships.

Regulators of Lysosome Function and Dynamics in Caenorhabditis elegans

PubMed Central

Gee, Kevin; Zamora, Danniel; Horm, Teresa; George, Laeth; Upchurch, Cameron; Randall, Justin; Weaver, Colby; Sanford, Caitlin; Miller, Austin; Hernandez, Sebastian; Dang, Hope; Fares, Hanna

2017-01-01

Lysosomes, the major membrane-bound degradative organelles, have a multitude of functions in eukaryotic cells. Lysosomes are the terminal compartments in the endocytic pathway, though they display highly dynamic behaviors, fusing with each other and with late endosomes in the endocytic pathway, and with the plasma membrane during regulated exocytosis and for wound repair. After fusing with late endosomes, lysosomes are reformed from the resulting hybrid organelles through a process that involves budding of a nascent lysosome, extension of the nascent lysosome from the hybrid organelle, while remaining connected by a membrane bridge, and scission of the membrane bridge to release the newly formed lysosome. The newly formed lysosomes undergo cycles of homotypic fusion and fission reactions to form mature lysosomes. In this study, we used a forward genetic screen in Caenorhabditis elegans to identify six regulators of lysosome biology. We show that these proteins function in different steps of lysosome biology, regulating lysosome formation, lysosome fusion, and lysosome degradation. PMID:28122949

SPED light sheet microscopy: fast mapping of biological system structure and function

PubMed Central

Tomer, Raju; Lovett-Barron, Matthew; Kauvar, Isaac; Andalman, Aaron; Burns, Vanessa M.; Sankaran, Sethuraman; Grosenick, Logan; Broxton, Michael; Yang, Samuel; Deisseroth, Karl

2016-01-01

The goal of understanding living nervous systems has driven interest in high-speed and large field-of-view volumetric imaging at cellular resolution. Light-sheet microscopy approaches have emerged for cellular-resolution functional brain imaging in small organisms such as larval zebrafish, but remain fundamentally limited in speed. Here we have developed SPED light sheet microscopy, which combines large volumetric field-of-view via an extended depth of field with the optical sectioning of light sheet microscopy, thereby eliminating the need to physically scan detection objectives for volumetric imaging. SPED enables scanning of thousands of volumes-per-second, limited only by camera acquisition rate, through the harnessing of optical mechanisms that normally result in unwanted spherical aberrations. We demonstrate capabilities of SPED microscopy by performing fast sub-cellular resolution imaging of CLARITY mouse brains and cellular-resolution volumetric Ca2+ imaging of entire zebrafish nervous systems. Together, SPED light sheet methods enable high-speed cellular-resolution volumetric mapping of biological system structure and function. PMID:26687363

Modulating Transfer RNA Anticodon Modifications and Biologic Responses in Human Cells.

DTIC Science & Technology

1987-12-15

mercaptopurine and 6-ethylmercaptopurine were both able to inhibit the growth and induce functional differentiation of HGPRT-deficient HL-60 cells...with 6-ethylmercaptopurine mediating these responses at significantly lower concentrations than 6- mercaptopurine . In contrast to 6- mercaptopurine , 6...concentrations it was cytotoxic to both. The mechanism by which 6-ethyl- mercaptopurine elicits its effects on HL-60 cells remains to be established

Investigation of type-I interferon dysregulation by arenaviruses : a multidisciplinary approach.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozina, Carol L.; Moorman, Matthew Wallace; Branda, Catherine

2011-09-01

This report provides a detailed overview of the work performed for project number 130781, 'A Systems Biology Approach to Understanding Viral Hemorrhagic Fever Pathogenesis.' We report progress in five key areas: single cell isolation devices and control systems, fluorescent cytokine and transcription factor reporters, on-chip viral infection assays, molecular virology analysis of Arenavirus nucleoprotein structure-function, and development of computational tools to predict virus-host protein interactions. Although a great deal of work remains from that begun here, we have developed several novel single cell analysis tools and knowledge of Arenavirus biology that will facilitate and inform future publications and funding proposals.

STAT1 in cancer: friend or foe?

PubMed

Zhang, Ying; Liu, Zhaoyong

2017-08-01

The first STAT family member, STAT1, is an essential component of interferon (IFN)-signaling, which mediates several cellular functions in response to stimulation by cytokines, growth factors, and hormones, such as the IFNs and IL-6. The role and significance of STAT1 in cancer biology have been studied for a decade. The majority of evidence shows that activating STAT1 plays a tumor suppressor role in cancer cells. Nevertheless, results from some experiments and clinical studies suggest that STAT1 also exerts tumor promoter effects under specific conditions. In some malignant phenotypes, STAT1 can function either as an oncoprotein or tumor suppressor in the same cell type, depending on the specific genetic background. Thus, the function of STAT1 in cancer biology remains a mystery. In this review, we discuss both the "friend" and "foe" features of STAT1 by summarizing its tumor suppressor or oncogenic functions and mechanisms. To explain how STAT1 may mediate its tumor suppressor effects, we discuss several possible mechanisms, one of which is linked to the role of STAT1β, an isoform of STAT1.

Pushing the size limit of de novo structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX

PubMed Central

Fischer, Axel W.; Bordignon, Enrica; Bleicken, Stephanie; García-Sáez, Ana J.; Jeschke, Gunnar; Meiler, Jens

2016-01-01

Structure determination remains a challenge for many biologically important proteins. In particular, proteins that adopt multiple conformations often evade crystallization in all biologically relevant states. Although computational de novo protein folding approaches often sample biologically relevant conformations, the selection of the most accurate model for different functional states remains a formidable challenge, in particular, for proteins with more than about 150 residues. Electron paramagnetic resonance (EPR) spectroscopy can obtain limited structural information for proteins in well-defined biological states and thereby assist in selecting biologically relevant conformations. The present study demonstrates that de novo folding methods are able to accurately sample the folds of 192-residue long soluble monomeric Bcl-2-associated X protein (BAX). The tertiary structures of the monomeric and homodimeric forms of BAX were predicted using the primary structure as well as 25 and 11 EPR distance restraints, respectively. The predicted models were subsequently compared to respective NMR/X-ray structures of BAX. EPR restraints improve the protein-size normalized root-mean-square-deviation (RMSD100) of the most accurate models with respect to the NMR/crystal structure from 5.9 Å to 3.9 Å and from 5.7 Å to 3.3 Å, respectively. Additionally, the model discrimination is improved, which is demonstrated by an improvement of the enrichment from 5% to 15% and from 13% to 21%, respectively. PMID:27129417

Purification of Plant Receptor Kinases from Plant Plasma Membranes.

PubMed

Lee, Jin Suk

2017-01-01

Receptor kinases play a central role in various biological processes, but due to their low abundance and highly hydrophobic and dynamic nature, only a few of them have been functionally characterized, and their partners and ligands remain unidentified. Receptor protein extraction and purification from plant tissues is one of the most challenging steps for the success of various biochemical analyses to characterize their function. Immunoprecipitation is a widely used and selective method for enriching or purifying a specific protein. Here we describe two different optimized protein purification protocols, batch and on-chip immunoprecipitation, which efficiently isolate plant membrane receptor kinases for functional analysis.

Reconstructing temperatures from lake sediments in northern Europe: what do the biological proxies really tell us?

NASA Astrophysics Data System (ADS)

Cunningham, Laura; Holmes, Naomi; Bigler, Christian; Dadal, Anna; Bergman, Jonas; Eriksson, Lars; Brooks, Stephen; Langdon, Pete; Caseldine, Chris

2010-05-01

Over the past two decades considerable effort has been devoted to quantitatively reconstructing temperatures from biological proxies preserved in lake sediments, via transfer functions. Such transfer functions typically consist of modern sediment samples, collected over a broad environmental gradient. Correlations between the biological communities and environmental parameters observed over these broad gradients are assumed to be equally valid temporally. The predictive ability of such spatially based transfer functions has traditionally been assessed by comparisons of measured and inferred temperatures within the calibration sets, with little validation against historical data. Although statistical techniques such as bootstrapping may improve error estimation, this approach remains partly a circular argument. This raises the question of how reliable such reconstructions are for inferring past changes in temperature? In order to address this question, we used transfer functions to reconstruct July temperatures from diatoms and chironomids from several locations across northern Europe. The transfer functions used showed good internal calibration statistics (r2 = 0.66 - 0.91). The diatom and chironomid inferred July air temperatures were compared to local observational records. As the sediment records were non-annual, all data were first smoothed using a 15 yr moving average filter. None of the five biologically-inferred temperature records were correlated with the local meteorological records. Furthermore, diatom inferred temperatures did not agree with chironomid inferred temperatures from the same cores from the same sites. In an attempt to understand this poor performance the biological proxy data was compressed using principal component analysis (PCA), and the PCA axes compared to the local meteorological data. These analyses clearly demonstrated that July temperatures were not correlated with the biological data at these locations. Some correlations were observed between the biological proxies and autumn and spring temperatures, although this varied slightly between sites and proxies. For example, chironomid data from Iceland was most strongly correlated with temperatures in February, March and April whilst in northern Sweden, the chironomid data was most strongly correlated with temperatures in March, April and May. It is suggested that the biological data at these sites may be responding to changes in the length of the ice-free period or hydrological regimes (including snow melt), rather than temperature per se. Our findings demonstrate the need to validate inferred temperatures against local meteorological data. Where such validation cannot be undertaken, inferred temperature reconstructions should be treated cautiously.

Executive summary of NIH workshop on the Use and Biology of Energy Drinks: Current Knowledge and Critical Gaps

PubMed Central

Sorkin, Barbara C; Camp, Kathryn M; Haggans, Carol J; Deuster, Patricia A; Haverkos, Lynne; Maruvada, Padma; Witt, Ellen; Coates, Paul M

2014-01-01

Sales of energy drinks in the United States reached $12.5 billion in 2012. Emergency department visits related to consumption of these products have increased sharply, and while these numbers remain small relative to product sales, they raise important questions regarding biological and behavioral effects. Although some common ingredients of energy drinks have been extensively studied (e.g., caffeine, B vitamins, sugars, inositol), data on other ingredients (e.g., taurine) are limited. Summarized here are data presented elsewhere in this issue on the prevalence and patterns of caffeine-containing energy drink use, the effects of these products on alertness, fatigue, cognitive functions, sleep, mood, homeostasis, as well as on exercise physiology and metabolism, and the biological mechanisms mediating the observed effects. There are substantial data on the effects of some energy drink ingredients, such as caffeine and sugars, on many of these outcomes; however, even for these ingredients many controversies and gaps remain, and data on other ingredients in caffeine-containing energy drinks, and on ingredient interactions, are sparse. This summary concludes with a discussion of critical gaps in the data and potential next steps. PMID:25293538

Emerging concepts and future challenges in innate lymphoid cell biology

PubMed Central

Artis, David

2016-01-01

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role. PMID:27811053

m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells

PubMed Central

Cui, Qi; Shi, Hailing; Ye, Peng; Li, Li; Qu, Qiuhao; Sun, Guoqiang; Sun, Guihua; Lu, Zhike; Huang, Yue; Yang, Cai-Guang; Riggs, Arthur D.

2017-01-01

Summary RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma. PMID:28297667

Mass spectrometry-based proteomics: from cancer biology to protein biomarkers, drug targets, and clinical applications.

PubMed

Jimenez, Connie R; Verheul, Henk M W

2014-01-01

Proteomics is optimally suited to bridge the gap between genomic information on the one hand and biologic functions and disease phenotypes at the other, since it studies the expression and/or post-translational modification (especially phosphorylation) of proteins--the major cellular players bringing about cellular functions--at a global level in biologic specimens. Mass spectrometry technology and (bio)informatic tools have matured to the extent that they can provide high-throughput, comprehensive, and quantitative protein inventories of cells, tissues, and biofluids in clinical samples at low level. In this article, we focus on next-generation proteomics employing nanoliquid chromatography coupled to high-resolution tandem mass spectrometry for in-depth (phospho)protein profiling of tumor tissues and (proximal) biofluids, with a focus on studies employing clinical material. In addition, we highlight emerging proteogenomic approaches for the identification of tumor-specific protein variants, and targeted multiplex mass spectrometry strategies for large-scale biomarker validation. Below we provide a discussion of recent progress, some research highlights, and challenges that remain for clinical translation of proteomic discoveries.

Junk DNA and the long non-coding RNA twist in cancer genetics

PubMed Central

Ling, Hui; Vincent, Kimberly; Pichler, Martin; Fodde, Riccardo; Berindan-Neagoe, Ioana; Slack, Frank J.; Calin, George A

2015-01-01

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions, and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function, and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer. PMID:25619839

Meconium proteins as a source of biomarkers for the assessment of the intrauterine environment of the fetus.

PubMed

Lisowska-Myjak, B; Skarżyńska, E; Bakun, M

2018-06-01

Intrauterine environmental factors can be associated with perinatal complications and long-term health outcomes although the underlying mechanisms remain poorly defined. Meconium formed exclusively in utero and passed naturally by a neonate may contain proteins which characterise the intrauterine environment. The aim of the study was proteomic analysis of the composition of meconium proteins and their classification by biological function. Proteomic techniques combining isoelectrofocussing fractionation and LC-MS/MS analysis were used to study the protein composition of a meconium sample obtained by pooling 50 serial meconium portions from 10 healthy full-term neonates. The proteins were classified by function based on the literature search for each protein in the PubMed database. A total of 946 proteins were identified in the meconium, including 430 proteins represented by two or more peptides. When the proteins were classified by their biological function the following were identified: immunoglobulin fragments and enzymatic, neutrophil-derived, structural and fetal intestine-specific proteins. Meconium is a rich source of proteins deposited in the fetal intestine during its development in utero. A better understanding of their specific biological functions in the intrauterine environment may help to identify these proteins which may serve as biomarkers associated with specific clinical conditions/diseases with the possible impact on the fetal development and further health consequences in infants, older children and adults.

Mast cells: potential positive and negative roles in tumor biology.

PubMed

Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

2013-11-01

Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. ©2013 AACR.

Mouse interleukin-2 structure-function studies: substitutions in the first alpha-helix can specifically inactivate p70 receptor binding and mutations in the fifth alpha-helix can specifically inactivate p55 receptor binding.

PubMed Central

Zurawski, S M; Zurawski, G

1989-01-01

The function of two alpha-helical regions of mouse interleukin-2 were analyzed by saturation substitution analysis. The functional parts of the first alpha-helix (A) was defined as residues 31-39 by the observation that proline substitutions within this region inactivate the protein. Four residues within alpha-helix A, Leu31, Asp34, Leu35 and Leu38, were found to be crucial for biological activity. Structural modeling suggested that these four residues are clustered on one face of alpha-helix A. Residues 31 and 35 had to remain hydrophobic for the molecule to be functional. At residue 38 there was a preference for hydrophobic side chain residues, while at residue 34 some small side chain residues as well as acidic or amide side chain residues were functionally acceptable. Inactivating changes at residue 34 had no effect upon the ability of the protein to interact with the p55 receptor. Disruption of the fifth alpha-helix (E), which had little effect upon biological activity, resulted in an inability of the protein to interact with the p55 receptor. Mutagenesis of the alpha-helix E region demonstrated that alpha-helicity and the nature of the side chain residues in this region were unimportant for biological activity. The region immediately proximal to alpha-helix E was important only for the single intramolecular disulfide linkage. PMID:2583124

Selenistasis: Epistatic Effects of Selenium on Cardiovascular Phenotype

PubMed Central

Joseph, Jacob; Loscalzo, Joseph

2013-01-01

Although selenium metabolism is intricately linked to cardiovascular biology and function, and deficiency of selenium is associated with cardiac pathology, utilization of selenium in the prevention and treatment of cardiovascular disease remains an elusive goal. From a reductionist standpoint, the major function of selenium in vivo is antioxidant defense via its incorporation as selenocysteine into enzyme families such as glutathione peroxidases and thioredoxin reductases. In addition, selenium compounds are heterogeneous and have complex metabolic fates resulting in effects that are not entirely dependent on selenoprotein expression. This complex biology of selenium in vivo may underlie the fact that beneficial effects of selenium supplementation demonstrated in preclinical studies using models of oxidant stress-induced cardiovascular dysfunction, such as ischemia-reperfusion injury and myocardial infarction, have not been consistently observed in clinical trials. In fact, recent studies have yielded data that suggest that unselective supplementation of selenium may, indeed, be harmful. Interesting biologic actions of selenium are its simultaneous effects on redox balance and methylation status, a combination that may influence gene expression. These combined actions may explain some of the biphasic effects seen with low and high doses of selenium, the potentially harmful effects seen in normal individuals, and the beneficial effects noted in preclinical studies of disease. Given the complexity of selenium biology, systems biology approaches may be necessary to reach the goal of optimization of selenium status to promote health and prevent disease. PMID:23434902

Why magnetic and electromagnetic effects in biology are irreproducible and contradictory?

PubMed

Buchachenko, Anatoly

2016-01-01

The main source of magnetic and electromagnetic effects in biological systems is now generally accepted and demonstrated in this paper to be radical pair mechanism which implies pairwise generation of radicals in biochemical reactions. This mechanism was convincingly established for enzymatic adenosine triphosphate (ATP) and desoxynucleic acid (DNA) synthesis by using catalyzing metal ions with magnetic nuclei ((25)Mg, (43)Ca, (67)Zn) and supported by magnetic field effects on these reactions. The mechanism, is shown to function in medicine as a medical remedy or technology (trans-cranial magnetic stimulation, nuclear magnetic control of the ATP synthesis in heart muscle, the killing of cancer cells by suppression of DNA synthesis). However, the majority of magnetic effects in biology remain to be irreproducible, contradictory, and enigmatic. Three sources of such a state are shown in this paper to be: the presence of paramagnetic metal ions as a component of enzymatic site or as an impurity in an uncontrollable amount; the property of the radical pair mechanism to function at a rather high concentration of catalyzing metal ions, when at least two ions enter into the catalytic site; and the kinetic restrictions, which imply compatibility of chemical and spin dynamics in radical pair. It is important to keep in mind these factors to properly understand and predict magnetic effects in magneto-biology and biology itself and deliberately use them in medicine. © 2015 Wiley Periodicals, Inc.

Bioinformatics tools in predictive ecology: applications to fisheries

PubMed Central

Tucker, Allan; Duplisea, Daniel

2012-01-01

There has been a huge effort in the advancement of analytical techniques for molecular biological data over the past decade. This has led to many novel algorithms that are specialized to deal with data associated with biological phenomena, such as gene expression and protein interactions. In contrast, ecological data analysis has remained focused to some degree on off-the-shelf statistical techniques though this is starting to change with the adoption of state-of-the-art methods, where few assumptions can be made about the data and a more explorative approach is required, for example, through the use of Bayesian networks. In this paper, some novel bioinformatics tools for microarray data are discussed along with their ‘crossover potential’ with an application to fisheries data. In particular, a focus is made on the development of models that identify functionally equivalent species in different fish communities with the aim of predicting functional collapse. PMID:22144390

Protein-protein recognition control by modulating electrostatic interactions.

PubMed

Han, Song; Yin, Shijin; Yi, Hong; Mouhat, Stéphanie; Qiu, Su; Cao, Zhijian; Sabatier, Jean-Marc; Wu, Yingliang; Li, Wenxin

2010-06-04

Protein-protein control recognition remains a huge challenge, and its development depends on understanding the chemical and biological mechanisms by which these interactions occur. Here we describe a protein-protein control recognition technique based on the dominant electrostatic interactions occurring between the proteins. We designed a potassium channel inhibitor, BmP05-T, that was 90.32% identical to wild-type BmP05. Negatively charged residues were translocated from the nonbinding interface to the binding interface of BmP05 inhibitor, such that BmP05-T now used BmP05 nonbinding interface as the binding interface. This switch demonstrated that nonbinding interfaces were able to control the orientation of protein binding interfaces in the process of protein-protein recognition. The novel function findings of BmP05-T peptide suggested that the control recognition technique described here had the potential for use in designing and utilizing functional proteins in many biological scenarios.

Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm.

PubMed

Yu, Isseki; Mori, Takaharu; Ando, Tadashi; Harada, Ryuhei; Jung, Jaewoon; Sugita, Yuji; Feig, Michael

2016-11-01

Biological macromolecules function in highly crowded cellular environments. The structure and dynamics of proteins and nucleic acids are well characterized in vitro, but in vivo crowding effects remain unclear. Using molecular dynamics simulations of a comprehensive atomistic model cytoplasm we found that protein-protein interactions may destabilize native protein structures, whereas metabolite interactions may induce more compact states due to electrostatic screening. Protein-protein interactions also resulted in significant variations in reduced macromolecular diffusion under crowded conditions, while metabolites exhibited significant two-dimensional surface diffusion and altered protein-ligand binding that may reduce the effective concentration of metabolites and ligands in vivo. Metabolic enzymes showed weak non-specific association in cellular environments attributed to solvation and entropic effects. These effects are expected to have broad implications for the in vivo functioning of biomolecules. This work is a first step towards physically realistic in silico whole-cell models that connect molecular with cellular biology.

Artificial transmembrane ion channels from self-assembling peptide nanotubes

NASA Astrophysics Data System (ADS)

Ghadiri, M. Reza; Granja, Juan R.; Buehler, Lukas K.

1994-05-01

NATURALLY occurring membrane channels and pores are formed from a large family of diverse proteins, peptides and organic secon-dary metabolites whose vital biological functions include control of ion flow, signal transduction, molecular transport and produc-tion of cellular toxins. But despite the availability of a large amount of biochemical information about these molecules1, the design and synthesis of artificial systems that can mimic the bio-logical function of natural compounds remains a formidable task2-12. Here we present a simple strategy for the design of artifi-cial membrane ion channels based on a self-assembled cylindrical β-sheet peptide architecture13. Our systems-essentially stacks of peptide rings-display good channel-mediated ion-transport activ-ity with rates exceeding 107 ions s-1, rivalling the performance of many naturally occurring counterparts. Such molecular assemblies should find use in the design of novel cytotoxic agents, membrane transport vehicles and drug-delivery systems.

A 3D printing method for droplet-based biomolecular materials

NASA Astrophysics Data System (ADS)

Challita, Elio J.; Najem, Joseph S.; Freeman, Eric C.; Leo, Donald J.

2017-04-01

The field of developing biomolecular droplet-based materials using a bottom-up approach remains underexplored. Producing tissue-like materials, from entirely synthetic components, presents an innovative method to reconstruct the functions of life within artificial materials. Aqueous droplets, encased with lipid monolayers, may be linked via bilayer interfaces to make up structures that resemble biological tissues. Here we present the design and development of an easy-to-build 3D printer for the fabrication of tissue-like biomolecular materials from cell-sized aqueous droplets. The droplets are generated using a snap off technique, capable of generating 30 droplets per minute. The printed network of droplets may also be functionalized with various types of membrane proteins to achieve desired engineering applications like sensing and actuation, or to mimic electrical communication in biological systems. Voltage sensitive channels are introduced into selected droplets to create a conductive path with the material in the presence of an external field.

The multidimensional ionotropic receptors of Drosophila melanogaster.

PubMed

Rimal, S; Lee, Y

2018-02-01

Ionotropic receptors (IRs), which form ion channels, can be categorized into conserved 'antennal IRs', which define the first olfactory receptor family of insects, and species-specific 'divergent IRs', which are expressed in gustatory receptor neurones. These receptors are located primarily in cell bodies and dendrites, and are highly enriched in the tips of the dendritic terminals that convey sensory information to higher brain centres. Antennal IRs play important roles in odour and thermosensation, whereas divergent IRs are involved in other important biological processes such as taste sensation. Some IRs are known to play specific biological roles in the perception of various molecules; however, many of their functions have not yet been defined. Although progress has been made in this field, many functions and mechanisms of these receptors remain unknown. In this review, we provide a comprehensive summary of the current state of knowledge in this field. © 2017 The Royal Entomological Society.

Physiological significance of polyploidization in mammalian cells.

PubMed

Pandit, Shusil K; Westendorp, Bart; de Bruin, Alain

2013-11-01

Programmed polyploidization occurs in all mammalian species during development and aging in selected tissues, but the biological properties of polyploid cells remain obscure. Spontaneous polyploidization arises during stress and has been observed in a variety of pathological conditions, such as cancer and degenerative diseases. A major challenge in the field is to test the predicted functions of polyploidization in vivo. However, recent genetic mouse models with diminished polyploidization phenotypes represent novel, powerful tools to unravel the biological function of polyploidization. Contrary to a longstanding hypothesis, polyploidization appears to not be required for differentiation and has no obvious impact on proliferation. Instead, polyploidization leads to increased cell size and genetic diversity, which could promote better adaptation to chronic injury or stress. We discuss here the consequences of reducing polyploidization in mice and review which stress responses and molecular signals trigger polyploidization during development and disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Syntheses of some α-cyclic tripeptides as potential inhibitors for HMG-CoA Reductase.

PubMed

Chakraborty, Subrata; Lin, Shih-Hung; Shiuan, David; Tai, Dar-Fu

2015-08-01

α-Cyclic tripeptides (CtPs) are the most rigid members of the cyclic peptide family. However, due to their synthetic difficulty, biological activity has remained undisclosed. The incorporation of side-chain-protected natural amino acids into functional CtPs was performed to explore the potential biological functions. Several novel CtPs that consist of protected serine (S(Bn)) and/or glutamate (E(OBn)) were prepared from corresponding linear tripeptides by chemical synthesis. There is a strong possibility for CtPs that contain 3 phenyl groups to correlate with atorvastatin structure. The binding effects in human HMG-CoA reductase (hHMGR) activities were first evaluated by molecular docking. High docking scores were received with these CtPs for enzyme. Therefore, enzymatic assays were carried out and the compound cyclo(S(Bn))3 was indeed able to moderately inhibit hHMGR (IC50 = 110 μM).

Partial regularity of weak solutions to a PDE system with cubic nonlinearity

NASA Astrophysics Data System (ADS)

Liu, Jian-Guo; Xu, Xiangsheng

2018-04-01

In this paper we investigate regularity properties of weak solutions to a PDE system that arises in the study of biological transport networks. The system consists of a possibly singular elliptic equation for the scalar pressure of the underlying biological network coupled to a diffusion equation for the conductance vector of the network. There are several different types of nonlinearities in the system. Of particular mathematical interest is a term that is a polynomial function of solutions and their partial derivatives and this polynomial function has degree three. That is, the system contains a cubic nonlinearity. Only weak solutions to the system have been shown to exist. The regularity theory for the system remains fundamentally incomplete. In particular, it is not known whether or not weak solutions develop singularities. In this paper we obtain a partial regularity theorem, which gives an estimate for the parabolic Hausdorff dimension of the set of possible singular points.

Bioinformatics tools in predictive ecology: applications to fisheries.

PubMed

Tucker, Allan; Duplisea, Daniel

2012-01-19

There has been a huge effort in the advancement of analytical techniques for molecular biological data over the past decade. This has led to many novel algorithms that are specialized to deal with data associated with biological phenomena, such as gene expression and protein interactions. In contrast, ecological data analysis has remained focused to some degree on off-the-shelf statistical techniques though this is starting to change with the adoption of state-of-the-art methods, where few assumptions can be made about the data and a more explorative approach is required, for example, through the use of Bayesian networks. In this paper, some novel bioinformatics tools for microarray data are discussed along with their 'crossover potential' with an application to fisheries data. In particular, a focus is made on the development of models that identify functionally equivalent species in different fish communities with the aim of predicting functional collapse.

Advances in Proteomics of Mycobacterium leprae.

PubMed

Parkash, O; Singh, B P

2012-04-01

Although Mycobacterium leprae was the first bacterial pathogen identified causing human disease, it remains one of the few that is non-cultivable. Understanding the biology of M. leprae is one of the primary challenges in current leprosy research. Genomics has been extremely valuable, nonetheless, functional proteins are ultimately responsible for controlling most aspects of cellular functions, which in turn could facilitate parasitizing the host. Furthermore, bacterial proteins provide targets for most of the vaccines and immunodiagnostic tools. Better understanding of the proteomics of M. leprae could also help in developing new drugs against M. leprae. During the past nearly 15 years, there have been several developments towards the identification of M. leprae proteins employing contemporary proteomics tools. In this review, we discuss the knowledge gained on the biology and pathogenesis of M. leprae from current proteomic studies. © 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd.

Teleology and its constitutive role for biology as the science of organized systems in nature.

PubMed

Toepfer, Georg

2012-03-01

'Nothing in biology makes sense, except in the light of teleology'. This could be the first sentence in a textbook about the methodology of biology. The fundamental concepts in biology, e.g. 'organism' and 'ecosystem', are only intelligible given a teleological framework. Since early modern times, teleology has often been considered methodologically unscientific. With the acceptance of evolutionary theory, one popular strategy for accommodating teleological reasoning was to explain it by reference to selection in the past: functions were reconstructed as 'selected effects'. But the theory of evolution obviously presupposes the existence of organisms as organized and regulated, i.e. functional systems. Therefore, evolutionary theory cannot provide the foundation for teleology. The underlying reason for the central methodological role of teleology in biology is not its potential to offer particular forms of (evolutionary) explanations for the presence of parts, but rather an ontological one: organisms and other basic biological entities do not exist as physical bodies do, as amounts of matter with a definite form. Rather, they are dynamic systems in stable equilibrium; despite changes of their matter and form (in metabolism and metamorphosis) they maintain their identity. What remains constant in these kinds of systems is their 'organization', i.e. the causal pattern of interdependence of parts with certain effects of each part being relevant for the working of the system. Teleological analysis consists in the identification of these system-relevant effects and at the same time of the system as a whole. Therefore, the identity of biological systems cannot be specified without teleological reasoning. Copyright © 2011 Elsevier Ltd. All rights reserved.

The role of the oncogenic Rab35 in cancer invasion, metastasis, and immune evasion, especially in leukemia.

PubMed

Villagomez, Fabian R; Medina-Contreras, Oscar; Cerna-Cortes, Jorge Francisco; Patino-Lopez, Genaro

2018-05-28

The study of cancer has allowed researchers to describe some biological characteristics that tumor cells acquire during their development, known as the "hallmarks of cancer" but more research is needed to expand our knowledge about cancer biology and to generate new strategies of treatment. The role that RabGTPases might play in some hallmarks of cancer represents interesting areas of study since these proteins are frequently altered in cancer. However, their participation is not well known. Recently, Rab35was recognized as an oncogenic RabGTPase and and because of its association with different cellular functions, distinctly important in immune cells, a possible role of Rab35 in leukemia can be suggested. Nevertheless, the involvement of Rab35 in cancer remains poorly understood and its possible specific role in leukemia remains unknown. In this review, we analyze general aspects of the participation of RabGTPases in cancer, and especially, the plausible role of Rab35 in leukemia.

Stress and DNA repair biology of the Fanconi anemia pathway

PubMed Central

Longerich, Simonne; Li, Jian; Xiong, Yong; Sung, Patrick

2014-01-01

Fanconi anemia (FA) represents a paradigm of rare genetic diseases, where the quest for cause and cure has led to seminal discoveries in cancer biology. Although a total of 16 FA genes have been identified thus far, the biochemical function of many of the FA proteins remains to be elucidated. FA is rare, yet the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. Importantly, recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. Moreover, despite improved outcomes in stem cell transplantation in the treatment of FA, many challenges remain in patient care. PMID:25237197

New insights into the mechanisms of mammalian erythroid chromatin condensation and enucleation.

PubMed

Ji, Peng

2015-01-01

A unique feature in mammalian erythropoiesis is the dramatic chromatin condensation followed by enucleation. This step-by-step process starts at the beginning of terminal erythropoiesis after the hematopoietic stem cells are committed to erythroid lineage. Although this phenomenon is known for decades, the mechanisms of chromatin condensation and enucleation remain elusive. Recent advances in cell and molecular biology have started to reveal the molecular pathways in the regulation of chromatin condensation, the establishment of nuclear polarity prior enucleation, and the rearrangement of actin cytoskeleton in enucleation. However, many challenging questions, especially whether and how the apoptotic mechanisms are involved in chromatin condensation and how to dissect the functions of many actin cytoskeleton proteins in cytokinesis and enucleation, remain to be answered. Here I review our current understanding of mammalian erythroid chromatin condensation and enucleation during terminal differentiation with a focus on more recent studies. I conclude with my perspective of future works in this rising topic in developmental and cell biology. Copyright © 2015 Elsevier Inc. All rights reserved.

Shear thinning in soft particle suspensions

NASA Astrophysics Data System (ADS)

Voudouris, Panayiotis; van der Zanden, Berco; Florea, Daniel; Fahimi, Zahra; Wyss, Hans

2012-02-01

Suspensions of soft deformable particles are encountered in a wide range of food and biological materials. Examples are biological cells, micelles, vesicles or microgel particles. While the behavior of suspenions of hard spheres - the classical model system of colloid science - is reasonably well understood, a full understanding of these soft particle suspensions remains elusive. The relation between single particle properties and macroscopic mechanical behavior still remains poorly understood in these materials. Here we examine the surprising shear thinning behavior that is observed in soft particle suspensions as a function of particle softness. We use poly-N-isopropylacrylamide (p-NIPAM) microgel particles as a model system to study this effect in detail. These soft spheres show significant shear thinning even at very large Peclet numbers, where this would not be observed for hard particles. The degree of shear thinning is directly related to the single particle elastic properties, which we characterize by the recently developed Capillary Micromechanics technique. We present a simple model that qualitatively accounts for the observed behavior.

Biocompatible and Biomimetic Self-Assembly of Functional

DTIC Science & Technology

2007-10-03

rearrangement of the lipid/silica matrix to create a bio/nano interface quite similar to that formed by direct CDA. This approach has several advantages over CDA...precursors with a biologically compatible surfactant, glycerol monooleate ( GMO ) via dip-coating, spin-coating, drop-casting, or aerosol deposition...with water and remains in a semi-solid state. Upon exposure to UV/ozone, the GMO begins to photodecompose and the silanol precursors become more

Assembly of Terpenoid Cores by a Simple, Tunable Strategy.

PubMed

Lahtigui, Ouidad; Emmetiere, Fabien; Zhang, Wei; Jirmo, Liban; Toledo-Roy, Samira; Hershberger, John C; Macho, Jocelyn M; Grenning, Alexander J

2016-12-19

Oxygenated, polycyclic terpenoid natural products have important biological activities. Although total synthesis of such terpenes is widely studied, synthetic strategies that allow for controlled placement of oxygen atoms and other functionality remains a challenge. Herein, we present a simple, scalable, and tunable synthetic strategy to assemble terpenoid-like polycycloalkanes from cycloalkanones, malononitrile, and allylic electrophiles, abundantly available reagent classes. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pathogenomic Inference of Virulence-Associated Genes in Leptospira interrogans

PubMed Central

Lehmann, Jason S.; Fouts, Derrick E.; Haft, Daniel H.; Cannella, Anthony P.; Ricaldi, Jessica N.; Brinkac, Lauren; Harkins, Derek; Durkin, Scott; Sanka, Ravi; Sutton, Granger; Moreno, Angelo; Vinetz, Joseph M.; Matthias, Michael A.

2013-01-01

Leptospirosis is a globally important, neglected zoonotic infection caused by spirochetes of the genus Leptospira. Since genetic transformation remains technically limited for pathogenic Leptospira, a systems biology pathogenomic approach was used to infer leptospiral virulence genes by whole genome comparison of culture-attenuated Leptospira interrogans serovar Lai with its virulent, isogenic parent. Among the 11 pathogen-specific protein-coding genes in which non-synonymous mutations were found, a putative soluble adenylate cyclase with host cell cAMP-elevating activity, and two members of a previously unstudied ∼15 member paralogous gene family of unknown function were identified. This gene family was also uniquely found in the alpha-proteobacteria Bartonella bacilliformis and Bartonella australis that are geographically restricted to the Andes and Australia, respectively. How the pathogenic Leptospira and these two Bartonella species came to share this expanded gene family remains an evolutionary mystery. In vivo expression analyses demonstrated up-regulation of 10/11 Leptospira genes identified in the attenuation screen, and profound in vivo, tissue-specific up-regulation by members of the paralogous gene family, suggesting a direct role in virulence and host-pathogen interactions. The pathogenomic experimental design here is generalizable as a functional systems biology approach to studying bacterial pathogenesis and virulence and should encourage similar experimental studies of other pathogens. PMID:24098822

Pathogenomic inference of virulence-associated genes in Leptospira interrogans.

PubMed

Lehmann, Jason S; Fouts, Derrick E; Haft, Daniel H; Cannella, Anthony P; Ricaldi, Jessica N; Brinkac, Lauren; Harkins, Derek; Durkin, Scott; Sanka, Ravi; Sutton, Granger; Moreno, Angelo; Vinetz, Joseph M; Matthias, Michael A

2013-01-01

Leptospirosis is a globally important, neglected zoonotic infection caused by spirochetes of the genus Leptospira. Since genetic transformation remains technically limited for pathogenic Leptospira, a systems biology pathogenomic approach was used to infer leptospiral virulence genes by whole genome comparison of culture-attenuated Leptospira interrogans serovar Lai with its virulent, isogenic parent. Among the 11 pathogen-specific protein-coding genes in which non-synonymous mutations were found, a putative soluble adenylate cyclase with host cell cAMP-elevating activity, and two members of a previously unstudied ∼15 member paralogous gene family of unknown function were identified. This gene family was also uniquely found in the alpha-proteobacteria Bartonella bacilliformis and Bartonella australis that are geographically restricted to the Andes and Australia, respectively. How the pathogenic Leptospira and these two Bartonella species came to share this expanded gene family remains an evolutionary mystery. In vivo expression analyses demonstrated up-regulation of 10/11 Leptospira genes identified in the attenuation screen, and profound in vivo, tissue-specific up-regulation by members of the paralogous gene family, suggesting a direct role in virulence and host-pathogen interactions. The pathogenomic experimental design here is generalizable as a functional systems biology approach to studying bacterial pathogenesis and virulence and should encourage similar experimental studies of other pathogens.

Conserved noncoding sequences conserve biological networks and influence genome evolution.

PubMed

Xie, Jianbo; Qian, Kecheng; Si, Jingna; Xiao, Liang; Ci, Dong; Zhang, Deqiang

2018-05-01

Comparative genomics approaches have identified numerous conserved cis-regulatory sequences near genes in plant genomes. Despite the identification of these conserved noncoding sequences (CNSs), our knowledge of their functional importance and selection remains limited. Here, we used a combination of DNA methylome analysis, microarray expression analyses, and functional annotation to study these sequences in the model tree Populus trichocarpa. Methylation in CG contexts and non-CG contexts was lower in CNSs, particularly CNSs in the 5'-upstream regions of genes, compared with other sites in the genome. We observed that CNSs are enriched in genes with transcription and binding functions, and this also associated with syntenic genes and those from whole-genome duplications, suggesting that cis-regulatory sequences play a key role in genome evolution. We detected a significant positive correlation between CNS number and protein interactions, suggesting that CNSs may have roles in the evolution and maintenance of biological networks. The divergence of CNSs indicates that duplication-degeneration-complementation drives the subfunctionalization of a proportion of duplicated genes from whole-genome duplication. Furthermore, population genomics confirmed that most CNSs are under strong purifying selection and only a small subset of CNSs shows evidence of adaptive evolution. These findings provide a foundation for future studies exploring these key genomic features in the maintenance of biological networks, local adaptation, and transcription.

The effect of music performance on the transcriptome of professional musicians.

PubMed

Kanduri, Chakravarthi; Kuusi, Tuire; Ahvenainen, Minna; Philips, Anju K; Lähdesmäki, Harri; Järvelä, Irma

2015-03-25

Music performance by professional musicians involves a wide-spectrum of cognitive and multi-sensory motor skills, whose biological basis is unknown. Several neuroscientific studies have demonstrated that the brains of professional musicians and non-musicians differ structurally and functionally and that musical training enhances cognition. However, the molecules and molecular mechanisms involved in music performance remain largely unexplored. Here, we investigated the effect of music performance on the genome-wide peripheral blood transcriptome of professional musicians by analyzing the transcriptional responses after a 2-hr concert performance and after a 'music-free' control session. The up-regulated genes were found to affect dopaminergic neurotransmission, motor behavior, neuronal plasticity, and neurocognitive functions including learning and memory. Particularly, candidate genes such as SNCA, FOS and DUSP1 that are involved in song perception and production in songbirds, were identified, suggesting an evolutionary conservation in biological processes related to sound perception/production. Additionally, modulation of genes related to calcium ion homeostasis, iron ion homeostasis, glutathione metabolism, and several neuropsychiatric and neurodegenerative diseases implied that music performance may affect the biological pathways that are otherwise essential for the proper maintenance of neuronal function and survival. For the first time, this study provides evidence for the candidate genes and molecular mechanisms underlying music performance.

Cell-free synthetic biology for in vitro prototype engineering.

PubMed

Moore, Simon J; MacDonald, James T; Freemont, Paul S

2017-06-15

Cell-free transcription-translation is an expanding field in synthetic biology as a rapid prototyping platform for blueprinting the design of synthetic biological devices. Exemplar efforts include translation of prototype designs into medical test kits for on-site identification of viruses (Zika and Ebola), while gene circuit cascades can be tested, debugged and re-designed within rapid turnover times. Coupled with mathematical modelling, this discipline lends itself towards the precision engineering of new synthetic life. The next stages of cell-free look set to unlock new microbial hosts that remain slow to engineer and unsuited to rapid iterative design cycles. It is hoped that the development of such systems will provide new tools to aid the transition from cell-free prototype designs to functioning synthetic genetic circuits and engineered natural product pathways in living cells. © 2017 The Author(s).

Cell-free synthetic biology for in vitro prototype engineering

PubMed Central

Moore, Simon J.; MacDonald, James T.

2017-01-01

Cell-free transcription–translation is an expanding field in synthetic biology as a rapid prototyping platform for blueprinting the design of synthetic biological devices. Exemplar efforts include translation of prototype designs into medical test kits for on-site identification of viruses (Zika and Ebola), while gene circuit cascades can be tested, debugged and re-designed within rapid turnover times. Coupled with mathematical modelling, this discipline lends itself towards the precision engineering of new synthetic life. The next stages of cell-free look set to unlock new microbial hosts that remain slow to engineer and unsuited to rapid iterative design cycles. It is hoped that the development of such systems will provide new tools to aid the transition from cell-free prototype designs to functioning synthetic genetic circuits and engineered natural product pathways in living cells. PMID:28620040

Development of a Mouse Model of Menopausal Ovarian Cancer

PubMed Central

Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

2014-01-01

Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

Prolegomenon to patterns in evolution.

PubMed

Kauffman, Stuart A

2014-09-01

Despite Darwin, we remain children of Newton and dream of a grand theory that is epistemologically complete and would allow prediction of the evolution of the biosphere. The main purpose of this article is to show that this dream is false, and bears on studying patterns of evolution. To do so, I must justify the use of the word "function" in biology, when physics has only happenings. The concept of "function" lifts biology irreducibly above physics, for as we shall see, we cannot prestate the ever new biological functions that arise and constitute the very phase space of evolution. Hence, we cannot mathematize the detailed becoming of the biosphere, nor write differential equations for functional variables we do not know ahead of time, nor integrate those equations, so no laws "entail" evolution. The dream of a grand theory fails. In place of entailing laws, I propose a post-entailing law explanatory framework in which Actuals arise in evolution that constitute new boundary conditions that are enabling constraints that create new, typically unprestatable, adjacent possible opportunities for further evolution, in which new Actuals arise, in a persistent becoming. Evolution flows into a typically unprestatable succession of adjacent possibles. Given the concept of function, the concept of functional closure of an organism making a living in its world becomes central. Implications for patterns in evolution include historical reconstruction, and statistical laws such as the distribution of extinction events, or species per genus, and the use of formal cause, not efficient cause, laws. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A biomimetic colorimetric logic gate system based on multi-functional peptide-mediated gold nanoparticle assembly.

PubMed

Li, Yong; Li, Wang; He, Kai-Yu; Li, Pei; Huang, Yan; Nie, Zhou; Yao, Shou-Zhuo

2016-04-28

In natural biological systems, proteins exploit various functional peptide motifs to exert target response and activity switch, providing a functional and logic basis for complex cellular activities. Building biomimetic peptide-based bio-logic systems is highly intriguing but remains relatively unexplored due to limited logic recognition elements and complex signal outputs. In this proof-of-principle work, we attempted to address these problems by utilizing multi-functional peptide probes and the peptide-mediated nanoparticle assembly system. Here, the rationally designed peptide probes function as the dual-target responsive element specifically responsive to metal ions and enzymes as well as the mediator regulating the assembly of gold nanoparticles (AuNPs). Taking advantage of Zn2+ ions and chymotrypsin as the model inputs of metal ions and enzymes, respectively, we constructed the peptide logic system computed by the multi-functional peptide probes and outputted by the readable colour change of AuNPs. In this way, the representative binary basic logic gates (AND, OR, INHIBIT, NAND, IMPLICATION) have been achieved by delicately coding the peptide sequence, demonstrating the versatility of our logic system. Additionally, we demonstrated that the three-input combinational logic gate (INHIBIT-OR) could also be successfully integrated and applied as a multi-tasking biosensor for colorimetric detection of dual targets. This nanoparticle-based peptide logic system presents a valid strategy to illustrate peptide information processing and provides a practical platform for executing peptide computing or peptide-related multiplexing sensing, implying that the controllable nanomaterial assembly is a promising and potent methodology for the advancement of biomimetic bio-logic computation.

Analysis of miRNA expression profiles in melatonin-exposed GC-1 spg cell line.

PubMed

Zhu, Xiaoling; Chen, Shuxiong; Jiang, Yanwen; Xu, Ying; Zhao, Yun; Chen, Lu; Li, Chunjin; Zhou, Xu

2018-02-05

Melatonin is an endocrine neurohormone secreted by pinealocytes in the pineal gland. It exerts diverse physiological effects, such as circadian rhythm regulator and antioxidant. However, the functional importance of melatonin in spermatogenesis regulation remains unclear. The objectives of this study are to: (1) detect melatonin affection on miRNA expression profiles in GC-1 spg cells by miRNA deep sequencing (DeepSeq) and (2) define melatonin affected miRNA-mRNA interactions and associated biological processes using bioinformatics analysis. GC-1 spg cells were cultured with melatonin (10 -7 M) for 24h. DeepSeq data were validated using quantitative real-time reverse transcription polymerase chain reaction analysis (qRT-PCR). A total of 176 miRNA expressions were found to be significantly different between two groups (fold change of >2 or <0.5 and FDR<0.05). Among these expressions, 171 were up-regulated, and 5 were down-regulated. Ontology analysis of biological processes of these targets indicated a variety of biological functions. Pathway analysis indicated that the predicted targets were involved in cancers, apoptosis and signaling pathways, such as VEGF, TNF, Ras and Notch. Results implicated that melatonin could regulate the expression of miRNA to perform its physiological effects in GC-1 spg cells. These results should be useful to investigate the biological function of miRNAs regulated by melatonin in spermatogenesis and testicular germ cell tumor. Copyright © 2017 Elsevier B.V. All rights reserved.

Future directions of electron crystallography.

PubMed

Fujiyoshi, Yoshinori

2013-01-01

In biological science, there are still many interesting and fundamental yet difficult questions, such as those in neuroscience, remaining to be answered. Structural and functional studies of membrane proteins, which are key molecules of signal transduction in neural and other cells, are essential for understanding the molecular mechanisms of many fundamental biological processes. Technological and instrumental advancements of electron microscopy have facilitated comprehension of structural studies of biological components, such as membrane proteins. While X-ray crystallography has been the main method of structure analysis of proteins including membrane proteins, electron crystallography is now an established technique to analyze structures of membrane proteins in the lipid bilayer, which is close to their natural biological environment. By utilizing cryo-electron microscopes with helium-cooled specimen stages, structures of membrane proteins were analyzed at a resolution better than 3 Å. Such high-resolution structural analysis of membrane proteins by electron crystallography opens up the new research field of structural physiology. Considering the fact that the structures of integral membrane proteins in their native membrane environment without artifacts from crystal contacts are critical in understanding their physiological functions, electron crystallography will continue to be an important technology for structural analysis. In this chapter, I will present several examples to highlight important advantages and to suggest future directions of this technique.

Galectin-3 as a Potential Target to Prevent Cancer Metastasis

PubMed Central

Ahmed, Hafiz; AlSadek, Dina M. M.

2015-01-01

Interactions between two cells or between cell and extracellular matrix mediated by protein–carbohydrate interactions play pivotal roles in modulating various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Galectin-3, a member of the β-galactoside-binding lectin family, is involved in fibrosis as well as cancer progression and metastasis, but the detailed mechanisms of its functions remain elusive. This review discusses its structure, carbohydrate-binding properties, and involvement in various aspects of tumorigenesis and some potential carbohydrate ligands that are currently investigated to block galectin-3 activity. PMID:26640395

New genes and new biological roles for expansins

NASA Technical Reports Server (NTRS)

Cosgrove, D. J.

2000-01-01

Expansins are extracellular proteins that loosen plant cell walls in novel ways. They are thought to function in cell enlargement, pollen tube invasion of the stigma (in grasses), wall disassembly during fruit ripening, abscission and other cell separation events. Expansins are encoded by two multigene families and each gene is often expressed in highly specific locations and cell types. Structural analysis indicates that one expansin region resembles the catalytic domain of family-45 endoglucanases but glucanase activity has not been detected. The genome projects have revealed numerous expansin-related sequences but their putative wall-loosening functions remain to be assessed.

Plasmodium vivax trophozoite-stage proteomes

PubMed Central

Anderson, D.C.; Lapp, Stacey A.; Akinyi, Sheila; Meyer, Esmeralda V.S.; Barnwell, John W.; Korir-Morrison, Cindy; Galinski, Mary R.

2015-01-01

Plasmodium vivax is the causative infectious agent of 80–300 million annual cases of malaria. Many aspects of this parasite’s biology remain unknown. To further elucidate the interaction of P. vivax with its Saimiri boliviensis host, we obtained detailed proteomes of infected red blood cells, representing the trophozoite-enriched stage of development. Data from two of three biological replicate proteomes, emphasized here, were analyzed using five search engines, which enhanced identifications and resulted in the most comprehensive P. vivax proteomes to date, with 1375 P. vivax and 3209 S. boliviensis identified proteins. Ribosome subunit proteins were noted for both P. vivax and S. boliviensis, consistent with P. vivax’s known reticulocyte host–cell specificity. A majority of the host and pathogen proteins identified belong to specific functional categories, and several parasite gene families, while 33% of the P. vivax proteins have no reported function. Hemoglobin was significantly oxidized in both proteomes, and additional protein oxidation and nitration was detected in one of the two proteomes. Detailed analyses of these post-translational modifications are presented. The proteins identified here significantly expand the known P. vivax proteome and complexity of available host protein functionality underlying the host–parasite interactive biology, and reveal unsuspected oxidative modifications that may impact protein function. Biological significance Plasmodium vivax malaria is a serious neglected disease, causing an estimated 80 to 300 million cases annually in 95 countries. Infection can result in significant morbidity and possible death. P. vivax, unlike the much better-studied Plasmodium falciparum species, cannot be grown in long-term culture, has a dormant form in the liver called the hypnozoite stage, has a reticulocyte host–cell preference in the blood, and creates caveolae vesicle complexes at the surface of the infected reticulocyte membranes. Studies of stage-specific P. vivax expressed proteomes have been limited in scope and focused mainly on pathogen proteins, thus limiting understanding of the biology of this pathogen and its host interactions. Here three P. vivax proteomes are reported from biological replicates based on purified trophozoite-infected reticulocytes from different Saimiri boliviensis infections (the main non-human primate experimental model for P. vivax biology and pathogenesis). An in-depth analysis of two of the proteomes using 2D LC/MS/MS and multiple search engines identified 1375 pathogen proteins and 3209 host proteins. Numerous functional categories of both host and pathogen proteins were identified, including several known P. vivax protein family members (e.g., PHIST, eTRAMP and VIR), and 33% of protein identifications were classified as hypothetical. Ribosome subunit proteins were noted for both P. vivax and S. boliviensis, consistent with this parasite species’ known reticulocyte host–cell specificity. In two biological replicates analyzed for post-translational modifications, hemoglobin was extensively oxidized, and various other proteins were also oxidized or nitrated in one of the two replicates. The cause of such protein modification remains to be determined but could include oxidized heme and oxygen radicals released from the infected red blood cell’s parasite-induced acidic digestive vacuoles. In any case, the data suggests the presence of distinct infection-specific conditions whereby both the pathogen and host infected red blood cell proteins may be subject to significant oxidative stress. PMID:25545414

Recent Understandings of Biology, Prophylaxis and Treatment Strategies for Hypertrophic Scars and Keloids

PubMed Central

Jang, Yong Ju

2018-01-01

Hypertrophic scars and keloids are fibroproliferative disorders that may arise after any deep cutaneous injury caused by trauma, burns, surgery, etc. Hypertrophic scars and keloids are cosmetically problematic, and in combination with functional problems such as contractures and subjective symptoms including pruritus, these significantly affect patients’ quality of life. There have been many studies on hypertrophic scars and keloids; but the mechanisms underlying scar formation have not yet been well established, and prophylactic and treatment strategies remain unsatisfactory. In this review, the authors introduce and summarize classical concepts surrounding wound healing and review recent understandings of the biology, prevention and treatment strategies for hypertrophic scars and keloids. PMID:29498630

Immunoisolation to prevent tissue graft rejection: Current knowledge and future use.

PubMed

David, Anu; Day, James; Shikanov, Ariella

2016-05-01

This review focuses on the concept of immunoisolation and how this method has evolved over the last few decades. The concept of immunoisolation came out of the need to protect allogeneic transplant tissue from the host immune system and avoid systemic side effects of immunosuppression. The latter remains a significant hurdle in clinical translation of using tissue transplants for restoring endocrine function in diabetes, growth hormone deficiency, and other conditions. Herein, we review the most significant works studying the use of hydrogels, specifically alginate and poly (ethylene glycol), and membranes for immunoisolation and discuss how this approach can be applied in reproductive biology. © 2016 by the Society for Experimental Biology and Medicine.

How to train your microbe: methods for dynamically characterizing gene networks

PubMed Central

Castillo-Hair, Sebastian M.; Igoshin, Oleg A.; Tabor, Jeffrey J.

2015-01-01

Gene networks regulate biological processes dynamically. However, researchers have largely relied upon static perturbations, such as growth media variations and gene knockouts, to elucidate gene network structure and function. Thus, much of the regulation on the path from DNA to phenotype remains poorly understood. Recent studies have utilized improved genetic tools, hardware, and computational control strategies to generate precise temporal perturbations outside and inside of live cells. These experiments have, in turn, provided new insights into the organizing principles of biology. Here, we introduce the major classes of dynamical perturbations that can be used to study gene networks, and discuss technologies available for creating them in a wide range of microbial pathways. PMID:25677419

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furlow, Julie Maupin-

Archaea, one of three major evolutionary lineages of life, are a fascinating and diverse group of microbes with deep roots overlapping those of eukaryotes. The focus of the 'Archaea: Ecology Metabolism & Molecular Biology' GRC conference expands on a number of emerging topics highlighting new paradigms in archaeal metabolism, genome function and systems biology; information processing; evolution and the tree of life; the ecology and diversity of archaea and their viruses; and industrial applications. The strength of this conference lies in its ability to couple a field with a rich history in high quality research with new scientific findings inmore » an atmosphere of stimulating exchange. This conference remains an excellent opportunity for younger scientists to interact with world experts in this field.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keneth Stedman

Archaea, one of three major evolutionary lineages of life, are a fascinating and diverse group of microbes with deep roots overlapping those of eukaryotes. The focus of the 'Archaea: Ecology Metabolism & Molecular Biology' GRC conference expands on a number of emerging topics highlighting new paradigms in archaeal metabolism, genome function and systems biology; information processing; evolution and the tree of life; the ecology and diversity of archaea and their viruses. The strength of this conference lies in its ability to couple a field with a rich history in high quality research with new scientific findings in an atmosphere ofmore » stimulating exchange. This conference remains an excellent opportunity for younger scientists to interact with world experts in this field.« less

Spectroscopic exploration of interaction between PEG-functionalized Ag2S nanoparticles with bovine serum albumin

NASA Astrophysics Data System (ADS)

Prasanth, S.; RitheshRaj, D.; Vineeshkumar, T. V.; Sudarsanakumar, C.

2018-05-01

The introduction of nanoparticles into biological fluids often leads to the formation of biocorona over the surface of nanoparticles. For the effective use of nanoparticles in biological applications it is very essential to understand their interactions with proteins. Herein, we investigated the interactions of Poly ethylene glycol capped Ag2S nanoparticles with Bovine Serum Albumin by spectroscopic techniques. By the addition of Ag2S nanoparticles, a ground state complex is formed. The CD spectroscopy reveals that the secondary structure of BSA is altered by complexation with PEG-Ag2S nanoparticles, while the overall tertiary structure remains closer to that of native BSA.

Prediction and redesign of protein–protein interactions

PubMed Central

Lua, Rhonald C.; Marciano, David C.; Katsonis, Panagiotis; Adikesavan, Anbu K.; Wilkins, Angela D.; Lichtarge, Olivier

2014-01-01

Understanding the molecular basis of protein function remains a central goal of biology, with the hope to elucidate the role of human genes in health and in disease, and to rationally design therapies through targeted molecular perturbations. We review here some of the computational techniques and resources available for characterizing a critical aspect of protein function – those mediated by protein–protein interactions (PPI). We describe several applications and recent successes of the Evolutionary Trace (ET) in identifying molecular events and shapes that underlie protein function and specificity in both eukaryotes and prokaryotes. ET is a part of analytical approaches based on the successes and failures of evolution that enable the rational control of PPI. PMID:24878423

Incorporating "motivation" into the functional analysis of challenging behavior: on the interactive and integrative potential of the motivating operation.

PubMed

Langthorne, Paul; McGill, Peter; O'Reilly, Mark

2007-07-01

Sensitivity theory attempts to account for the variability often observed in challenging behavior by recourse to the "aberrant motivation" of people with intellectual and developmental disabilities. In this article, we suggest that a functional analysis based on environmental (challenging environments) and biological (challenging needs) motivating operations provides a more parsimonious and empirically grounded account of challenging behavior than that proposed by sensitivity theory. It is argued that the concept of the motivating operation provides a means of integrating diverse strands of research without the undue inference of mentalistic constructs. An integrated model of challenging behavior is proposed, one that remains compatible with the central tenets of functional analysis.

Functional Anthology of Intrinsic Disorder. I. Biological Processes and Functions of Proteins with Long Disordered Regions

PubMed Central

Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Dunker, A. Keith; Uversky, Vladimir N.; Obradovic, Zoran

2008-01-01

Identifying relationships between function, amino acid sequence and protein structure represents a major challenge. In this study we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our statistical approach, outlines the major findings and provides illustrative examples of biological processes and functions positively and negatively correlated with intrinsic disorder. PMID:17391014

Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.

PubMed

Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M; Oldfield, Christopher J; Dunker, A Keith; Uversky, Vladimir N; Obradovic, Zoran

2007-05-01

Identifying relationships between function, amino acid sequence, and protein structure represents a major challenge. In this study, we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from the Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins, and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our statistical approach, outlines the major findings, and provides illustrative examples of biological processes and functions positively and negatively correlated with intrinsic disorder.

Synthetic biology meets tissue engineering

PubMed Central

Davies, Jamie A.; Cachat, Elise

2016-01-01

Classical tissue engineering is aimed mainly at producing anatomically and physiologically realistic replacements for normal human tissues. It is done either by encouraging cellular colonization of manufactured matrices or cellular recolonization of decellularized natural extracellular matrices from donor organs, or by allowing cells to self-organize into organs as they do during fetal life. For repair of normal bodies, this will be adequate but there are reasons for making unusual, non-evolved tissues (repair of unusual bodies, interface to electromechanical prostheses, incorporating living cells into life-support machines). Synthetic biology is aimed mainly at engineering cells so that they can perform custom functions: applying synthetic biological approaches to tissue engineering may be one way of engineering custom structures. In this article, we outline the ‘embryological cycle’ of patterning, differentiation and morphogenesis and review progress that has been made in constructing synthetic biological systems to reproduce these processes in new ways. The state-of-the-art remains a long way from making truly synthetic tissues, but there are now at least foundations for future work. PMID:27284030

A Computational Framework for Bioimaging Simulation.

PubMed

Watabe, Masaki; Arjunan, Satya N V; Fukushima, Seiya; Iwamoto, Kazunari; Kozuka, Jun; Matsuoka, Satomi; Shindo, Yuki; Ueda, Masahiro; Takahashi, Koichi

2015-01-01

Using bioimaging technology, biologists have attempted to identify and document analytical interpretations that underlie biological phenomena in biological cells. Theoretical biology aims at distilling those interpretations into knowledge in the mathematical form of biochemical reaction networks and understanding how higher level functions emerge from the combined action of biomolecules. However, there still remain formidable challenges in bridging the gap between bioimaging and mathematical modeling. Generally, measurements using fluorescence microscopy systems are influenced by systematic effects that arise from stochastic nature of biological cells, the imaging apparatus, and optical physics. Such systematic effects are always present in all bioimaging systems and hinder quantitative comparison between the cell model and bioimages. Computational tools for such a comparison are still unavailable. Thus, in this work, we present a computational framework for handling the parameters of the cell models and the optical physics governing bioimaging systems. Simulation using this framework can generate digital images of cell simulation results after accounting for the systematic effects. We then demonstrate that such a framework enables comparison at the level of photon-counting units.

L-GRAAL: Lagrangian graphlet-based network aligner.

PubMed

Malod-Dognin, Noël; Pržulj, Nataša

2015-07-01

Discovering and understanding patterns in networks of protein-protein interactions (PPIs) is a central problem in systems biology. Alignments between these networks aid functional understanding as they uncover important information, such as evolutionary conserved pathways, protein complexes and functional orthologs. A few methods have been proposed for global PPI network alignments, but because of NP-completeness of underlying sub-graph isomorphism problem, producing topologically and biologically accurate alignments remains a challenge. We introduce a novel global network alignment tool, Lagrangian GRAphlet-based ALigner (L-GRAAL), which directly optimizes both the protein and the interaction functional conservations, using a novel alignment search heuristic based on integer programming and Lagrangian relaxation. We compare L-GRAAL with the state-of-the-art network aligners on the largest available PPI networks from BioGRID and observe that L-GRAAL uncovers the largest common sub-graphs between the networks, as measured by edge-correctness and symmetric sub-structures scores, which allow transferring more functional information across networks. We assess the biological quality of the protein mappings using the semantic similarity of their Gene Ontology annotations and observe that L-GRAAL best uncovers functionally conserved proteins. Furthermore, we introduce for the first time a measure of the semantic similarity of the mapped interactions and show that L-GRAAL also uncovers best functionally conserved interactions. In addition, we illustrate on the PPI networks of baker's yeast and human the ability of L-GRAAL to predict new PPIs. Finally, L-GRAAL's results are the first to show that topological information is more important than sequence information for uncovering functionally conserved interactions. L-GRAAL is coded in C++. Software is available at: http://bio-nets.doc.ic.ac.uk/L-GRAAL/. n.malod-dognin@imperial.ac.uk Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

Measurement of 100 B. anthracis Ames spores within 15 minutes by SERS at the US Army Edgewood Chemical Biological Ctr.

NASA Astrophysics Data System (ADS)

Farquharson, Stuart; Shende, Chetan; Smith, Wayne; Huang, Hermes; Sperry, Jay; Sickler, Todd; Prugh, Amber; Guicheteau, Jason

2014-05-01

Since the distribution of Bacillus anthracis-Ames spores through the US Postal System, there has been a persistent fear that biological warfare agents will be used by terrorists against our military abroad and our civilians at home. While there has been substantial effort since the anthrax attack of 2001 to develop analyzers to detect this and other biological warfare agents, the analyzers remain either too slow, lack sensitivity, produce high false-positive rates, or cannot be fielded. In an effort to overcome these limitations we have been developing a surface-enhanced Raman spectroscopy system. Here we describe the use of silver nanoparticles functionalized with a short peptide to selectively capture Bacillus anthracis spores and produce SER scattering. Specifically, measurements of 100 B. anthracis-Ames spores/mL in ~25 minutes performed at the US Army's Edgewood Chemical Biological Center are presented. The measurements provide a basis for the development of systems that can detect spores collected from the air or water supplies with the potential of saving lives during a biological warfare attack.

The epigenomic landscape of African rainforest hunter-gatherers and farmers.

PubMed

Fagny, Maud; Patin, Etienne; MacIsaac, Julia L; Rotival, Maxime; Flutre, Timothée; Jones, Meaghan J; Siddle, Katherine J; Quach, Hélène; Harmant, Christine; McEwen, Lisa M; Froment, Alain; Heyer, Evelyne; Gessain, Antoine; Betsem, Edouard; Mouguiama-Daouda, Patrick; Hombert, Jean-Marie; Perry, George H; Barreiro, Luis B; Kobor, Michael S; Quintana-Murci, Lluis

2015-11-30

The genetic history of African populations is increasingly well documented, yet their patterns of epigenomic variation remain uncharacterized. Moreover, the relative impacts of DNA sequence variation and temporal changes in lifestyle and habitat on the human epigenome remain unknown. Here we generate genome-wide genotype and DNA methylation profiles for 362 rainforest hunter-gatherers and sedentary farmers. We find that the current habitat and historical lifestyle of a population have similarly critical impacts on the methylome, but the biological functions affected strongly differ. Specifically, methylation variation associated with recent changes in habitat mostly concerns immune and cellular functions, whereas that associated with historical lifestyle affects developmental processes. Furthermore, methylation variation--particularly that correlated with historical lifestyle--shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Our work provides new insight into the genetic and environmental factors affecting the epigenomic landscape of human populations over time.

[Current progress and future direction in the biology of ovarian germ stem cells in mammals].

PubMed

Li, Chao-Hui; Guo, Kun; Zheng, Ping

2012-12-01

Whether or not oogenesis continues after birth in mammalian ovaries remains controversial. Since the 1950's, it has been generally accepted that oogenesis takes place during embryogenesis in mammals and ceases at birth. At birth, germ cells in mammalian ovaries have progressed to the diplotene stage of meiotic prophase and have formed primordial follicles with surrounding somatic cells. These primordial follicles represent follicle reserves of the reproductive life. However, this view has been recently challenged by a growing body of evidence showing the isolation and propagation of germ stem cells from mouse and human ovaries. These ovarian germ stem cells are capable of regenerating functional oocytes when transplanted back into recipient ovaries. Despite the discovery of the potential germ stem cells in mammalian ovaries, it remains uncertain whether these cells exist and function in ovaries under physiological conditions. Herein we review the current progress and future direction in this infant area.

Developmental Outcomes of Foster Children: A Meta-Analytic Comparison With Children From the General Population and Children at Risk Who Remained at Home.

PubMed

Goemans, Anouk; van Geel, Mitch; van Beem, Merel; Vedder, Paul

2016-08-01

Foster care is often preferred to other placement options for children in the child welfare system. However, it is not clear how the developmental outcomes of foster children relate to children in other living arrangements. In this study, a series of meta-analyses are performed to compare the cognitive, adaptive, and behavioral functioning of children placed in foster care (n = 2,305) with children at risk who remained with their biological parents (n = 4,335) and children from the general population (n = 4,971). A systematic literature search in PsycINFO, Medline, ERIC, and ProQuest identified 31 studies suitable for inclusion (N = 11,611). Results showed that foster children had generally lower levels of functioning than children from the general population. No clear differences were found between foster children and children at risk who remained at home, but both groups experienced developmental problems. Improving the quality of foster care and future research to identify which children are best served by either foster care or in-home services are recommended. © The Author(s) 2016.

Screening vaccine formulations for biological activity using fresh human whole blood

PubMed Central

Brookes, Roger H; Hakimi, Jalil; Ha, Yukyung; Aboutorabian, Sepideh; Ausar, Salvador F; Hasija, Manvi; Smith, Steven G; Todryk, Stephen M; Dockrell, Hazel M; Rahman, Nausheen

2014-01-01

Understanding the relevant biological activity of any pharmaceutical formulation destined for human use is crucial. For vaccine-based formulations, activity must reflect the expected immune response, while for non-vaccine therapeutic agents, such as monoclonal antibodies, a lack of immune response to the formulation is desired. During early formulation development, various biochemical and biophysical characteristics can be monitored in a high-throughput screening (HTS) format. However, it remains impractical and arguably unethical to screen samples in this way for immunological functionality in animal models. Furthermore, data for immunological functionality lag formulation design by months, making it cumbersome to relate back to formulations in real-time. It is also likely that animal testing may not accurately reflect the response in humans. For a more effective formulation screen, a human whole blood (hWB) approach can be used to assess immunological functionality. The functional activity relates directly to the human immune response to a complete formulation (adjuvant/antigen) and includes adjuvant response, antigen response, adjuvant-modulated antigen response, stability, and potentially safety. The following commentary discusses the hWB approach as a valuable new tool to de-risk manufacture, formulation design, and clinical progression. PMID:24401565

Screening vaccine formulations for biological activity using fresh human whole blood.

PubMed

Brookes, Roger H; Hakimi, Jalil; Ha, Yukyung; Aboutorabian, Sepideh; Ausar, Salvador F; Hasija, Manvi; Smith, Steven G; Todryk, Stephen M; Dockrell, Hazel M; Rahman, Nausheen

2014-01-01

Understanding the relevant biological activity of any pharmaceutical formulation destined for human use is crucial. For vaccine-based formulations, activity must reflect the expected immune response, while for non-vaccine therapeutic agents, such as monoclonal antibodies, a lack of immune response to the formulation is desired. During early formulation development, various biochemical and biophysical characteristics can be monitored in a high-throughput screening (HTS) format. However, it remains impractical and arguably unethical to screen samples in this way for immunological functionality in animal models. Furthermore, data for immunological functionality lag formulation design by months, making it cumbersome to relate back to formulations in real-time. It is also likely that animal testing may not accurately reflect the response in humans. For a more effective formulation screen, a human whole blood (hWB) approach can be used to assess immunological functionality. The functional activity relates directly to the human immune response to a complete formulation (adjuvant/antigen) and includes adjuvant response, antigen response, adjuvant-modulated antigen response, stability, and potentially safety. The following commentary discusses the hWB approach as a valuable new tool to de-risk manufacture, formulation design, and clinical progression.

Plasmodesmata: channels for intercellular signaling during plant growth and development.

PubMed

Sevilem, Iris; Yadav, Shri Ram; Helariutta, Ykä

2015-01-01

Plants have evolved strategies for short- and long-distance communication to coordinate plant development and to adapt to changing environmental conditions. Plasmodesmata (PD) are intercellular nanochannels that provide an effective pathway for both selective and nonselective movement of various molecules that function in diverse biological processes. Numerous non-cell-autonomous proteins (NCAP) and small RNAs have been identified that have crucial roles in cell fate determination and organ patterning during development. Both the density and aperture size of PD are developmentally regulated, allowing formation of spatial symplastic domains for establishment of tissue-specific developmental programs. The PD size exclusion limit (SEL) is controlled by reversible deposition of callose, as well as by some PD-associated proteins. Although a large number of PD-associated proteins have been identified, many of their functions remain unknown. Despite the fact that PD are primarily membranous structures, surprisingly very little is known about their lipid composition. Thus, future studies in PD biology will provide deeper insights into the high-resolution structure and tightly regulated functions of PD and the evolution of PD-mediated cell-to-cell communication in plants.

Identification of three critical regions within mouse interleukin 2 by fine structural deletion analysis.

PubMed Central

Zurawski, S M; Zurawski, G

1988-01-01

We have analyzed structure--function relationships of the protein hormone murine interleukin 2 by fine structural deletion mapping. A total of 130 deletion mutant proteins, together with some substitution and insertion mutant proteins, was expressed in Escherichia coli and analyzed for their ability to sustain the proliferation of a cloned murine T cell line. This analysis has permitted a functional map of the protein to be drawn and classifies five segments of the protein, which together contain 48% of the sequence, as unessential to the biological activity of the protein. A further 26% of the protein is classified as important, but not crucial, for the activity. Three regions, consisting of amino acids 32-35, 66-77 and 119-141 contain the remaining 26% of the protein and are critical to the biological activity of the protein. The functional map is discussed in the context of the possible role of the identified critical regions in the structure of the hormone and its binding to the interleukin 2 receptor complex. Images PMID:3261239

Bending Genders: The Biology of Natural Sex Change in Fish.

PubMed

Todd, Erica V; Liu, Hui; Muncaster, Simon; Gemmell, Neil J

2016-01-01

Sexual fate is no longer seen as an irreversible deterministic switch set during early embryonic development but as an ongoing battle for primacy between male and female developmental trajectories. That sexual fate is not final and must be actively maintained via continuous suppression of the opposing sexual network creates the potential for flexibility into adulthood. In many fishes, sexuality is not only extremely plastic, but sex change is a usual and adaptive part of the life cycle. Sequential hermaphrodites begin life as one sex, changing sometime later to the other, and include species capable of protandrous (male-to-female), protogynous (female-to-male), or serial (bidirectional) sex change. Natural sex change involves coordinated transformations across multiple biological systems, including behavioural, anatomical, neuroendocrine, and molecular axes. We here review the biological processes underlying this amazing transformation, focussing particularly on its molecular basis, which remains poorly understood, but where new genomic technologies are significantly advancing our understanding of how sex change is initiated and progressed at the molecular level. Knowledge of how a usually committed developmental process remains plastic in sequentially hermaphroditic fishes is relevant to understanding the evolution and functioning of sexual developmental systems in vertebrates generally, as well as pathologies of sexual development in humans. © 2016 S. Karger AG, Basel.

Advances in Dyslexia Genetics-New Insights Into the Role of Brain Asymmetries.

PubMed

Paracchini, S; Diaz, R; Stein, J

2016-01-01

Dyslexia is a common condition affecting up to 10% school-aged children. There is strong evidence that genetics plays an important role in dyslexia and is expected to be complex in nature. Few specific susceptibility factors have been identified so far, but their functional characterization has provided novel insights into the biology of dyslexia. In particular, they point to an unexpected role of candidate genes for dyslexia in the biology of cilia, cellular organelles required in many processes including the establishment of left-right asymmetries early in development. This observation has brought back into the spotlight the old idea of a link between dyslexia and handedness. Yet much of the genetics contributing to dyslexia remains unexplained. The lack of biological markers, clear diagnostic criteria, and homogeneous assessment strategies are just some of the factors preventing the collection of the cohorts powered enough for large-scale genetic studies. While the technology and methods to generate and handle large-scale data have reached unprecedented potential, the main challenge remains in establishing universal guidelines to collect suitable phenotype information across independent studies. These difficulties reflect the complex nature of dyslexia which is highly heterogeneous and often co-occurs with other neurodevelopmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Executive summary of NIH workshop on the Use and Biology of Energy Drinks: Current Knowledge and Critical Gaps.

PubMed

Sorkin, Barbara C; Camp, Kathryn M; Haggans, Carol J; Deuster, Patricia A; Haverkos, Lynne; Maruvada, Padma; Witt, Ellen; Coates, Paul M

2014-10-01

Sales of energy drinks in the United States reached $12.5 billion in 2012. Emergency department visits related to consumption of these products have increased sharply, and while these numbers remain small relative to product sales, they raise important questions regarding biological and behavioral effects. Although some common ingredients of energy drinks have been extensively studied (e.g., caffeine, B vitamins, sugars, inositol), data on other ingredients (e.g., taurine) are limited. Summarized here are data presented elsewhere in this issue on the prevalence and patterns of caffeine-containing energy drink use, the effects of these products on alertness, fatigue, cognitive functions, sleep, mood, homeostasis, as well as on exercise physiology and metabolism, and the biological mechanisms mediating the observed effects. There are substantial data on the effects of some energy drink ingredients, such as caffeine and sugars, on many of these outcomes; however, even for these ingredients many controversies and gaps remain, and data on other ingredients in caffeine-containing energy drinks, and on ingredient interactions, are sparse. This summary concludes with a discussion of critical gaps in the data and potential next steps. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? What Really Constitutes the Study of "Systems Biology" and How Might Such an Approach Facilitate Vaccine Design.

PubMed

Germain, Ronald N

2017-10-16

A dichotomy exists in the field of vaccinology about the promise versus the hype associated with application of "systems biology" approaches to rational vaccine design. Some feel it is the only way to efficiently uncover currently unknown parameters controlling desired immune responses or discover what elements actually mediate these responses. Others feel that traditional experimental, often reductionist, methods for incrementally unraveling complex biology provide a more solid way forward, and that "systems" approaches are costly ways to collect data without gaining true insight. Here I argue that both views are inaccurate. This is largely because of confusion about what can be gained from classical experimentation versus statistical analysis of large data sets (bioinformatics) versus methods that quantitatively explain emergent properties of complex assemblies of biological components, with the latter reflecting what was previously called "physiology." Reductionist studies will remain essential for generating detailed insight into the functional attributes of specific elements of biological systems, but such analyses lack the power to provide a quantitative and predictive understanding of global system behavior. But by employing (1) large-scale screening methods for discovery of unknown components and connections in the immune system ( omics ), (2) statistical analysis of large data sets ( bioinformatics ), and (3) the capacity of quantitative computational methods to translate these individual components and connections into models of emergent behavior ( systems biology ), we will be able to better understand how the overall immune system functions and to determine with greater precision how to manipulate it to produce desired protective responses. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Linking soil biology and chemistry in biological soil crust using isolate exometabolomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swenson, Tami L.; Karaoz, Ulas; Swenson, Joel M.

Metagenomic sequencing provides a window into microbial community structure and metabolic potential; however, linking these data to exogenous metabolites that microorganisms process and produce (the exometabolome) remains challenging. Previously, we observed strong exometabolite niche partitioning among bacterial isolates from biological soil crust (biocrust). For this study, we examine native biocrust to determine if these patterns are reproduced in the environment. Overall, most soil metabolites display the expected relationship (positive or negative correlation) with four dominant bacteria following a wetting event and across biocrust developmental stages. For metabolites that were previously found to be consumed by an isolate, 70% are negativelymore » correlated with the abundance of the isolate's closest matching environmental relative in situ, whereas for released metabolites, 67% were positively correlated. Our results demonstrate that metabolite profiling, shotgun sequencing and exometabolomics may be successfully integrated to functionally link microbial community structure with environmental chemistry in biocrust.« less

Linking soil biology and chemistry in biological soil crust using isolate exometabolomics

DOE PAGES

Swenson, Tami L.; Karaoz, Ulas; Swenson, Joel M.; ...

2018-01-02

Metagenomic sequencing provides a window into microbial community structure and metabolic potential; however, linking these data to exogenous metabolites that microorganisms process and produce (the exometabolome) remains challenging. Previously, we observed strong exometabolite niche partitioning among bacterial isolates from biological soil crust (biocrust). For this study, we examine native biocrust to determine if these patterns are reproduced in the environment. Overall, most soil metabolites display the expected relationship (positive or negative correlation) with four dominant bacteria following a wetting event and across biocrust developmental stages. For metabolites that were previously found to be consumed by an isolate, 70% are negativelymore » correlated with the abundance of the isolate's closest matching environmental relative in situ, whereas for released metabolites, 67% were positively correlated. Our results demonstrate that metabolite profiling, shotgun sequencing and exometabolomics may be successfully integrated to functionally link microbial community structure with environmental chemistry in biocrust.« less

Long Non-Coding RNA as Potential Biomarker for Prostate Cancer: Is It Making a Difference?

PubMed

Deng, Junli; Tang, Jie; Wang, Guo; Zhu, Yuan-Shan

2017-03-07

Whole genome transcriptomic analyses have identified numerous long non-coding RNA (lncRNA) transcripts that are increasingly implicated in cancer biology. LncRNAs are found to promote essential cancer cell functions such as proliferation, invasion, and metastasis, with the potential to serve as novel biomarkers of various cancers and to further reveal uncharacterized aspects of tumor biology. However, the biological and molecular mechanisms as well as the clinical applications of lncRNAs in diverse diseases are not completely understood, and remain to be fully explored. LncRNAs may be critical players and regulators in prostate cancer carcinogenesis and progression, and could serve as potential biomarkers for prostate cancer. This review focuses on lncRNA biomarkers that are already available for clinical use and provides an overview of lncRNA biomarkers that are under investigation for clinical development in prostate cancer.

Potential in vivo roles of nucleic acid triple-helices

PubMed Central

Buske, Fabian A

2011-01-01

The ability of double-stranded DNA to form a triple-helical structure by hydrogen bonding with a third strand is well established, but the biological functions of these structures remain largely unknown. There is considerable albeit circumstantial evidence for the existence of nucleic triplexes in vivo and their potential participation in a variety of biological processes including chromatin organization, DNA repair, transcriptional regulation and RNA processing has been investigated in a number of studies to date. There is also a range of possible mechanisms to regulate triplex formation through differential expression of triplex-forming RNAs, alteration of chromatin accessibility, sequence unwinding and nucleotide modifications. With the advent of next generation sequencing technology combined with targeted approaches to isolate triplexes, it is now possible to survey triplex formation with respect to their genomic context, abundance and dynamical changes during differentiation and development, which may open up new vistas in understanding genome biology and gene regulation. PMID:21525785

Plant Metabolomics: An Indispensable System Biology Tool for Plant Science

PubMed Central

Hong, Jun; Yang, Litao; Zhang, Dabing; Shi, Jianxin

2016-01-01

As genomes of many plant species have been sequenced, demand for functional genomics has dramatically accelerated the improvement of other omics including metabolomics. Despite a large amount of metabolites still remaining to be identified, metabolomics has contributed significantly not only to the understanding of plant physiology and biology from the view of small chemical molecules that reflect the end point of biological activities, but also in past decades to the attempts to improve plant behavior under both normal and stressed conditions. Hereby, we summarize the current knowledge on the genetic and biochemical mechanisms underlying plant growth, development, and stress responses, focusing further on the contributions of metabolomics to practical applications in crop quality improvement and food safety assessment, as well as plant metabolic engineering. We also highlight the current challenges and future perspectives in this inspiring area, with the aim to stimulate further studies leading to better crop improvement of yield and quality. PMID:27258266

The genomic landscape of chronic lymphocytic leukaemia: biological and clinical implications.

PubMed

Strefford, Jonathan C

2015-04-01

Chronic lymphocytic leukaemia (CLL) remains at the forefront of the genetic analysis of human tumours, principally due its prevalence, protracted natural history and accessibility to suitable material for analysis. With the application of high-throughput genetic technologies, we have an unbridled view of the architecture of the CLL genome, including a comprehensive description of the copy number and mutational landscape of the disease, a detailed picture of clonal evolution during pathogenesis, and the molecular mechanisms that drive genomic instability and therapeutic resistance. This work has nuanced the prognostic importance of established copy number alterations, and identified novel prognostically relevant gene mutations that function within biological pathways that are attractive treatment targets. Herein, an overview of recent genomic discoveries will be reviewed, with associated biological and clinical implications, and a view into how clinical implementation may be facilitated. © 2014 John Wiley & Sons Ltd.

Biologic Treatments for Sports Injuries II Think Tank—Current Concepts, Future Research, and Barriers to Advancement, Part 2

PubMed Central

Murray, Iain R.; LaPrade, Robert F.; Musahl, Volker; Geeslin, Andrew G.; Zlotnicki, Jason P.; Mann, Barton J.; Petrigliano, Frank A.

2016-01-01

Rotator cuff tears are common and result in considerable morbidity. Tears within the tendon substance or at its insertion into the humeral head represent a considerable clinical challenge because of the hostile local environment that precludes healing. Tears often progress without intervention, and current surgical treatments are inadequate. Although surgical implants, instrumentation, and techniques have improved, healing rates have not improved, and a high failure rate remains for large and massive rotator cuff tears. The use of biologic adjuvants that contribute to a regenerative microenvironment have great potential for improving healing rates and function after surgery. This article presents a review of current and emerging biologic approaches to augment rotator cuff tendon and muscle regeneration focusing on the scientific rationale, preclinical, and clinical evidence for efficacy, areas for future research, and current barriers to advancement and implementation. PMID:27099865

Plant Metabolomics: An Indispensable System Biology Tool for Plant Science.

PubMed

Hong, Jun; Yang, Litao; Zhang, Dabing; Shi, Jianxin

2016-06-01

As genomes of many plant species have been sequenced, demand for functional genomics has dramatically accelerated the improvement of other omics including metabolomics. Despite a large amount of metabolites still remaining to be identified, metabolomics has contributed significantly not only to the understanding of plant physiology and biology from the view of small chemical molecules that reflect the end point of biological activities, but also in past decades to the attempts to improve plant behavior under both normal and stressed conditions. Hereby, we summarize the current knowledge on the genetic and biochemical mechanisms underlying plant growth, development, and stress responses, focusing further on the contributions of metabolomics to practical applications in crop quality improvement and food safety assessment, as well as plant metabolic engineering. We also highlight the current challenges and future perspectives in this inspiring area, with the aim to stimulate further studies leading to better crop improvement of yield and quality.

Unraveling the Pathogenesis of Hoyeraal-Hreidarsson Syndrome, a Complex Telomere Biology Disorder

PubMed Central

Glousker, Galina; Touzot, Fabien; Revy, Patrick; Tzfati, Yehuda; Savage, Sharon A.

2015-01-01

SUMMARY Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita (DC). The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease. PMID:25940403

Linking soil biology and chemistry in biological soil crust using isolate exometabolomics.

PubMed

Swenson, Tami L; Karaoz, Ulas; Swenson, Joel M; Bowen, Benjamin P; Northen, Trent R

2018-01-02

Metagenomic sequencing provides a window into microbial community structure and metabolic potential; however, linking these data to exogenous metabolites that microorganisms process and produce (the exometabolome) remains challenging. Previously, we observed strong exometabolite niche partitioning among bacterial isolates from biological soil crust (biocrust). Here we examine native biocrust to determine if these patterns are reproduced in the environment. Overall, most soil metabolites display the expected relationship (positive or negative correlation) with four dominant bacteria following a wetting event and across biocrust developmental stages. For metabolites that were previously found to be consumed by an isolate, 70% are negatively correlated with the abundance of the isolate's closest matching environmental relative in situ, whereas for released metabolites, 67% were positively correlated. Our results demonstrate that metabolite profiling, shotgun sequencing and exometabolomics may be successfully integrated to functionally link microbial community structure with environmental chemistry in biocrust.

Decoding Mechanisms by which Silent Codon Changes Influence Protein Biogenesis and Function

PubMed Central

Bali, Vedrana; Bebok, Zsuzsanna

2015-01-01

Scope Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. Purpose This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Physiological and medical relevance Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies. PMID:25817479

Amphiphilic, cross-linkable diblock copolymers for multifunctionalized nanoparticles as biological probes

NASA Astrophysics Data System (ADS)

Schmidtke, Christian; Pöselt, Elmar; Ostermann, Johannes; Pietsch, Andrea; Kloust, Hauke; Tran, Huong; Schotten, Theo; Bastús, Neus G.; Eggers, Robin; Weller, Horst

2013-07-01

Nanoparticles (NPs) play an increasingly important role in biological labeling and imaging applications. However, preserving their useful properties in an aqueous biological environment remains challenging, even more as NPs therein have to be long-time stable, biocompatible and nontoxic. For in vivo applications, size control is crucial in order to route excretion pathways, e.g. renal clearance vs. hepato-biliary accumulation. Equally necessary, cellular and tissue specific targeting demands suitable linker chemistry for surface functionalization with affinity molecules, like peptides, proteins, carbohydrates and nucleotides. Herein, we report a three stage encapsulation process for NPs comprised of (1) a partial ligand exchange by a multidentate polyolefinic amine ligand, PI-N3, (2) micellar encapsulation with a precisely tuned amphiphilic diblock PI-b-PEG copolymer, in which the PI chains intercalate to the PI-N3 prepolymer and (3) radical cross-linking of the adjacent alkenyl bonds. As a result, water-soluble NPs were obtained, which virtually maintained their primal physical properties and were exceptionally stable in biological media. PEG-terminal functionalization of the diblock PI-b-PEG copolymer with numerous functional groups was mostly straightforward by chain termination of the living anionic polymerization (LAP) with the respective reagents. More complex affinity ligands, e.g. carbohydrates or biotin, were introduced in a two-step process, prior to micellar encapsulation. Advantageously, this pre-assembly approach opens up rapid access to precisely tuned multifunctional NPs, just by using mixtures of diverse functional PI-b-PEG polymers in a combinatorial manner. All constructs showed no toxicity from 0.001 to 1 μM (particle concentration) in standard WST and LDH assays on A549 cells, as well as only marginal unspecific cellular uptake, even in serum-free medium.Nanoparticles (NPs) play an increasingly important role in biological labeling and imaging applications. However, preserving their useful properties in an aqueous biological environment remains challenging, even more as NPs therein have to be long-time stable, biocompatible and nontoxic. For in vivo applications, size control is crucial in order to route excretion pathways, e.g. renal clearance vs. hepato-biliary accumulation. Equally necessary, cellular and tissue specific targeting demands suitable linker chemistry for surface functionalization with affinity molecules, like peptides, proteins, carbohydrates and nucleotides. Herein, we report a three stage encapsulation process for NPs comprised of (1) a partial ligand exchange by a multidentate polyolefinic amine ligand, PI-N3, (2) micellar encapsulation with a precisely tuned amphiphilic diblock PI-b-PEG copolymer, in which the PI chains intercalate to the PI-N3 prepolymer and (3) radical cross-linking of the adjacent alkenyl bonds. As a result, water-soluble NPs were obtained, which virtually maintained their primal physical properties and were exceptionally stable in biological media. PEG-terminal functionalization of the diblock PI-b-PEG copolymer with numerous functional groups was mostly straightforward by chain termination of the living anionic polymerization (LAP) with the respective reagents. More complex affinity ligands, e.g. carbohydrates or biotin, were introduced in a two-step process, prior to micellar encapsulation. Advantageously, this pre-assembly approach opens up rapid access to precisely tuned multifunctional NPs, just by using mixtures of diverse functional PI-b-PEG polymers in a combinatorial manner. All constructs showed no toxicity from 0.001 to 1 μM (particle concentration) in standard WST and LDH assays on A549 cells, as well as only marginal unspecific cellular uptake, even in serum-free medium. Electronic supplementary information (ESI) available: Images of the QDs, toxicity data and NMR spectra. See DOI: 10.1039/c3nr01520c

Untargeted Metabolomics Strategies—Challenges and Emerging Directions

NASA Astrophysics Data System (ADS)

Schrimpe-Rutledge, Alexandra C.; Codreanu, Simona G.; Sherrod, Stacy D.; McLean, John A.

2016-12-01

Metabolites are building blocks of cellular function. These species are involved in enzyme-catalyzed chemical reactions and are essential for cellular function. Upstream biological disruptions result in a series of metabolomic changes and, as such, the metabolome holds a wealth of information that is thought to be most predictive of phenotype. Uncovering this knowledge is a work in progress. The field of metabolomics is still maturing; the community has leveraged proteomics experience when applicable and developed a range of sample preparation and instrument methodology along with myriad data processing and analysis approaches. Research focuses have now shifted toward a fundamental understanding of the biology responsible for metabolomic changes. There are several types of metabolomics experiments including both targeted and untargeted analyses. While untargeted, hypothesis generating workflows exhibit many valuable attributes, challenges inherent to the approach remain. This Critical Insight comments on these challenges, focusing on the identification process of LC-MS-based untargeted metabolomics studies—specifically in mammalian systems. Biological interpretation of metabolomics data hinges on the ability to accurately identify metabolites. The range of confidence associated with identifications that is often overlooked is reviewed, and opportunities for advancing the metabolomics field are described.

A Proteomic Approach to Analyze the Aspirin-mediated Lysine Acetylome*

PubMed Central

Tatham, Michael H.; Cole, Christian; Scullion, Paul; Wilkie, Ross; Westwood, Nicholas J.; Stark, Lesley A.; Hay, Ronald T.

2017-01-01

Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino acid side-chains, leading to the possibility that aspirin-mediated lysine acetylation could explain some of its as-yet unexplained drug actions or side-effects. Using isotopically labeled aspirin-d3, in combination with acetylated lysine purification and LC-MS/MS, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies endogenous acetylation signals at the majority of detectable endogenous sites, cells tolerate aspirin mediated acetylation very well unless cellular deacetylases are inhibited. Although most endogenous acetylations are amplified by orders of magnitude, lysine acetylation site occupancies remain very low even after high doses of aspirin. This work shows that while aspirin has enormous potential to alter protein function, in the majority of cases aspirin-mediated acetylations do not accumulate to levels likely to elicit biological effects. These findings are consistent with an emerging model for cellular acetylation whereby stoichiometry correlates with biological relevance, and deacetylases act to minimize the biological consequences of nonspecific chemical acetylations. PMID:27913581

Iridescence: a functional perspective

PubMed Central

Doucet, Stéphanie M.; Meadows, Melissa G.

2009-01-01

In animals, iridescence is generated by the interaction of light with biological tissues that are nanostructured to produce thin films or diffraction gratings. Uniquely among animal visual signals, the study of iridescent coloration contributes to biological and physical sciences by enhancing our understanding of the evolution of communication strategies, and by providing insights into physical optics and inspiring biomimetic technologies useful to humans. Iridescent colours are found in a broad diversity of animal taxa ranging from diminutive marine copepods to terrestrial insects and birds. Iridescent coloration has received a surge of research interest of late, and studies have focused on both characterizing the nanostructures responsible for producing iridescence and identifying the behavioural functions of iridescent colours. In this paper, we begin with a brief description of colour production mechanisms in animals and provide a general overview of the taxonomic distribution of iridescent colours. We then highlight unique properties of iridescent signals and review the proposed functions of iridescent coloration, focusing, in particular, on the ways in which iridescent colours allow animals to communicate with conspecifics and avoid predators. We conclude with a brief overview of non-communicative functions of iridescence in animals. Despite the vast amount of recent work on animal iridescence, our review reveals that many proposed functions of iridescent coloration remain virtually unexplored, and this area is clearly ripe for future research. PMID:19336344

Cohesin Function in Cohesion, Condensation, and DNA Repair Is Regulated by Wpl1p via a Common Mechanism in Saccharomyces cerevisiae.

PubMed

Bloom, Michelle S; Koshland, Douglas; Guacci, Vincent

2018-01-01

Cohesin tethers DNA to mediate sister chromatid cohesion, chromosome condensation, and DNA repair. How the cell regulates cohesin to perform these distinct functions remains to be elucidated. One cohesin regulator, Wpl1p, was characterized in Saccharomyces cerevisiae as a promoter of efficient cohesion and an inhibitor of condensation. Wpl1p is also required for resistance to DNA-damaging agents. Here, we provide evidence that Wpl1p promotes the timely repair of DNA damage induced during S-phase. Previous studies have indicated that Wpl1p destabilizes cohesin's binding to DNA by modulating the interface between the cohesin subunits Mcd1p and Smc3p Our results suggest that Wpl1p likely modulates this interface to regulate all of cohesin's biological functions. Furthermore, we show that Wpl1p regulates cohesion and condensation through the formation of a functional complex with another cohesin-associated factor, Pds5p In contrast, Wpl1p regulates DNA repair independently of its interaction with Pds5p Together, these results suggest that Wpl1p regulates distinct biological functions of cohesin by Pds5p-dependent and -independent modulation of the Smc3p/Mcd1p interface. Copyright © 2018 by the Genetics Society of America.

Cohesin Function in Cohesion, Condensation, and DNA Repair Is Regulated by Wpl1p via a Common Mechanism in Saccharomyces cerevisiae

PubMed Central

Bloom, Michelle S.; Koshland, Douglas; Guacci, Vincent

2018-01-01

Cohesin tethers DNA to mediate sister chromatid cohesion, chromosome condensation, and DNA repair. How the cell regulates cohesin to perform these distinct functions remains to be elucidated. One cohesin regulator, Wpl1p, was characterized in Saccharomyces cerevisiae as a promoter of efficient cohesion and an inhibitor of condensation. Wpl1p is also required for resistance to DNA-damaging agents. Here, we provide evidence that Wpl1p promotes the timely repair of DNA damage induced during S-phase. Previous studies have indicated that Wpl1p destabilizes cohesin’s binding to DNA by modulating the interface between the cohesin subunits Mcd1p and Smc3p. Our results suggest that Wpl1p likely modulates this interface to regulate all of cohesin’s biological functions. Furthermore, we show that Wpl1p regulates cohesion and condensation through the formation of a functional complex with another cohesin-associated factor, Pds5p. In contrast, Wpl1p regulates DNA repair independently of its interaction with Pds5p. Together, these results suggest that Wpl1p regulates distinct biological functions of cohesin by Pds5p-dependent and -independent modulation of the Smc3p/Mcd1p interface. PMID:29158426

FamNet: A Framework to Identify Multiplied Modules Driving Pathway Expansion in Plants1

PubMed Central

Tohge, Takayuki; Klie, Sebastian; Fernie, Alisdair R.

2016-01-01

Gene duplications generate new genes that can acquire similar but often diversified functions. Recent studies of gene coexpression networks have indicated that, not only genes, but also pathways can be multiplied and diversified to perform related functions in different parts of an organism. Identification of such diversified pathways, or modules, is needed to expand our knowledge of biological processes in plants and to understand how biological functions evolve. However, systematic explorations of modules remain scarce, and no user-friendly platform to identify them exists. We have established a statistical framework to identify modules and show that approximately one-third of the genes of a plant’s genome participate in hundreds of multiplied modules. Using this framework as a basis, we implemented a platform that can explore and visualize multiplied modules in coexpression networks of eight plant species. To validate the usefulness of the platform, we identified and functionally characterized pollen- and root-specific cell wall modules that multiplied to confer tip growth in pollen tubes and root hairs, respectively. Furthermore, we identified multiplied modules involved in secondary metabolite synthesis and corroborated them by metabolite profiling of tobacco (Nicotiana tabacum) tissues. The interactive platform, referred to as FamNet, is available at http://www.gene2function.de/famnet.html. PMID:26754669

The functional role of long non-coding RNA in digestive system carcinomas.

PubMed

Wang, Guang-Yu; Zhu, Yuan-Yuan; Zhang, Yan-Qiao

2014-09-01

In recent years, long non-coding RNAs (lncRNAs) are emerging as either oncogenes or tumor suppressor genes. Recent evidences suggest that lncRNAs play a very important role in digestive system carcinomas. However, the biological function of lncRNAs in the vast majority of digestive system carcinomas remains unclear. Recently, increasing studies has begun to explore their molecular mechanisms and regulatory networks that they are implicated in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in digestive system carcinomas. It is becoming clear that lncRNAs will be exciting and potentially useful for diagnosis and treatment of digestive system carcinomas, some of these lncRNAs might function as both diagnostic markers and the treatment targets of digestive system carcinomas.

Unified Deep Learning Architecture for Modeling Biology Sequence.

PubMed

Wu, Hongjie; Cao, Chengyuan; Xia, Xiaoyan; Lu, Qiang

2017-10-09

Prediction of the spatial structure or function of biological macromolecules based on their sequence remains an important challenge in bioinformatics. When modeling biological sequences using traditional sequencing models, characteristics, such as long-range interactions between basic units, the complicated and variable output of labeled structures, and the variable length of biological sequences, usually lead to different solutions on a case-by-case basis. This study proposed the use of bidirectional recurrent neural networks based on long short-term memory or a gated recurrent unit to capture long-range interactions by designing the optional reshape operator to adapt to the diversity of the output labels and implementing a training algorithm to support the training of sequence models capable of processing variable-length sequences. Additionally, the merge and pooling operators enhanced the ability to capture short-range interactions between basic units of biological sequences. The proposed deep-learning model and its training algorithm might be capable of solving currently known biological sequence-modeling problems through the use of a unified framework. We validated our model on one of the most difficult biological sequence-modeling problems currently known, with our results indicating the ability of the model to obtain predictions of protein residue interactions that exceeded the accuracy of current popular approaches by 10% based on multiple benchmarks.

The Double-Edged Sword: Conserved Functions of Extracellular Hsp90 in Wound Healing and Cancer

PubMed Central

Hance, Michael W.; Nolan, Krystal D.; Isaacs, Jennifer S.

2014-01-01

Heat shock proteins (Hsps) represent a diverse group of chaperones that play a vital role in the protection of cells against numerous environmental stresses. Although our understanding of chaperone biology has deepened over the last decade, the “atypical” extracellular functions of Hsps have remained somewhat enigmatic and comparatively understudied. The heat shock protein 90 (Hsp90) chaperone is a prototypic model for an Hsp family member exhibiting a duality of intracellular and extracellular functions. Intracellular Hsp90 is best known as a master regulator of protein folding. Cancers are particularly adept at exploiting this function of Hsp90, providing the impetus for the robust clinical development of small molecule Hsp90 inhibitors. However, in addition to its maintenance of protein homeostasis, Hsp90 has also been identified as an extracellular protein. Although early reports ascribed immunoregulatory functions to extracellular Hsp90 (eHsp90), recent studies have illuminated expanded functions for eHsp90 in wound healing and cancer. While the intended physiological role of eHsp90 remains enigmatic, its evolutionarily conserved functions in wound healing are easily co-opted during malignancy, a pathology sharing many properties of wounded tissue. This review will highlight the emerging functions of eHsp90 and shed light on its seemingly dichotomous roles as a benevolent facilitator of wound healing and as a sinister effector of tumor progression. PMID:24805867

Ligand-dependent nucleo-cytoplasmic shuttling of peroxisome proliferator-activated receptors, PPARα and PPARγ.

PubMed

Umemoto, Tomoe; Fujiki, Yukio

2012-07-01

Peroxisome proliferator-activated receptors (PPARs) play important roles in diverse biological processes including metabolisms of sugars and lipids and differentiation of cells such as adipocytes. PPARs are transcription factors belonging to the ligand-dependent hormone receptor group. To function as transcription factors, PPARs translocate into nucleus where they associate with transcription apparatus. However, mechanisms underlying nuclear transport of PPARs remain enigmatic. We show here that PPARα and PPARγ dynamically shuttle between nucleus and cytoplasm, although they constitutively and predominantly appear in nucleus. With a series of truncation mutants, we identify that PPAR nuclear transport is mediated by at least two nuclear localization signals (NLSs) in DNA-binding domain (DBD)-hinge and activation function 1 (AF1) regions and their respective receptors including importinα/β, importin 7, and an unidentified receptor. PPARs also harbor two nuclear export signals in DBD and ligand-binding domain regions that are recognized by distinct export receptors, calreticulin and CRM1. Moreover, we show that nuclear-cytoplasmic shuttling of PPARs is regulated by respective PPAR ligands and Ca2+ concentration. Taken together, we suggest that the multiple pathways for the nuclear-cytoplasmic transport of PPARs regulate the biological functions of PPARs in response to external signals. © 2012 The Authors Journal compilation © 2012 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

MacroH2A1 associates with nuclear lamina and maintains chromatin architecture in mouse liver cells.

PubMed

Fu, Yuhua; Lv, Pin; Yan, Guoquan; Fan, Hui; Cheng, Lu; Zhang, Feng; Dang, Yongjun; Wu, Hao; Wen, Bo

2015-11-25

In the interphase nucleus, chromatin is organized into three-dimensional conformation to coordinate genome functions. The lamina-chromatin association is important to facilitate higher-order chromatin in mammalian cells, but its biological significances and molecular mechanisms remain poorly understood. One obstacle is that the list of lamina-associated proteins remains limited, presumably due to the inherent insolubility of lamina proteins. In this report, we identified 182 proteins associated with lamin B1 (a constitutive component of lamina) in mouse hepatocytes, by adopting virus-based proximity-dependent biotin identification. These proteins are functionally related to biological processes such as chromatin organization. As an example, we validated the association between lamin B1 and core histone macroH2A1, a histone associated with repressive chromatin. Furthermore, we mapped Lamina-associated domains (LADs) in mouse liver cells and found that boundaries of LADs are enriched for macroH2A. More interestingly, knocking-down of macroH2A1 resulted in the release of heterochromatin foci marked by histone lysine 9 trimethylation (H3K9me3) and the decondensation of global chromatin structure. However, down-regulation of lamin B1 led to redistribution of macroH2A1. Taken together, our data indicated that macroH2A1 is associated with lamina and is required to maintain chromatin architecture in mouse liver cells.

Anthropogenic areas as incidental substitutes for original habitat.

PubMed

Martínez-Abraín, Alejandro; Jiménez, Juan

2016-06-01

One speaks of ecological substitutes when an introduced species performs, to some extent, the ecosystem function of an extirpated native species. We suggest that a similar case exists for habitats. Species evolve within ecosystems, but habitats can be destroyed or modified by natural and human-made causes. Sometimes habitat alteration forces animals to move to or remain in a suboptimal habitat type. In that case, the habitat is considered a refuge, and the species is called a refugee. Typically refugee species have lower population growth rates than in their original habitats. Human action may lead to the unintended generation of artificial or semiartificial habitat types that functionally resemble the essential features of the original habitat and thus allow a population growth rate of the same magnitude or higher than in the original habitat. We call such areas substitution habitats and define them as human-made habitats within the focal species range that by chance are partial substitutes for the species' original habitat. We call species occupying a substitution habitat adopted species. These are 2 new terms in conservation biology. Examples of substitution habitats are dams for European otters, wheat and rice fields for many steppeland and aquatic birds, and urban areas for storks, falcons, and swifts. Although substitution habitats can bring about increased resilience against the agents of global change, the conservation of original habitat types remains a conservation priority. © 2016 Society for Conservation Biology.

Modeling fMRI signals can provide insights into neural processing in the cerebral cortex

PubMed Central

Sharifian, Fariba; Heikkinen, Hanna; Vigário, Ricardo

2015-01-01

Every stimulus or task activates multiple areas in the mammalian cortex. These distributed activations can be measured with functional magnetic resonance imaging (fMRI), which has the best spatial resolution among the noninvasive brain imaging methods. Unfortunately, the relationship between the fMRI activations and distributed cortical processing has remained unclear, both because the coupling between neural and fMRI activations has remained poorly understood and because fMRI voxels are too large to directly sense the local neural events. To get an idea of the local processing given the macroscopic data, we need models to simulate the neural activity and to provide output that can be compared with fMRI data. Such models can describe neural mechanisms as mathematical functions between input and output in a specific system, with little correspondence to physiological mechanisms. Alternatively, models can be biomimetic, including biological details with straightforward correspondence to experimental data. After careful balancing between complexity, computational efficiency, and realism, a biomimetic simulation should be able to provide insight into how biological structures or functions contribute to actual data processing as well as to promote theory-driven neuroscience experiments. This review analyzes the requirements for validating system-level computational models with fMRI. In particular, we study mesoscopic biomimetic models, which include a limited set of details from real-life networks and enable system-level simulations of neural mass action. In addition, we discuss how recent developments in neurophysiology and biophysics may significantly advance the modelling of fMRI signals. PMID:25972586

Modeling fMRI signals can provide insights into neural processing in the cerebral cortex.

PubMed

Vanni, Simo; Sharifian, Fariba; Heikkinen, Hanna; Vigário, Ricardo

2015-08-01

Every stimulus or task activates multiple areas in the mammalian cortex. These distributed activations can be measured with functional magnetic resonance imaging (fMRI), which has the best spatial resolution among the noninvasive brain imaging methods. Unfortunately, the relationship between the fMRI activations and distributed cortical processing has remained unclear, both because the coupling between neural and fMRI activations has remained poorly understood and because fMRI voxels are too large to directly sense the local neural events. To get an idea of the local processing given the macroscopic data, we need models to simulate the neural activity and to provide output that can be compared with fMRI data. Such models can describe neural mechanisms as mathematical functions between input and output in a specific system, with little correspondence to physiological mechanisms. Alternatively, models can be biomimetic, including biological details with straightforward correspondence to experimental data. After careful balancing between complexity, computational efficiency, and realism, a biomimetic simulation should be able to provide insight into how biological structures or functions contribute to actual data processing as well as to promote theory-driven neuroscience experiments. This review analyzes the requirements for validating system-level computational models with fMRI. In particular, we study mesoscopic biomimetic models, which include a limited set of details from real-life networks and enable system-level simulations of neural mass action. In addition, we discuss how recent developments in neurophysiology and biophysics may significantly advance the modelling of fMRI signals. Copyright © 2015 the American Physiological Society.

Linking Microbiota to Human Diseases: A Systems Biology Perspective.

PubMed

Wu, Hao; Tremaroli, Valentina; Bäckhed, Fredrik

2015-12-01

The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Vascular biology in altered gravity conditions

NASA Astrophysics Data System (ADS)

Bradamante, Silvia; Maier, Janette A. M.; Duncker, Dirk J.

2005-10-01

The physical environment of Endothelial Cells profoundly affects their gene expression, structure, function, growth differentiation and apoptosis. However, the mechanisms by which the genetic and local growth determinants driving morphogenesis are established and maintained remain unknown. Understanding how gravity affects vascular cells will offer new insights for novel therapeutical approaches for cardiovascular disease in general. In terms of tissue engineering and stem-cell therapy, significant future developments will depend on a profound understanding of the cellular and molecular basis of angiogenesis and of the biology of circulating Endothelial Precursor Cells. this MAP project has demonstrated how modelled microgravity influences endothelial proliferation and differentiation with the involvement of anti-angiogenic factors that may be responsible for the non-spontaneous formation of blood vessels.

Visual gravity cues in the interpretation of biological movements: neural correlates in humans.

PubMed

Maffei, Vincenzo; Indovina, Iole; Macaluso, Emiliano; Ivanenko, Yuri P; A Orban, Guy; Lacquaniti, Francesco

2015-01-01

Our visual system takes into account the effects of Earth gravity to interpret biological motion (BM), but the neural substrates of this process remain unclear. Here we measured functional magnetic resonance (fMRI) signals while participants viewed intact or scrambled stick-figure animations of walking, running, hopping, and skipping recorded at normal or reduced gravity. We found that regions sensitive to BM configuration in the occipito-temporal cortex (OTC) were more active for reduced than normal gravity but with intact stimuli only. Effective connectivity analysis suggests that predictive coding of gravity effects underlies BM interpretation. This process might be implemented by a family of snapshot neurons involved in action monitoring. Copyright © 2014 Elsevier Inc. All rights reserved.

The contribution of early language development to children's emotional and behavioural functioning at 6 years: an analysis of data from the Children in Focus sample from the ALSPAC birth cohort.

PubMed

Clegg, Judy; Law, James; Rush, Robert; Peters, Tim J; Roulstone, Susan

2015-01-01

An association between children's early language development and their emotional and behavioural functioning is reported in the literature. The nature of the association remains unclear and it has not been established if such an association is found in a population-based cohort in addition to clinical populations. This study examines the reported association between language development and emotional and behavioural functioning in a population-based cohort. Data from 1,314 children in the Children in Focus (CiF) sample from the Avon Longitudinal Study of Parents and Children (ALSPAC) were analysed. Regression models identified the extent to which early language ability at 2 years of age and later language ability at 4 years of age is associated with emotional and behavioural functioning at 6 years while accounting for biological and social risk and adjusting for age and performance intelligence (PIQ). A series of univariable and multivariable analyses identified a strong influence of biological risk, social risk and early and later language ability to emotional and behavioural functioning. Interestingly, social risk dropped out of the multivariate analyses when age and PIQ were controlled for. Early expressive vocabulary at 2 years and receptive language at 4 years made a strong contribution to emotional and behavioural functioning at 6 years in addition to biological risk. The final model accounted for 11.6% of the variance in emotional and behavioural functioning at 6 years. The study identified that early language ability at 2 years, specifically expressive vocabulary and later receptive language at 4 years both made a moderate, but important contribution to emotional and behavioural functioning at 6 years of age. Although children's language development is important in understanding children's emotional and behavioural functioning, the study shows that it is one of many developmental factors involved. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

Role of IL-9 and STATs in hematological malignancies (Review).

PubMed

Chen, Na; Wang, Xin

2014-03-01

Although interleukin-9 (IL-9) exhibits pleiotropic functions in the immune system, it remains a well-known cytokine in hematological malignancies. Previous cell culture and animal model studies have revealed that the Janus kinase-signal transducer and activator of transcription signaling pathway, which may be activated by a number of cytokines including IL-9, is critical in hematological malignancies. The current review summarizes the characterization of the biological activities of IL-9, highlights the clearly defined roles of the cytokine, and outlines questions with regard to the functions of IL-9 that require further exploration and their downstream signaling proteins, signal transducers and activators of transcription.

Enzymes of yeast polyphosphate metabolism: structure, enzymology and biological roles.

PubMed

Gerasimaitė, Rūta; Mayer, Andreas

2016-02-01

Inorganic polyphosphate (polyP) is found in all living organisms. The known polyP functions in eukaryotes range from osmoregulation and virulence in parasitic protozoa to modulating blood coagulation, inflammation, bone mineralization and cellular signalling in mammals. However mechanisms of regulation and even the identity of involved proteins in many cases remain obscure. Most of the insights obtained so far stem from studies in the yeast Saccharomyces cerevisiae. Here, we provide a short overview of the properties and functions of known yeast polyP metabolism enzymes and discuss future directions for polyP research. © 2016 Authors; published by Portland Press Limited.

Roles of long non-coding RNAs in gastric cancer metastasis

PubMed Central

Yang, Zi-Guo; Gao, Ling; Guo, Xiao-Bo; Shi, Yu-Long

2015-01-01

Gastric cancer is the second leading cause of cancer-related deaths. Metastasis, which is an important element of gastric cancer, leads to a high mortality rate and to a poor prognosis. Gastric cancer metastasis has a complex progression that involves multiple biological processes. The comprehensive mechanisms of metastasis remain unclear, though traditional regulation modulates the molecular functions associated with metastasis. Long non-coding RNAs (lncRNAs) have a role in different gene regulatory pathways by epigenetic modification and by transcriptional and post-transcription regulation. lncRNAs participate in various diseases, including Alzheimer’s disease, cardiovascular disease, and cancer. The altered expressions of certain lncRNAs are linked to gastric cancer metastasis and invasion, as with tumor suppressor genes or oncogenes. Studies have partly elucidated the roles of lncRNAs as biomarkers and in therapies, as well as their gene regulatory mechanisms. However, comprehensive knowledge regarding the functional mechanisms of gene regulation in metastatic gastric cancer remains scarce. To provide a theoretical basis for therapeutic intervention in metastatic gastric cancer, we reviewed the functions of lncRNAs and their regulatory roles in gastric cancer metastasis. PMID:25954095

Structural and functional diversity in Listeria cell wall teichoic acids.

PubMed

Shen, Yang; Boulos, Samy; Sumrall, Eric; Gerber, Benjamin; Julian-Rodero, Alicia; Eugster, Marcel R; Fieseler, Lars; Nyström, Laura; Ebert, Marc-Olivier; Loessner, Martin J

2017-10-27

Wall teichoic acids (WTAs) are the most abundant glycopolymers found on the cell wall of many Gram-positive bacteria, whose diverse surface structures play key roles in multiple biological processes. Despite recent technological advances in glycan analysis, structural elucidation of WTAs remains challenging due to their complex nature. Here, we employed a combination of ultra-performance liquid chromatography-coupled electrospray ionization tandem-MS/MS and NMR to determine the structural complexity of WTAs from Listeria species. We unveiled more than 10 different types of WTA polymers that vary in their linkage and repeating units. Disparity in GlcNAc to ribitol connectivity, as well as variable O -acetylation and glycosylation of GlcNAc contribute to the structural diversity of WTAs. Notably, SPR analysis indicated that constitution of WTA determines the recognition by bacteriophage endolysins. Collectively, these findings provide detailed insight into Listeria cell wall-associated carbohydrates, and will guide further studies on the structure-function relationship of WTAs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Bio-Fluid Dynamics in a Centimeter-Scale Diagnostics Incubator with Integrated Perfusion

NASA Astrophysics Data System (ADS)

Vukasinovic, J.; Cullen, D. K.; Glezer, A.; Laplaca, M. C.

2006-11-01

Growing demands for long-term incubation of biologically faithful, three-dimensional neuronal and other cultures during extended physiological studies require efficient perfusion platforms with functional vasculatures that mimic the in vivo condition in a thermally regulated environment. While thermostatically controlled incubation baths with capillary action perfusion are available, their use is confined to specific experimental conditions. The interstitial nutrient and gas delivery remains diffusion limited over the long term and cultures decay metabolically. To overcome these problems, we describe simple fabrication and experimental characterization of a compact, diagnostics incubator that allows in situ monitoring of culture activity with a superior control of critical biological functions using convectively enhanced heat and mass transport. To overcome intercellular diffusion barriers culture is exposed to a direct flow of media issuing from an array of micro-nozzles that are directed normal to the substrate upholding the culture, and further improved by 3-D convection induced by jet interactions and biased, peripheral perfusate extraction through an array of microchannels as demonstrated by microPIV measurements.

Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm

PubMed Central

Yu, Isseki; Mori, Takaharu; Ando, Tadashi; Harada, Ryuhei; Jung, Jaewoon; Sugita, Yuji; Feig, Michael

2016-01-01

Biological macromolecules function in highly crowded cellular environments. The structure and dynamics of proteins and nucleic acids are well characterized in vitro, but in vivo crowding effects remain unclear. Using molecular dynamics simulations of a comprehensive atomistic model cytoplasm we found that protein-protein interactions may destabilize native protein structures, whereas metabolite interactions may induce more compact states due to electrostatic screening. Protein-protein interactions also resulted in significant variations in reduced macromolecular diffusion under crowded conditions, while metabolites exhibited significant two-dimensional surface diffusion and altered protein-ligand binding that may reduce the effective concentration of metabolites and ligands in vivo. Metabolic enzymes showed weak non-specific association in cellular environments attributed to solvation and entropic effects. These effects are expected to have broad implications for the in vivo functioning of biomolecules. This work is a first step towards physically realistic in silico whole-cell models that connect molecular with cellular biology. DOI: http://dx.doi.org/10.7554/eLife.19274.001 PMID:27801646

Physiological roles of zinc transporters: molecular and genetic importance in zinc homeostasis.

PubMed

Hara, Takafumi; Takeda, Taka-Aki; Takagishi, Teruhisa; Fukue, Kazuhisa; Kambe, Taiho; Fukada, Toshiyuki

2017-03-01

Zinc (Zn) is an essential trace mineral that regulates the expression and activation of biological molecules such as transcription factors, enzymes, adapters, channels, and growth factors, along with their receptors. Zn deficiency or excessive Zn absorption disrupts Zn homeostasis and affects growth, morphogenesis, and immune response, as well as neurosensory and endocrine functions. Zn levels must be adjusted properly to maintain the cellular processes and biological responses necessary for life. Zn transporters regulate Zn levels by controlling Zn influx and efflux between extracellular and intracellular compartments, thus, modulating the Zn concentration and distribution. Although the physiological functions of the Zn transporters remain to be clarified, there is growing evidence that Zn transporters are related to human diseases, and that Zn transporter-mediated Zn ion acts as a signaling factor, called "Zinc signal". Here we describe critical roles of Zn transporters in the body and their contribution at the molecular, biochemical, and genetic levels, and review recently reported disease-related mutations in the Zn transporter genes.

Role of microglia in glioma biology.

PubMed

Badie, B; Schartner, J

2001-07-15

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors or malignant gliomas. Although the function of these cells in CNS inflammatory processes is being studied, their role in malignant glioma biology remains unclear. On one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Copyright 2001 Wiley-Liss, Inc.

Melanin, Radiation, and Energy Transduction in Fungi.

PubMed

Casadevall, Arturo; Cordero, Radames J B; Bryan, Ruth; Nosanchuk, Joshua; Dadachova, Ekaterina

2017-03-01

Melanin pigments are found in many diverse fungal species, where they serve a variety of functions that promote fitness and cell survival. Melanotic fungi inhabit some of the most extreme habitats on earth such as the damaged nuclear reactor at Chernobyl and the highlands of Antarctica, both of which are high-radiation environments. Melanotic fungi migrate toward radioactive sources, which appear to enhance their growth. This phenomenon, combined with the known capacities of melanin to absorb a broad spectrum of electromagnetic radiation and transduce this radiation into other forms of energy, raises the possibility that melanin also functions in harvesting such energy for biological usage. The ability of melanotic fungi to harness electromagnetic radiation for physiological processes has enormous implications for biological energy flows in the biosphere and for exobiology, since it provides new mechanisms for survival in extraterrestrial conditions. Whereas some features of the way melanin-related energy transduction works can be discerned by linking various observations and circumstantial data, the mechanistic details remain to be discovered.

A biomimetic three-dimensional woven composite scaffold for functional tissue engineering of cartilage

NASA Astrophysics Data System (ADS)

Moutos, Franklin T.; Freed, Lisa E.; Guilak, Farshid

2007-02-01

Tissue engineering seeks to repair or regenerate tissues through combinations of implanted cells, biomaterial scaffolds and biologically active molecules. The rapid restoration of tissue biomechanical function remains an important challenge, emphasizing the need to replicate structural and mechanical properties using novel scaffold designs. Here we present a microscale 3D weaving technique to generate anisotropic 3D woven structures as the basis for novel composite scaffolds that are consolidated with a chondrocyte-hydrogel mixture into cartilage tissue constructs. Composite scaffolds show mechanical properties of the same order of magnitude as values for native articular cartilage, as measured by compressive, tensile and shear testing. Moreover, our findings showed that porous composite scaffolds could be engineered with initial properties that reproduce the anisotropy, viscoelasticity and tension-compression nonlinearity of native articular cartilage. Such scaffolds uniquely combine the potential for load-bearing immediately after implantation in vivo with biological support for cell-based tissue regeneration without requiring cultivation in vitro.

How many human proteoforms are there?

PubMed

Aebersold, Ruedi; Agar, Jeffrey N; Amster, I Jonathan; Baker, Mark S; Bertozzi, Carolyn R; Boja, Emily S; Costello, Catherine E; Cravatt, Benjamin F; Fenselau, Catherine; Garcia, Benjamin A; Ge, Ying; Gunawardena, Jeremy; Hendrickson, Ronald C; Hergenrother, Paul J; Huber, Christian G; Ivanov, Alexander R; Jensen, Ole N; Jewett, Michael C; Kelleher, Neil L; Kiessling, Laura L; Krogan, Nevan J; Larsen, Martin R; Loo, Joseph A; Ogorzalek Loo, Rachel R; Lundberg, Emma; MacCoss, Michael J; Mallick, Parag; Mootha, Vamsi K; Mrksich, Milan; Muir, Tom W; Patrie, Steven M; Pesavento, James J; Pitteri, Sharon J; Rodriguez, Henry; Saghatelian, Alan; Sandoval, Wendy; Schlüter, Hartmut; Sechi, Salvatore; Slavoff, Sarah A; Smith, Lloyd M; Snyder, Michael P; Thomas, Paul M; Uhlén, Mathias; Van Eyk, Jennifer E; Vidal, Marc; Walt, David R; White, Forest M; Williams, Evan R; Wohlschlager, Therese; Wysocki, Vicki H; Yates, Nathan A; Young, Nicolas L; Zhang, Bing

2018-02-14

Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA- and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.

Bacterial membrane vesicles, an overlooked environmental colloid: Biology, environmental perspectives and applications.

PubMed

Toyofuku, Masanori; Tashiro, Yosuke; Hasegawa, Yusuke; Kurosawa, Masaharu; Nomura, Nobuhiko

2015-12-01

Phospholipid vesicles play important roles in biological systems. Bacteria are one of the most abundant organisms on Earth, and bacterial membrane vesicles (MVs) were first observed 50 years ago. Many bacteria release MVs to the environment that mainly consist of the cell membrane and typically range from 20 to 400 nm in size. Bacterial MVs are involved in several biological functions, such as delivery of cargo, virulence and gene transfer. MVs can be isolated from laboratory culture and directly from the environment, indicating their high abundance in and impact on ecosystems. Many colloidal particles in the environment ranging in size from 1 nm to 1 μm have been reported but not characterized at the molecular level, and MVs remain to be explored. Hence, MVs can be considered terra incognita in environmental colloid research. Although MV biogenesis and biological roles are yet to be fully understood, the accumulation of knowledge has opened new avenues for their applications. Via genetic engineering, the MV yield can be greatly increased, and the components of MVs can be tailored. Recent studies have demonstrated that MVs have promising potential for applications such as drug delivery systems and nanobiocatalysts. For instance, MV vaccines have been extensively studied and have already been approved in Europe. Recent MV studies have evoked great interest in the fields of biology and biotechnology, but fundamental questions, such as their transport in the environment or physicochemical features of MVs, remain to be addressed. In this review, we present the current understanding of bacterial MVs and environmental perspectives and further introduce their applications. Copyright © 2015. Published by Elsevier B.V.

A Perspective on Micro-Evo-Devo: Progress and Potential

PubMed Central

Nunes, Maria D. S.; Arif, Saad; Schlötterer, Christian; McGregor, Alistair P.

2013-01-01

The term “micro-evo-devo” refers to the combined study of the genetic and developmental bases of natural variation in populations and the evolutionary forces that have shaped this variation. It thus represents a synthesis of the fields of evolutionary developmental biology and population genetics. As has been pointed out by several others, this synthesis can provide insights into the evolution of organismal form and function that have not been possible within these individual disciplines separately. Despite a number of important successes in micro-evo-devo, however, it appears that evo devo and population genetics remain largely separate spheres of research, limiting their ability to address evolutionary questions. This also risks pushing contemporary evo devo to the fringes of evolutionary biology because it does not describe the causative molecular changes underlying evolution or the evolutionary forces involved. Here we reemphasize the theoretical and practical importance of micro-evo-devo as a strategy for understanding phenotypic evolution, review the key recent insights that it has provided, and present a perspective on both the potential and the remaining challenges of this exciting interdisciplinary field. PMID:24190920

Phylogenetics beyond biology.

PubMed

Retzlaff, Nancy; Stadler, Peter F

2018-06-21

Evolutionary processes have been described not only in biology but also for a wide range of human cultural activities including languages and law. In contrast to the evolution of DNA or protein sequences, the detailed mechanisms giving rise to the observed evolution-like processes are not or only partially known. The absence of a mechanistic model of evolution implies that it remains unknown how the distances between different taxa have to be quantified. Considering distortions of metric distances, we first show that poor choices of the distance measure can lead to incorrect phylogenetic trees. Based on the well-known fact that phylogenetic inference requires additive metrics, we then show that the correct phylogeny can be computed from a distance matrix [Formula: see text] if there is a monotonic, subadditive function [Formula: see text] such that [Formula: see text] is additive. The required metric-preserving transformation [Formula: see text] can be computed as the solution of an optimization problem. This result shows that the problem of phylogeny reconstruction is well defined even if a detailed mechanistic model of the evolutionary process remains elusive.

A perspective on micro-evo-devo: progress and potential.

PubMed

Nunes, Maria D S; Arif, Saad; Schlötterer, Christian; McGregor, Alistair P

2013-11-01

The term "micro-evo-devo" refers to the combined study of the genetic and developmental bases of natural variation in populations and the evolutionary forces that have shaped this variation. It thus represents a synthesis of the fields of evolutionary developmental biology and population genetics. As has been pointed out by several others, this synthesis can provide insights into the evolution of organismal form and function that have not been possible within these individual disciplines separately. Despite a number of important successes in micro-evo-devo, however, it appears that evo devo and population genetics remain largely separate spheres of research, limiting their ability to address evolutionary questions. This also risks pushing contemporary evo devo to the fringes of evolutionary biology because it does not describe the causative molecular changes underlying evolution or the evolutionary forces involved. Here we reemphasize the theoretical and practical importance of micro-evo-devo as a strategy for understanding phenotypic evolution, review the key recent insights that it has provided, and present a perspective on both the potential and the remaining challenges of this exciting interdisciplinary field.

[The biological reaction of inflammation, methylglyoxal of blood plasma, functional and structural alterations in elastic type arteries at the early stage of hypertension disease].

PubMed

Titov, V N; Dmitriev, V A; Oshchepkov, E V; Balakhonova, T V; Tripoten', M I; Shiriaeva, Iu K

2012-08-01

The article deals with studying of the relationship between biologic reaction of inflammation with glycosylation reaction and content of methylglyoxal in blood serum. The positive correlation between pulse wave velocity and content of methylglyoxal, C-reactive protein in intercellular medium and malleolar brachial index value was established. This data matches the experimental results concerning involvement of biological reaction of inflammation into structural changes of elastic type arteries under hypertension disease, formation of arteries' rigidity and increase of pulse wave velocity. The arterial blood pressure is a biological reaction of hydrodynamic pressure which is used in vivo by several biological functions: biological function of homeostasis, function of endoecology, biological function of adaptation and function of locomotion. The biological reaction of hydrodynamic (hydraulic) pressure is a mode of compensation of derangement of several biological functions which results in the very high rate of hypertension disease in population. As a matter of fact, hypertension disease is a syndrome of lingering pathological compensation by higher arterial blood pressure of the biological functions derangements occurring in the distal section at the level of paracrine cenoses of cells. The arterial blood pressure is a kind of in vivo integral indicator of deranged metabolism. The essential hypertension disease pathogenically is a result of the derangement of three biological functions: biological function of homeostasis, biological function of trophology - nutrition (biological reaction of external feeding - exotrophia) and biological function of endoecology. In case of "littering" of intercellular medium in vivo with nonspecific endogenic flogogens a phylogenetically earlier activation of biological reactions of excretion, inflammation and hydrodynamic arterial blood pressure occur. In case of derangement of biological function of homeostasis, decreasing of perfusion even in single paracrine cenoses and derangement of biological function of endoecology ("purity" of intercellular medium) the only response always will be the increase of arterial blood pressure.

Relations between Intuitive Biological Thinking and Biological Misconceptions in Biology Majors and Nonmajors

ERIC Educational Resources Information Center

Coley, John D.; Tanner, Kimberly

2015-01-01

Research and theory development in cognitive psychology and science education research remain largely isolated. Biology education researchers have documented persistent scientifically inaccurate ideas, often termed "misconceptions," among biology students across biological domains. In parallel, cognitive and developmental psychologists…

An introduction to microbiome analysis for human biology applications.

PubMed

Amato, Katherine R

2017-01-01

Research examining the gut microbiota is currently exploding, and results are providing new perspectives on human biology. Factors such as host diet and physiology influence the composition and function of the gut microbiota, which in turn affects human nutrition, health, and behavior via interactions with metabolism, the immune system, and the brain. These findings represent an exciting new twist on familiar topics, and as a result, gut microbiome research is likely to provide insight into unresolved biological mechanisms driving human health. However, much remains to be learned about the broader ecological and evolutionary contexts within which gut microbes and humans are affecting each other. Here, I outline the procedures for generating data describing the gut microbiota with the goal of facilitating the wider integration of microbiome analyses into studies of human biology. I describe the steps involved in sample collection, DNA extraction, PCR amplification, high-throughput sequencing, and bioinformatics. While this review serves only as an introduction to these topics, it provides sufficient resources for researchers interested in launching new microbiome initiatives. As knowledge of these methods spreads, microbiome analysis should become a standard tool in the arsenal of human biology research. © 2016 Wiley Periodicals, Inc.

Synthetic biology meets tissue engineering.

PubMed

Davies, Jamie A; Cachat, Elise

2016-06-15

Classical tissue engineering is aimed mainly at producing anatomically and physiologically realistic replacements for normal human tissues. It is done either by encouraging cellular colonization of manufactured matrices or cellular recolonization of decellularized natural extracellular matrices from donor organs, or by allowing cells to self-organize into organs as they do during fetal life. For repair of normal bodies, this will be adequate but there are reasons for making unusual, non-evolved tissues (repair of unusual bodies, interface to electromechanical prostheses, incorporating living cells into life-support machines). Synthetic biology is aimed mainly at engineering cells so that they can perform custom functions: applying synthetic biological approaches to tissue engineering may be one way of engineering custom structures. In this article, we outline the 'embryological cycle' of patterning, differentiation and morphogenesis and review progress that has been made in constructing synthetic biological systems to reproduce these processes in new ways. The state-of-the-art remains a long way from making truly synthetic tissues, but there are now at least foundations for future work. © 2016 Authors; published by Portland Press Limited.

A biochemical network can control formation of a synthetic material by sensing numerous specific stimuli

NASA Astrophysics Data System (ADS)

Hun Yeon, Ju; Chan, Karen Y. T.; Wong, Ting-Chia; Chan, Kelvin; Sutherland, Michael R.; Ismagilov, Rustem F.; Pryzdial, Edward L. G.; Kastrup, Christian J.

2015-05-01

Developing bio-compatible smart materials that assemble in response to environmental cues requires strategies that can discriminate multiple specific stimuli in a complex milieu. Synthetic materials have yet to achieve this level of sensitivity, which would emulate the highly evolved and tailored reaction networks of complex biological systems. Here we show that the output of a naturally occurring network can be replaced with a synthetic material. Exploiting the blood coagulation system as an exquisite biological sensor, the fibrin clot end-product was replaced with a synthetic material under the biological control of a precisely regulated cross-linking enzyme. The functions of the coagulation network remained intact when the material was incorporated. Clot-like polymerization was induced in indirect response to distinct small molecules, phospholipids, enzymes, cells, viruses, an inorganic solid, a polyphenol, a polysaccharide, and a membrane protein. This strategy demonstrates for the first time that an existing stimulus-responsive biological network can be used to control the formation of a synthetic material by diverse classes of physiological triggers.

A Computational Framework for Bioimaging Simulation

PubMed Central

Watabe, Masaki; Arjunan, Satya N. V.; Fukushima, Seiya; Iwamoto, Kazunari; Kozuka, Jun; Matsuoka, Satomi; Shindo, Yuki; Ueda, Masahiro; Takahashi, Koichi

2015-01-01

Using bioimaging technology, biologists have attempted to identify and document analytical interpretations that underlie biological phenomena in biological cells. Theoretical biology aims at distilling those interpretations into knowledge in the mathematical form of biochemical reaction networks and understanding how higher level functions emerge from the combined action of biomolecules. However, there still remain formidable challenges in bridging the gap between bioimaging and mathematical modeling. Generally, measurements using fluorescence microscopy systems are influenced by systematic effects that arise from stochastic nature of biological cells, the imaging apparatus, and optical physics. Such systematic effects are always present in all bioimaging systems and hinder quantitative comparison between the cell model and bioimages. Computational tools for such a comparison are still unavailable. Thus, in this work, we present a computational framework for handling the parameters of the cell models and the optical physics governing bioimaging systems. Simulation using this framework can generate digital images of cell simulation results after accounting for the systematic effects. We then demonstrate that such a framework enables comparison at the level of photon-counting units. PMID:26147508

Rosen's (M,R) system in process algebra.

PubMed

Gatherer, Derek; Galpin, Vashti

2013-11-17

Robert Rosen's Metabolism-Replacement, or (M,R), system can be represented as a compact network structure with a single source and three products derived from that source in three consecutive reactions. (M,R) has been claimed to be non-reducible to its components and algorithmically non-computable, in the sense of not being evaluable as a function by a Turing machine. If (M,R)-like structures are present in real biological networks, this suggests that many biological networks will be non-computable, with implications for those branches of systems biology that rely on in silico modelling for predictive purposes. We instantiate (M,R) using the process algebra Bio-PEPA, and discuss the extent to which our model represents a true realization of (M,R). We observe that under some starting conditions and parameter values, stable states can be achieved. Although formal demonstration of algorithmic computability remains elusive for (M,R), we discuss the extent to which our Bio-PEPA representation of (M,R) allows us to sidestep Rosen's fundamental objections to computational systems biology. We argue that the behaviour of (M,R) in Bio-PEPA shows life-like properties.

FFPred 2.0: Improved Homology-Independent Prediction of Gene Ontology Terms for Eukaryotic Protein Sequences

PubMed Central

Minneci, Federico; Piovesan, Damiano; Cozzetto, Domenico; Jones, David T.

2013-01-01

To understand fully cell behaviour, biologists are making progress towards cataloguing the functional elements in the human genome and characterising their roles across a variety of tissues and conditions. Yet, functional information – either experimentally validated or computationally inferred by similarity – remains completely missing for approximately 30% of human proteins. FFPred was initially developed to bridge this gap by targeting sequences with distant or no homologues of known function and by exploiting clear patterns of intrinsic disorder associated with particular molecular activities and biological processes. Here, we present an updated and improved version, which builds on larger datasets of protein sequences and annotations, and uses updated component feature predictors as well as revised training procedures. FFPred 2.0 includes support vector regression models for the prediction of 442 Gene Ontology (GO) terms, which largely expand the coverage of the ontology and of the biological process category in particular. The GO term list mainly revolves around macromolecular interactions and their role in regulatory, signalling, developmental and metabolic processes. Benchmarking experiments on newly annotated proteins show that FFPred 2.0 provides more accurate functional assignments than its predecessor and the ProtFun server do; also, its assignments can complement information obtained using BLAST-based transfer of annotations, improving especially prediction in the biological process category. Furthermore, FFPred 2.0 can be used to annotate proteins belonging to several eukaryotic organisms with a limited decrease in prediction quality. We illustrate all these points through the use of both precision-recall plots and of the COGIC scores, which we recently proposed as an alternative numerical evaluation measure of function prediction accuracy. PMID:23717476

Downregulation of the expression of HDGF attenuates malignant biological behaviors of hilar cholangiocarcinoma cells.

PubMed

Liu, Yanfeng; Sun, Jingxian; Yang, Guangyun; Liu, Zhaojian; Guo, Sen; Zhao, Rui; Xu, Kesen; Wu, Xiaopeng; Zhang, Zhaoyang

2015-09-01

Hepatoma-derived growth factor (HDGF) has been reported to be a potential predictive and prognostic marker for several types of cancer and important in malignant biological behaviors. However, its role in human hilar cholangiocarcinoma remains to be elucidated. Our previous study demonstrated that high expression levels of HDGF in hilar cholangiocarcinoma tissues correlates with tumor progression and patient outcome. The present study aimed to elucidate the detailed functions of the HDGF protein. This was performed by downregulating the protein expression of HDGF in the FRH0201 hilar cholangiocarcinoma cell line by RNA interference (RNAi) in vitro, and revealed that downregulation of the HDGF protein significantly inhibited the malignant biological behavior of the FRH0201 cells. In addition, further investigation revealed that downregulation of the protein expression of HDGF significantly decreased the secretion of vascular endothelial growth factor, which may be the mechanism partially responsible for the inhibition of malignant biological behaviors. These findings demonstrated that HDGF is important in promoting malignant biological behaviors, including proliferation, migration and invasion of hilar cholangiocarcinoma FRH0201 cells. Inhibition of the expression of HDGF downregulated the malignant biological behaviors, suggesting that downregulation of the protein expression of HDGF by RNAi may be a novel therapeutic approach to inhibit the progression of hilar cholangiocarcinoma.

Differential electrophoretic separation of cells and its effect on cell viability

NASA Technical Reports Server (NTRS)

Leise, E. M.; Lesane, F.

1974-01-01

An electrophoretic separation method was applied to the separation of cells. To determine the efficiency of the separation, it was necessary to apply existing methodology and develop new methods to assess the characteristics and functions of the separated subpopulations. Through appropriate application of the widely used isoelectric focusing procedure, a reproducible separation method was developed. Cells accumulated at defined pH and 70-80% remained viable. The cells were suitable for further biologic, biochemical and immunologic studies.

Myeloid leukemia factor

PubMed Central

Gobert, Vanessa; Haenlin, Marc; Waltzer, Lucas

2012-01-01

Even though deregulation of human MLF1, the founding member of the Myeloid Leukemia Factor family, has been associated with acute myeloid leukemia, the function and mode of action of this family of genes have remained rather mysterious. Yet, recent findings in Drosophila shed new light on their biological activity and suggest that they play an important role in hematopoiesis and leukemia, notably by regulating the stability of RUNX transcription factors, another family of conserved proteins with prominent roles in normal and malignant blood cell development. PMID:22885977

Is biological aging accelerated in drug addiction?

PubMed

Bachi, Keren; Sierra, Salvador; Volkow, Nora D; Goldstein, Rita Z; Alia-Klein, Nelly

2017-02-01

Drug-addiction may trigger early onset of age-related disease, due to drug-induced multi-system toxicity and perilous lifestyle, which remains mostly undetected and untreated. We present the literature on pathophysiological processes that may hasten aging and its relevance to addiction, including: oxidative stress and cellular aging, inflammation in periphery and brain, decline in brain volume and function, and early onset of cardiac, cerebrovascular, kidney, and liver disease. Timely detection of accelerated aging in addiction is crucial for the prevention of premature morbidity and mortality.

Genetic Interaction Maps in Escherichia coli Reveal Functional Crosstalk among Cell Envelope Biogenesis Pathways

PubMed Central

Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J.; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F.; Emili, Andrew

2011-01-01

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among >235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target. PMID:22125496

Protein Science by DNA Sequencing: How Advances in Molecular Biology Are Accelerating Biochemistry.

PubMed

Higgins, Sean A; Savage, David F

2018-01-09

A fundamental goal of protein biochemistry is to determine the sequence-function relationship, but the vastness of sequence space makes comprehensive evaluation of this landscape difficult. However, advances in DNA synthesis and sequencing now allow researchers to assess the functional impact of every single mutation in many proteins, but challenges remain in library construction and the development of general assays applicable to a diverse range of protein functions. This Perspective briefly outlines the technical innovations in DNA manipulation that allow massively parallel protein biochemistry and then summarizes the methods currently available for library construction and the functional assays of protein variants. Areas in need of future innovation are highlighted with a particular focus on assay development and the use of computational analysis with machine learning to effectively traverse the sequence-function landscape. Finally, applications in the fundamentals of protein biochemistry, disease prediction, and protein engineering are presented.

Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways.

PubMed

Babu, Mohan; Díaz-Mejía, J Javier; Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F; Emili, Andrew

2011-11-01

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target.

Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

PubMed

Zhang, Shuxiao; Ross, Kevin D; Seidner, Glen A; Gorman, Michael R; Poon, Tiffany H; Wang, Xiaobo; Keithley, Elizabeth M; Lee, Patricia N; Martindale, Mark Q; Joiner, William J; Hamilton, Bruce A

2015-07-01

Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for null mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

Bile acids modulate signaling by functional perturbation of plasma membrane domains.

PubMed

Zhou, Yong; Maxwell, Kelsey N; Sezgin, Erdinc; Lu, Maryia; Liang, Hong; Hancock, John F; Dial, Elizabeth J; Lichtenberger, Lenard M; Levental, Ilya

2013-12-13

Eukaryotic cell membranes are organized into functional lipid and protein domains, the most widely studied being membrane rafts. Although rafts have been associated with numerous plasma membrane functions, the mechanisms by which these domains themselves are regulated remain undefined. Bile acids (BAs), whose primary function is the solubilization of dietary lipids for digestion and absorption, can affect cells by interacting directly with membranes. To investigate whether these interactions affected domain organization in biological membranes, we assayed the effects of BAs on biomimetic synthetic liposomes, isolated plasma membranes, and live cells. At cytotoxic concentrations, BAs dissolved synthetic and cell-derived membranes and disrupted live cell plasma membranes, implicating plasma membrane damage as the mechanism for BA cellular toxicity. At subtoxic concentrations, BAs dramatically stabilized domain separation in Giant Plasma Membrane Vesicles without affecting protein partitioning between coexisting domains. Domain stabilization was the result of BA binding to and disordering the nonraft domain, thus promoting separation by enhancing domain immiscibility. Consistent with the physical changes observed in synthetic and isolated biological membranes, BAs reorganized intact cell membranes, as evaluated by the spatial distribution of membrane-anchored Ras isoforms. Nanoclustering of K-Ras, related to nonraft membrane domains, was enhanced in intact plasma membranes, whereas the organization of H-Ras was unaffected. BA-induced changes in Ras lateral segregation potentiated EGF-induced signaling through MAPK, confirming the ability of BAs to influence cell signal transduction by altering the physical properties of the plasma membrane. These observations suggest general, membrane-mediated mechanisms by which biological amphiphiles can produce their cellular effects.

Using human brain imaging studies as a guide towards animal models of schizophrenia

PubMed Central

BOLKAN, Scott S.; DE CARVALHO, Fernanda D.; KELLENDONK, Christoph

2015-01-01

Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID:26037801

X-rays in the Cryo-EM Era: Structural Biology’s Dynamic Future

PubMed Central

Shoemaker, Susannah C.; Ando, Nozomi

2018-01-01

Over the past several years, single-particle cryo-electron microscopy (cryo-EM) has emerged as a leading method for elucidating macromolecular structures at near-atomic resolution, rivaling even the established technique of X-ray crystallography. Cryo-EM is now able to probe proteins as small as hemoglobin (64 kDa), while avoiding the crystallization bottleneck entirely. The remarkable success of cryo-EM has called into question the continuing relevance of X-ray methods, particularly crystallography. To say that the future of structural biology is either cryo-EM or crystallography, however, would be misguided. Crystallography remains better suited to yield precise atomic coordinates of macromolecules under a few hundred kDa in size, while the ability to probe larger, potentially more disordered assemblies is a distinct advantage of cryo-EM. Likewise, crystallography is better equipped to provide high-resolution dynamic information as a function of time, temperature, pressure, and other perturbations, whereas cryo-EM offers increasing insight into conformational and energy landscapes, particularly as algorithms to deconvolute conformational heterogeneity become more advanced. Ultimately, the future of both techniques depends on how their individual strengths are utilized to tackle questions on the frontiers of structural biology. Structure determination is just one piece of a much larger puzzle: a central challenge of modern structural biology is to relate structural information to biological function. In this perspective, we share insight from several leaders in the field and examine the unique and complementary ways in which X-ray methods and cryo-EM can shape the future of structural biology. PMID:29227642

Born criminal? Differences in structural, functional and behavioural lateralization between criminals and noncriminals.

PubMed

Savopoulos, Priscilla; Lindell, Annukka K

2018-02-15

Over 100 years ago Lombroso [(1876/2006). Criminal man. Durham: Duke University Press] proposed a biological basis for criminality. Based on inspection of criminals' skulls he theorized that an imbalance of the cerebral hemispheres was amongst 18 distinguishing features of the criminal brain. Specifically, criminals were less lateralized than noncriminals. As the advent of neuroscientific techniques makes more fine-grained inspection of differences in brain structure and function possible, we review criminals' and noncriminals' structural, functional, and behavioural lateralization to evaluate the merits of Lombroso's thesis and investigate the evidence for the biological underpinning of criminal behaviour. Although the body of research is presently small, it appears consistent with Lombroso's proposal: criminal psychopaths' brains show atypical structural asymmetries, with reduced right hemisphere grey and white matter volumes, and abnormal interhemispheric connectivity. Functional asymmetries are also atypical, with criminal psychopaths showing a less lateralized cortical response than noncriminals across verbal, visuo-spatial, and emotional tasks. Finally, the incidence of non-right-handedness is higher in criminal than non-criminal populations, consistent with reduced cortical lateralization. Thus despite Lombroso's comparatively primitive and inferential research methods, his conclusion that criminals' lateralization differs from that of noncriminals is borne out by the neuroscientific research. How atypical cortical asymmetries predispose criminal behaviour remains to be determined.

Mesenchymal Stem/Progenitor Cells Derived from Articular Cartilage, Synovial Membrane and Synovial Fluid for Cartilage Regeneration: Current Status and Future Perspectives.

PubMed

Huang, Yi-Zhou; Xie, Hui-Qi; Silini, Antonietta; Parolini, Ornella; Zhang, Yi; Deng, Li; Huang, Yong-Can

2017-10-01

Large articular cartilage defects remain an immense challenge in the field of regenerative medicine because of their poor intrinsic repair capacity. Currently, the available medical interventions can relieve clinical symptoms to some extent, but fail to repair the cartilaginous injuries with authentic hyaline cartilage. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stem/progenitor cells with or without scaffolds. Mesenchymal stem/progenitor cells are promising graft cells for tissue regeneration, but the most suitable source of cells for cartilage repair remains controversial. The tissue origin of mesenchymal stem/progenitor cells notably influences the biological properties and therapeutic potential. It is well known that mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit superior chondrogenic ability compared with those derived from non-joint tissues; thus, these cell populations are considered ideal sources for cartilage regeneration. In addition to the progress in research and promising preclinical results, many important research questions must be answered before widespread success in cartilage regeneration is achieved. This review outlines the biology of stem/progenitor cells derived from the articular cartilage, the synovial membrane, and the synovial fluid, including their tissue distribution, function and biological characteristics. Furthermore, preclinical and clinical trials focusing on their applications for cartilage regeneration are summarized, and future research perspectives are discussed.

Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model.

PubMed

Li, Edward B; Truong, Dawn; Hallett, Shawn A; Mukherjee, Kusumika; Schutte, Brian C; Liao, Eric C

2017-09-01

Large-scale sequencing efforts have captured a rapidly growing catalogue of genetic variations. However, the accurate establishment of gene variant pathogenicity remains a central challenge in translating personal genomics information to clinical decisions. Interferon Regulatory Factor 6 (IRF6) gene variants are significant genetic contributors to orofacial clefts. Although approximately three hundred IRF6 gene variants have been documented, their effects on protein functions remain difficult to interpret. Here, we demonstrate the protein functions of human IRF6 missense gene variants could be rapidly assessed in detail by their abilities to rescue the irf6 -/- phenotype in zebrafish through variant mRNA microinjections at the one-cell stage. The results revealed many missense variants previously predicted by traditional statistical and computational tools to be loss-of-function and pathogenic retained partial or full protein function and rescued the zebrafish irf6 -/- periderm rupture phenotype. Through mRNA dosage titration and analysis of the Exome Aggregation Consortium (ExAC) database, IRF6 missense variants were grouped by their abilities to rescue at various dosages into three functional categories: wild type function, reduced function, and complete loss-of-function. This sensitive and specific biological assay was able to address the nuanced functional significances of IRF6 missense gene variants and overcome many limitations faced by current statistical and computational tools in assigning variant protein function and pathogenicity. Furthermore, it unlocked the possibility for characterizing yet undiscovered human IRF6 missense gene variants from orofacial cleft patients, and illustrated a generalizable functional genomics paradigm in personalized medicine.

Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes.

PubMed

Bedada, Fikru B; Wheelwright, Matthew; Metzger, Joseph M

2016-07-01

Human heart failure due to myocardial infarction is a major health concern. The paucity of organs for transplantation limits curative approaches for the diseased and failing adult heart. Human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) have the potential to provide a long-term, viable, regenerative-medicine alternative. Significant progress has been made with regard to efficient cardiac myocyte generation from hiPSCs. However, directing hiPSC-CMs to acquire the physiological structure, gene expression profile and function akin to mature cardiac tissue remains a major obstacle. Thus, hiPSC-CMs have several hurdles to overcome before they find their way into translational medicine. In this review, we address the progress that has been made, the void in knowledge and the challenges that remain. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

The sensory ecology of ocean navigation.

PubMed

Lohmann, Kenneth J; Lohmann, Catherine M F; Endres, Courtney S

2008-06-01

How animals guide themselves across vast expanses of open ocean, sometimes to specific geographic areas, has remained an enduring mystery of behavioral biology. In this review we briefly contrast underwater oceanic navigation with terrestrial navigation and summarize the advantages and constraints of different approaches used to analyze animal navigation in the sea. In addition, we highlight studies and techniques that have begun to unravel the sensory cues that underlie navigation in sea turtles, salmon and other ocean migrants. Environmental signals of importance include geomagnetic, chemical and hydrodynamic cues, perhaps supplemented in some cases by celestial cues or other sources of information that remain to be discovered. An interesting similarity between sea turtles and salmon is that both have been hypothesized to complete long-distance reproductive migrations using navigational systems composed of two different suites of mechanisms that function sequentially over different spatial scales. The basic organization of navigation in these two groups of animals may be functionally similar, and perhaps also representative of other long-distance ocean navigators.

ACTH Action on StAR Biology

PubMed Central

Clark, Barbara J.

2016-01-01

Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies. PMID:27999527

ACTH Action on StAR Biology.

PubMed

Clark, Barbara J

2016-01-01

Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies.

Developing PFC representations using reinforcement learning.

PubMed

Reynolds, Jeremy R; O'Reilly, Randall C

2009-12-01

From both functional and biological considerations, it is widely believed that action production, planning, and goal-oriented behaviors supported by the frontal cortex are organized hierarchically [Fuster (1991); Koechlin, E., Ody, C., & Kouneiher, F. (2003). Neuroscience: The architecture of cognitive control in the human prefrontal cortex. Science, 424, 1181-1184; Miller, G. A., Galanter, E., & Pribram, K. H. (1960). Plans and the structure of behavior. New York: Holt]. However, the nature of the different levels of the hierarchy remains unclear, and little attention has been paid to the origins of such a hierarchy. We address these issues through biologically-inspired computational models that develop representations through reinforcement learning. We explore several different factors in these models that might plausibly give rise to a hierarchical organization of representations within the PFC, including an initial connectivity hierarchy within PFC, a hierarchical set of connections between PFC and subcortical structures controlling it, and differential synaptic plasticity schedules. Simulation results indicate that architectural constraints contribute to the segregation of different types of representations, and that this segregation facilitates learning. These findings are consistent with the idea that there is a functional hierarchy in PFC, as captured in our earlier computational models of PFC function and a growing body of empirical data.

Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

PubMed Central

Wells, Lance

2016-01-01

O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies. PMID:24524620

Large-Scale Analysis Exploring Evolution of Catalytic Machineries and Mechanisms in Enzyme Superfamilies.

PubMed

Furnham, Nicholas; Dawson, Natalie L; Rahman, Syed A; Thornton, Janet M; Orengo, Christine A

2016-01-29

Enzymes, as biological catalysts, form the basis of all forms of life. How these proteins have evolved their functions remains a fundamental question in biology. Over 100 years of detailed biochemistry studies, combined with the large volumes of sequence and protein structural data now available, means that we are able to perform large-scale analyses to address this question. Using a range of computational tools and resources, we have compiled information on all experimentally annotated changes in enzyme function within 379 structurally defined protein domain superfamilies, linking the changes observed in functions during evolution to changes in reaction chemistry. Many superfamilies show changes in function at some level, although one function often dominates one superfamily. We use quantitative measures of changes in reaction chemistry to reveal the various types of chemical changes occurring during evolution and to exemplify these by detailed examples. Additionally, we use structural information of the enzymes active site to examine how different superfamilies have changed their catalytic machinery during evolution. Some superfamilies have changed the reactions they perform without changing catalytic machinery. In others, large changes of enzyme function, in terms of both overall chemistry and substrate specificity, have been brought about by significant changes in catalytic machinery. Interestingly, in some superfamilies, relatives perform similar functions but with different catalytic machineries. This analysis highlights characteristics of functional evolution across a wide range of superfamilies, providing insights that will be useful in predicting the function of uncharacterised sequences and the design of new synthetic enzymes. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Natural product synthesis at the interface of chemistry and biology

PubMed Central

2014-01-01

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. PMID:25043880

Heme and blood-feeding parasites: friends or foes?

PubMed Central

2010-01-01

Hemoparasites, like malaria and schistosomes, are constantly faced with the challenges of storing and detoxifying large quantities of heme, released from their catabolism of host erythrocytes. Heme is an essential prosthetic group that forms the reactive core of numerous hemoproteins with diverse biological functions. However, due to its reactive nature, it is also a potentially toxic molecule. Thus, the acquisition and detoxification of heme is likely to be paramount for the survival and establishment of parasitism. Understanding the underlying mechanism involved in this interaction could possibly provide potential novel targets for drug and vaccine development, and disease treatment. However, there remains a wide gap in our understanding of these mechanisms. This review summarizes the biological importance of heme for hemoparasite, and the adaptations utilized in its sequestration and detoxification. PMID:21087517

Evolution and development of model membranes for physicochemical and functional studies of the membrane lateral heterogeneity.

PubMed

Morigaki, Kenichi; Tanimoto, Yasushi

2018-03-14

One of the main questions in the membrane biology is the functional roles of membrane heterogeneity and molecular localization. Although segregation and local enrichment of protein/lipid components (rafts) have been extensively studied, the presence and functions of such membrane domains still remain elusive. Along with biochemical, cell observation, and simulation studies, model membranes are emerging as an important tool for understanding the biological membrane, providing quantitative information on the physicochemical properties of membrane proteins and lipids. Segregation of fluid lipid bilayer into liquid-ordered (Lo) and liquid-disordered (Ld) phases has been studied as a simplified model of raft in model membranes, including giant unilamellar vesicles (GUVs), giant plasma membrane vesicles (GPMVs), and supported lipid bilayers (SLB). Partition coefficients of membrane proteins between Lo and Ld phases were measured to gauze their affinities to lipid rafts (raftophilicity). One important development in model membrane is patterned SLB based on the microfabrication technology. Patterned Lo/Ld phases have been applied to study the partition and function of membrane-bound molecules. Quantitative information of individual molecular species attained by model membranes is critical for elucidating the molecular functions in the complex web of molecular interactions. The present review gives a short account of the model membranes developed for studying the lateral heterogeneity, especially focusing on patterned model membranes on solid substrates. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional network analysis of genes differentially expressed during xylogenesis in soc1ful woody Arabidopsis plants.

PubMed

Davin, Nicolas; Edger, Patrick P; Hefer, Charles A; Mizrachi, Eshchar; Schuetz, Mathias; Smets, Erik; Myburg, Alexander A; Douglas, Carl J; Schranz, Michael E; Lens, Frederic

2016-06-01

Many plant genes are known to be involved in the development of cambium and wood, but how the expression and functional interaction of these genes determine the unique biology of wood remains largely unknown. We used the soc1ful loss of function mutant - the woodiest genotype known in the otherwise herbaceous model plant Arabidopsis - to investigate the expression and interactions of genes involved in secondary growth (wood formation). Detailed anatomical observations of the stem in combination with mRNA sequencing were used to assess transcriptome remodeling during xylogenesis in wild-type and woody soc1ful plants. To interpret the transcriptome changes, we constructed functional gene association networks of differentially expressed genes using the STRING database. This analysis revealed functionally enriched gene association hubs that are differentially expressed in herbaceous and woody tissues. In particular, we observed the differential expression of genes related to mechanical stress and jasmonate biosynthesis/signaling during wood formation in soc1ful plants that may be an effect of greater tension within woody tissues. Our results suggest that habit shifts from herbaceous to woody life forms observed in many angiosperm lineages could have evolved convergently by genetic changes that modulate the gene expression and interaction network, and thereby redeploy the conserved wood developmental program. © 2016 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.

Enzymatically Active Microgels from Self-Assembling Protein Nanofibrils for Microflow Chemistry.

PubMed

Zhou, Xiao-Ming; Shimanovich, Ulyana; Herling, Therese W; Wu, Si; Dobson, Christopher M; Knowles, Tuomas P J; Perrett, Sarah

2015-06-23

Amyloid fibrils represent a generic class of protein structure associated with both pathological states and with naturally occurring functional materials. This class of protein nanostructure has recently also emerged as an excellent foundation for sophisticated functional biocompatible materials including scaffolds and carriers for biologically active molecules. Protein-based materials offer the potential advantage that additional functions can be directly incorporated via gene fusion producing a single chimeric polypeptide that will both self-assemble and display the desired activity. To succeed, a chimeric protein system must self-assemble without the need for harsh triggering conditions which would damage the appended functional protein molecule. However, the micrometer to nanoscale patterning and morphological control of protein-based nanomaterials has remained challenging. This study demonstrates a general approach for overcoming these limitations through the microfluidic generation of enzymatically active microgels that are stabilized by amyloid nanofibrils. The use of scaffolds formed from biomaterials that self-assemble under mild conditions enables the formation of catalytic microgels while maintaining the integrity of the encapsulated enzyme. The enzymatically active microgel particles show robust material properties and their porous architecture allows diffusion in and out of reactants and products. In combination with microfluidic droplet trapping approaches, enzymatically active microgels illustrate the potential of self-assembling materials for enzyme immobilization and recycling, and for biological flow-chemistry. These design principles can be adopted to create countless other bioactive amyloid-based materials with diverse functions.

The effect of nanoparticle degradation on amphiphilic polymer-coated quantum dot toxicity: the importance of particle functionality assessment in toxicology [corrected].

PubMed

Soenen, Stefaan J; Montenegro, José-Maria; Abdelmonem, Abuelmagd M; Manshian, Bella B; Doak, Shareen H; Parak, Wolfgang J; De Smedt, Stefaan C; Braeckmans, Kevin

2014-02-01

Colloidal semiconductor nanoparticles (quantum dots) have attracted a lot of interest in technological and biomedical research, given their potent fluorescent properties. However, the use of heavy-metal-containing nanoparticles remains an issue of debate. The possible toxic effects of quantum dots remain a hot research topic and several questions such as possible intracellular degradation of quantum dots and the effect thereof on both cell viability and particle functionality remain unresolved. In the present work, amphiphilic polymer [corrected] coated CdSe/ZnS quantum dots were synthesized and characterized, after which their effects on cultured cells were evaluated using a multiparametric setup. The data reveal that the quantum dots are taken up through endocytosis and when exposed to the low pH of the endosomal structures, they partially degrade and release cadmium ions, which lowers their fluorescence intensity and augments particle toxicity. Using the multiparametric method, the quantum dots were evaluated at non-toxic doses in terms of their ability to visualize labeled cells for longer time periods. The data revealed that comparing different particles in terms of their applied dose is challenging, likely due to difficulties in obtaining accurate nanoparticle concentrations, but evaluating particle toxicity in terms of their biological functionality enables an easy and straightforward comparison. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Recent advances in lipid separations and structural elucidation using mass spectrometry combined with ion mobility spectrometry, ion-molecule reactions and fragmentation approaches

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Xueyun; Smith, Richard D.; Baker, Erin S.

Lipids are a vital class of molecules that play important and varied roles in biological processes. Fully understanding lipid roles, however, is extremely difficult since the number and diversity of lipid species is immense, with cells expressing hundreds of enzymes that synthesize tens of thousands of different lipids. While recent advances in chromatography and high resolution mass spectrometry have greatly progressed the understanding of lipid species and functions, effectively separating many lipids still remains problematic. Isomeric lipids have made lipid characterization especially difficult and occur due to subclasses having the same chemical composition, or species having multiple acyl chains connectivitiesmore » (sn-1, sn-2, or sn-3), double bond positions and orientations (cis or trans), and functional group stereochemistry (R versus S). Fully understanding the roles of lipids in biological processes therefore requires separating and evaluating how isomers change in biological and environmental samples. To address this challenge, ion mobility spectrometry separations, ion-molecule reactions and fragmentation techniques have increasingly been added to lipid analysis workflows to improve identifications. In this manuscript, we review the current state of these approaches and their capabilities for improving the identification of specific lipid species.« less

Protease inhibitor in scorpion (Mesobuthus eupeus) venom prolongs the biological activities of the crude venom.

PubMed

Ma, Hakim; Xiao-Peng, Tang; Yang, Shi-Long; Lu, Qiu-Min; Lai, Ren

2016-08-01

It is hypothesized that protease inhibitors play an essential role in survival of venomous animals through protecting peptide/protein toxins from degradation by proteases in their prey or predators. However, the biological function of protease inhibitors in scorpion venoms remains unknown. In the present study, a trypsin inhibitor was purified and characterized from the venom of scorpion Mesobuthus eupeus, which enhanced the biological activities of crude venom components in mice when injected in combination with crude venom. This protease inhibitor, named MeKTT-1, belonged to Kunitz-type toxins subfamily. Native MeKTT-1 selectively inhibited trypsin with a Kivalue of 130 nmol·L(-1). Furthermore, MeKTT-1 was shown to be a thermo-stable peptide. In animal behavioral tests, MeKTT-1 prolonged the pain behavior induced by scorpion crude venom, suggesting that protease inhibitors in scorpion venom inhibited proteases and protect the functionally important peptide/protein toxins from degradation, consequently keeping them active longer. In conclusion, this was the first experimental evidence about the natural existence of serine protease inhibitor in the venom of scorpion Mesobuthus eupeus, which preserved the activity of venom components, suggests that scorpions may use protease inhibitors for survival. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

A Native Threonine Coordinates Ordered Water to Tune Light-Oxygen-Voltage (LOV) Domain Photocycle Kinetics and Osmotic Stress Signaling in Trichoderma reesei ENVOY.

PubMed

Lokhandwala, Jameela; Silverman Y de la Vega, Rafael I; Hopkins, Hilary C; Britton, Collin W; Rodriguez-Iglesias, Aroa; Bogomolni, Roberto; Schmoll, Monika; Zoltowski, Brian D

2016-07-08

Light-oxygen-voltage (LOV) domain-containing proteins function as small light-activated modules capable of imparting blue light control of biological processes. Their small modular nature has made them model proteins for allosteric signal transduction and optogenetic devices. Despite intense research, key aspects of their signal transduction mechanisms and photochemistry remain poorly understood. In particular, ordered water has been identified as a possible key mediator of photocycle kinetics, despite the lack of ordered water in the LOV active site. Herein, we use recent crystal structures of a fungal LOV protein ENVOY to interrogate the role of Thr(101) in recruiting water to the flavin active site where it can function as an intrinsic base to accelerate photocycle kinetics. Kinetic and molecular dynamic simulations confirm a role in solvent recruitment to the active site and identify structural changes that correlate with solvent recruitment. In vivo analysis of T101I indicates a direct role of the Thr(101) position in mediating adaptation to osmotic stress, thereby verifying biological relevance of ordered water in LOV signaling. The combined studies identify position 101 as a mediator of both allostery and photocycle catalysis that can impact organism physiology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Predicting Amyloidogenic Proteins in the Proteomes of Plants.

PubMed

Antonets, Kirill S; Nizhnikov, Anton A

2017-10-16

Amyloids are protein fibrils with characteristic spatial structure. Though amyloids were long perceived to be pathogens that cause dozens of incurable pathologies in humans and mammals, it is currently clear that amyloids also represent a functionally important form of protein structure implicated in a variety of biological processes in organisms ranging from archaea and bacteria to fungi and animals. Despite their social significance, plants remain the most poorly studied group of organisms in the field of amyloid biology. To date, amyloid properties have only been demonstrated in vitro or in heterologous systems for a small number of plant proteins. Here, for the first time, we performed a comprehensive analysis of the distribution of potentially amyloidogenic proteins in the proteomes of approximately 70 species of land plants using the Waltz and SARP (Sequence Analysis based on the Ranking of Probabilities) bioinformatic algorithms. We analyzed more than 2.9 million protein sequences and found that potentially amyloidogenic proteins are abundant in plant proteomes. We found that such proteins are overrepresented among membrane as well as DNA- and RNA-binding proteins of plants. Moreover, seed storage and defense proteins of most plant species are rich in amyloidogenic regions. Taken together, our data demonstrate the diversity of potentially amyloidogenic proteins in plant proteomes and suggest biological processes where formation of amyloids might be functionally important.

Can mangrove plantation enhance the functional diversity of macrobenthic community in polluted mangroves?

PubMed

Leung, Jonathan Y S; Cheung, Napo K M

2017-03-15

Mangrove plantation is widely applied to re-establish the plant community in degraded mangroves, but its effectiveness to restore the ecological functions of macrobenthic community remains poorly known, especially when pollution may overwhelm its potential positive effect. Here, we tested the effect of mangrove plantation on the ecological functions of macrobenthic community in a polluted mangrove by analyzing biological traits of macrobenthos and calculating functional diversity. Mangrove plantation was shown to enhance the functional diversity and restore the ecological functions of macrobenthic community, depending on seasonality. Given the polluted sediment, however, typical traits of opportunistic species (e.g. small and short-lived) prevailed in all habitats and sampling times. We conclude that mangrove plantation can help diversify the ecological functions of macrobenthic community, but its effectiveness is likely reduced by pollution. From the management perspective, therefore, pollution sources must be stringently regulated and mangrove plantation should be conducted to fully recover degraded mangroves. Copyright © 2017 Elsevier Ltd. All rights reserved.

Phosphatidylenthanolamine Binding Protein aka Raf Kinase Inhibitor Protein: A Brief History of Its Discovery and the Remarkable Diversity of Biological Functions.

PubMed

Sedivy, John M

2011-01-01

Phosphatidylethanolamine-binding protein (PEBP) was identified almost three decades ago as an abundant protein in bovine brain. PEBP is the prototype of a highly conserved family of proteins represented in all three major phylogenetic divisions, eukaryota, bacteria, and archaea, with no significant sequence homology to other proteins. PEBP proteins have been studied in many species. The most thoroughly explored biological role of PEBP is that of a modulator of intracellular signaling pathways, which is mediated by its ability to bind and inhibit a number of protein kinases. The first such interaction that came to light was with the Raf1 kinase, and PEBP is thus widely referred to in the literature under its alternate name RKIP (Raf kinase inhibitory protein). The activity of RKIP itself is subject to regulation by phosphorylation. Intriguingly, PEBP has also been reported to possess additional, and diverse, biological functions unrelated to protein kinase networks that remain to be investigated in detail. Recent findings that RKIP may function as a suppressor of cancer metastasis are of great interest and importance. Prognostic and therapeutic applications of RKIP in human cancer were the subject of the first international workshop on RKIP that was held at the University of California, Los Angeles, in March 2010. This paper was presented at the workshop as a summary of the history of this still small but rapidly evolving field.

Translational Geroscience: Emphasizing function to achieve optimal longevity

PubMed Central

Seals, Douglas R.; Melov, Simon

2014-01-01

Among individuals, biological aging leads to cellular and organismal dysfunction and an increased risk of chronic degenerative diseases and disability. This sequence of events in combination with the projected increases in the number of older adults will result in a worldwide healthcare burden with dire consequences. Superimposed on this setting are the adults now reaching traditional retirement ages--the baby boomers--a group that wishes to remain active, productive and physically and cognitively fit as they grow older. Together, these conditions are producing an unprecedented demand for increased healthspan or what might be termed “optimal longevity”—to live long, but well. To meet this demand, investigators with interests in the biological aspects of aging from model organisms to human epidemiology (population aging) must work together within an interactive process that we describe as translational geroscience. An essential goal of this new investigational platform should be the optimization and preservation of physiological function throughout the lifespan, including integrative physical and cognitive function, which would serve to increase healthspan, compress morbidity and disability into a shorter period of late-life, and help achieve optimal longevity. To most effectively utilize this new approach, we must rethink how investigators and administrators working at different levels of the translational research continuum communicate and collaborate with each other, how best to train the next generation of scientists in this new field, and how contemporary biological-biomedical aging research should be organized and funded. PMID:25324468

Foxa2, a novel protein partner of the tumour suppressor menin, is deregulated in mouse and human MEN1 glucagonomas.

PubMed

Bonnavion, Rémy; Teinturier, Romain; Gherardi, Samuele; Leteurtre, Emmanuelle; Yu, Run; Cordier-Bussat, Martine; Du, Rui; Pattou, François; Vantyghem, Marie-Christine; Bertolino, Philippe; Lu, Jieli; Zhang, Chang Xian

2017-05-01

Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon. However, its expression and biological role in adult pancreatic α-cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α-cell-specific Men1 mutant mice, at both the transcriptional level and the protein level. More importantly, immunostaining analyses showed its prominent nuclear accumulation, specifically in α-cells, at a very early stage after Men1 disruption. Similar nuclear FOXA2 expression was also detected in a substantial proportion (12/19) of human multiple endocrine neoplasia type 1 (MEN1) glucagonomas. Interestingly, our data revealed an interaction between Foxa2 and menin encoded by the Men1 gene. Furthermore, using several approaches, we demonstrated the relevance of this interaction in the regulation of two tested Foxa2 target genes, including the autoregulation of the Foxa2 promoter by Foxa2 itself. The current study establishes menin, a novel protein partner of Foxa2, as a regulator of Foxa2, the biological functions of which extend beyond the pancreatic endocrine cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Molecular and comparative genetics of mental retardation.

PubMed Central

Inlow, Jennifer K; Restifo, Linda L

2004-01-01

Affecting 1-3% of the population, mental retardation (MR) poses significant challenges for clinicians and scientists. Understanding the biology of MR is complicated by the extraordinary heterogeneity of genetic MR disorders. Detailed analyses of >1000 Online Mendelian Inheritance in Man (OMIM) database entries and literature searches through September 2003 revealed 282 molecularly identified MR genes. We estimate that hundreds more MR genes remain to be identified. A novel test, in which we distributed unmapped MR disorders proportionately across the autosomes, failed to eliminate the well-known X-chromosome overrepresentation of MR genes and candidate genes. This evidence argues against ascertainment bias as the main cause of the skewed distribution. On the basis of a synthesis of clinical and laboratory data, we developed a biological functions classification scheme for MR genes. Metabolic pathways, signaling pathways, and transcription are the most common functions, but numerous other aspects of neuronal and glial biology are controlled by MR genes as well. Using protein sequence and domain-organization comparisons, we found a striking conservation of MR genes and genetic pathways across the approximately 700 million years that separate Homo sapiens and Drosophila melanogaster. Eighty-seven percent have one or more fruit fly homologs and 76% have at least one candidate functional ortholog. We propose that D. melanogaster can be used in a systematic manner to study MR and possibly to develop bioassays for therapeutic drug discovery. We selected 42 Drosophila orthologs as most likely to reveal molecular and cellular mechanisms of nervous system development or plasticity relevant to MR. PMID:15020472

Transcriptome Analysis of PA Gain and Loss of Function Mutants.

PubMed

Marco, Francisco; Carrasco, Pedro

2018-01-01

Functional genomics has become a forefront methodology for plant science thanks to the widespread development of microarray technology. While technical difficulties associated with the process of obtaining raw expression data have been diminishing, allowing the appearance of tremendous amounts of transcriptome data in different databases, a common problem using "omic" technologies remains: the interpretation of these data and the inference of its biological meaning. In order to assist to this complex task, a wide variety of software tools have been developed. In this chapter we describe our current workflow of the application of some of these analyses. We have used it to compare the transcriptome of plants with differences in their polyamine levels.

The Hippo pathway in tissue homeostasis and regeneration.

PubMed

Wang, Yu; Yu, Aijuan; Yu, Fa-Xing

2017-05-01

While several organs in mammals retain partial regenerative capability following tissue damage, the underlying mechanisms remain unclear. Recently, the Hippo signaling pathway, better known for its function in organ size control, has been shown to play a pivotal role in regulating tissue homeostasis and regeneration. Upon tissue injury, the activity of YAP, the major effector of the Hippo pathway, is transiently induced, which in turn promotes expansion of tissue-resident progenitors and facilitates tissue regeneration. In this review, with a general focus on the Hippo pathway, we will discuss its major components, functions in stem cell biology, involvement in tissue regeneration in different organs, and potential strategies for developing Hippo pathway-targeted regenerative medicines.

Deciphering CD30 ligand biology and its role in humoral immunity

PubMed Central

Kennedy, Mary K; Willis, Cynthia R; Armitage, Richard J

2006-01-01

Ligands and receptors in the tumour necrosis factor (TNF) and tumour necrosis factor receptor (TNFR) superfamilies have been the subject of extensive investigation over the past 10–15 years. For certain TNFR family members, such as Fas and CD40, some of the consequences of receptor ligation were predicted before the identification and cloning of their corresponding ligands through in vitro functional studies using agonistic receptor-specific antibodies. For other members of the TNFR family, including CD30, cross-linking the receptor with specific antibodies failed to yield many clues about the functional significance of the relevant ligand–receptor interactions. In many instances, the subsequent availability of TNF family ligands in the form of recombinant protein facilitated the determination of biological consequences of interactions with their relevant receptor in both in vitro and in vivo settings. In the case of CD30 ligand (CD30L; CD153), definition of its biological role remained frustratingly elusive. Early functional studies using CD30L+ cells or agonistic CD30-specific antibodies logically focused attention on cell types that had been shown to express CD30, namely certain lymphoid malignancies and subsets of activated T cells. However, it was not immediately clear how the reported activities from these in vitro studies relate to the biological activity of CD30L in the more complex whole animal setting. Recently, results from in vivo models involving CD30 or CD30L gene disruption, CD30L overexpression, or pharmacological blockade of CD30/CD30L interactions have begun to provide clues about the role played by CD30L in immunological processes. In this review we consider the reported biology of CD30L and focus on results from several recent studies that point to an important role for CD30/CD30L interactions in humoral immune responses. PMID:16771849

Cobra CRISP functions as an inflammatory modulator via a novel Zn2+- and heparan sulfate-dependent transcriptional regulation of endothelial cell adhesion molecules.

PubMed

Wang, Yu-Ling; Kuo, Je-Hung; Lee, Shao-Chen; Liu, Jai-Shin; Hsieh, Yin-Cheng; Shih, Yu-Tsung; Chen, Chun-Jung; Chiu, Jeng-Jiann; Wu, Wen-Guey

2010-11-26

Cysteine-rich secretory proteins (CRISPs) have been identified as a toxin family in most animal venoms with biological functions mainly associated with the ion channel activity of cysteine-rich domain (CRD). CRISPs also bind to Zn(2+) at their N-terminal pathogenesis-related (PR-1) domain, but their function remains unknown. Interestingly, similar the Zn(2+)-binding site exists in all CRISP family, including those identified in a wide range of organisms. Here, we report that the CRISP from Naja atra (natrin) could induce expression of vascular endothelial cell adhesion molecules, i.e. intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin, to promote monocytic cell adhesion in a heparan sulfate (HS)- and Zn(2+)-dependent manner. Using specific inhibitors and small interfering RNAs, the activation mechanisms are shown to involve both mitogen-activated protein kinases and nuclear factor-κB. Biophysical characterization of natrin by using fluorescence, circular dichroism, and x-ray crystallographic methods further reveals the presence of two Zn(2+)-binding sites for natrin. The strong binding site is located near the putative Ser-His-Glu catalytic triad of the N-terminal domain. The weak binding site remains to be characterized, but it may modulate HS binding by enhancing its interaction with long chain HS. Our results strongly suggest that natrin may serve as an inflammatory modulator that could perturb the wound-healing process of the bitten victim by regulating adhesion molecule expression in endothelial cells. Our finding uncovers a new aspect of the biological role of CRISP family in immune response and is expected to facilitate future development of new therapeutic strategy for the envenomed victims.

Heart Disease in Women: Unappreciated Challenges, GPER as a New Target.

PubMed

Feldman, Ross D

2016-05-18

Heart disease in women remains underappreciated, underdiagnosed and undertreated. Further, although we are starting to understand some of the social and behavioral determinants for this, the biological basis for the increased rate of rise in atherosclerosis risk in women after menopause remains very poorly understand. In this review we will outline the scope of the clinical issues related to heart disease in women, the emerging findings regarding the biological basis underlying the increased prevalence of atherosclerotic risk factors in postmenopausal women (vs. men) and the role of the G protein-coupled estrogen receptor (GPER) and its genetic regulation as a determinant of these sex-specific risks. GPER is a recently appreciated GPCR that mediates the rapid effects of estrogen and aldosterone. Recent studies have identified that GPER activation regulates both blood pressure. We have shown that regulation of GPER function via expression of a hypofunctional GPER genetic variant is an important determinant of blood pressure and risk of hypertension in women. Further, our most recent studies have identified that GPER activation is an important regulator of low density lipoprotein (LDL) receptor metabolism and that expression of the hypofunctional GPER genetic variant is an important contributor to the development of hypercholesterolemia in women. GPER appears to be an important determinant of the two major risk factors for coronary artery disease-blood pressure and LDL cholesterol. Further, the importance of this mechanism appears to be greater in women. Thus, the appreciation of the role of GPER function as a determinant of the progression of atherosclerotic disease may be important both in our understanding of cardiometabolic function but also in opening the way to greater appreciation of the sex-specific regulation of atherosclerotic risk factors.

Ventral aspect of the visual form pathway is not critical for the perception of biological motion

PubMed Central

Gilaie-Dotan, Sharon; Saygin, Ayse Pinar; Lorenzi, Lauren J.; Rees, Geraint; Behrmann, Marlene

2015-01-01

Identifying the movements of those around us is fundamental for many daily activities, such as recognizing actions, detecting predators, and interacting with others socially. A key question concerns the neurobiological substrates underlying biological motion perception. Although the ventral “form” visual cortex is standardly activated by biologically moving stimuli, whether these activations are functionally critical for biological motion perception or are epiphenomenal remains unknown. To address this question, we examined whether focal damage to regions of the ventral visual cortex, resulting in significant deficits in form perception, adversely affects biological motion perception. Six patients with damage to the ventral cortex were tested with sensitive point-light display paradigms. All patients were able to recognize unmasked point-light displays and their perceptual thresholds were not significantly different from those of three different control groups, one of which comprised brain-damaged patients with spared ventral cortex (n > 50). Importantly, these six patients performed significantly better than patients with damage to regions critical for biological motion perception. To assess the necessary contribution of different regions in the ventral pathway to biological motion perception, we complement the behavioral findings with a fine-grained comparison between the lesion location and extent, and the cortical regions standardly implicated in biological motion processing. This analysis revealed that the ventral aspects of the form pathway (e.g., fusiform regions, ventral extrastriate body area) are not critical for biological motion perception. We hypothesize that the role of these ventral regions is to provide enhanced multiview/posture representations of the moving person rather than to represent biological motion perception per se. PMID:25583504

The Role of Synthetic and Biologic Materials in the Treatment of Pelvic Organ Prolapse

PubMed Central

Brown, Ramon A.; Ellis, C. Neal

2014-01-01

Pelvic organ prolapse is a significant medical problem that poses a diagnostic and management dilemma. These diseases cause serious morbidity in those affected and treatment is sought for relief of pelvic pain, rectal bleeding, chronic constipation, obstructed defecation, and fecal incontinence. Numerous procedures have been proposed to treat these conditions; however, the search continues as colorectal surgeons attempt to find the procedure that would optimally treat these conditions. The use of prosthetics in the repair of pelvic organ prolapse has become prevalent as the benefits of their use are realized. While advances in biologic mesh and new surgical techniques promise improved functional outcomes with decreased complication rates without de novo symptoms, the debate concerning the best prosthetic material, synthetic or biologic, remains controversial. Furthermore, laparoscopic ventral mesh rectopexy has emerged as a procedure that could potentially fill this role and is rapidly becoming the procedure of choice for the surgical treatment of pelvic organ prolapse. PMID:25435827

The role of synthetic and biologic materials in the treatment of pelvic organ prolapse.

PubMed

Brown, Ramon A; Ellis, C Neal

2014-12-01

Pelvic organ prolapse is a significant medical problem that poses a diagnostic and management dilemma. These diseases cause serious morbidity in those affected and treatment is sought for relief of pelvic pain, rectal bleeding, chronic constipation, obstructed defecation, and fecal incontinence. Numerous procedures have been proposed to treat these conditions; however, the search continues as colorectal surgeons attempt to find the procedure that would optimally treat these conditions. The use of prosthetics in the repair of pelvic organ prolapse has become prevalent as the benefits of their use are realized. While advances in biologic mesh and new surgical techniques promise improved functional outcomes with decreased complication rates without de novo symptoms, the debate concerning the best prosthetic material, synthetic or biologic, remains controversial. Furthermore, laparoscopic ventral mesh rectopexy has emerged as a procedure that could potentially fill this role and is rapidly becoming the procedure of choice for the surgical treatment of pelvic organ prolapse.

Biology of portal hypertension.

PubMed

McConnell, Matthew; Iwakiri, Yasuko

2018-02-01

Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.

Animal behaviour and algal camouflage jointly structure predation and selection.

PubMed

Start, Denon

2018-05-01

Trait variation can structure interactions between individuals, thus shaping selection. Although antipredator strategies are an important component of many aquatic systems, how multiple antipredator traits interact to influence consumption and selection remains contentious. Here, I use a common larval dragonfly (Epitheca canis) and its predator (Anax junius) to test for the joint effects of activity rate and algal camouflage on predation and survival selection. I found that active and poorly camouflaged Epitheca were more likely to be consumed, and thus, survival selection favoured inactive and well-camouflaged individuals. Notably, camouflage dampened selection on activity rate, likely by reducing attack rates when Epitheca encountered a predator. Correlational selection is therefore conferred by the ecological interaction of traits, rather than by opposing selection acting on linked traits. I suggest that antipredator traits with different adaptive functions can jointly structure patterns of consumption and selection. © 2018 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2018 European Society For Evolutionary Biology.

The impact of detergents on the tissue decellularization process: a ToF-SIMS study

PubMed Central

White, Lisa J; Taylor, Adam J; Faulk, Denver M; Keane, Tim J; Saldin, Lindsey T; Reing, Janet E; Swinehart, Ilea T; Turner, Neill J; Ratner, Buddy D

2017-01-01

Biologic scaffolds are derived from mammalian tissues, which must be decellularized to remove cellular antigens that would otherwise incite an adverse immune response. Although widely used clinically, the optimum balance between cell removal and the disruption of matrix architecture and surface ligand landscape remains a considerable challenge. Here we describe the use of time of flight secondary ion mass spectroscopy (ToF-SIMS) to provide sensitive, molecular specific, localized analysis of detergent decellularized biologic scaffolds. We detected residual detergent fragments, specifically from Triton X-100, sodium deoxycholate and sodium dodecyl sulphate (SDS) in decellularized scaffolds; increased SDS concentrations from 0.1% to 1.0% increased both the intensity of SDS fragments and adverse cell outcomes. We also identified cellular remnants, by detecting phosphate and phosphocholine ions in PAA and CHAPS decellularized scaffolds. The present study demonstrates ToF-SIMS is not only a powerful tool for characterization of biologic scaffold surface molecular functionality, but also enables sensitive assessment of decellularization efficacy. PMID:27993639

Real-time imaging of nitric oxide production in living cells with 1,3,5,7-tetramethyl-2,6-dicarbethoxy-8-(3',4'-diaminophenyl)-difluoroboradiaza-s-indacence by invert fluorescence microscope.

PubMed

Huang, Ke-Jing; Wang, Hong; Ma, Ming; Zhang, Xian; Zhang, Hua-Shan

2007-02-01

Although the importance of nitric oxide (NO) as a signalling molecule in many biological processes is becoming increasingly evident, many proposed and potential biological functions of NO still remain unclear. Bioimaging is a good technique to visualize observation of nitric oxide in biological samples. In this report, a fluorescent probe, 1,3,5,7-tetramethyl-2,6-dicarbethoxy-8-(3',4'-diaminophenyl)-difluoroboradiaza-s-indacence (TMDCDABODIPY), has been first applied to real-time image NO produced in PC12 cells, Sf9 cells and human vascular endothelial cells at the presence of l-arginine with inverted fluorescence microscope. NO production in the cells is successfully captured and imaged with fine temporal and spatial resolution. The results prove that the probe combined with inverted fluorescence microscope can be developed into a sensitive and selective method for further study of NO release from cells.

Two-dimensional flow nanometry of biological nanoparticles for accurate determination of their size and emission intensity

NASA Astrophysics Data System (ADS)

Block, Stephan; Fast, Björn Johansson; Lundgren, Anders; Zhdanov, Vladimir P.; Höök, Fredrik

2016-09-01

Biological nanoparticles (BNPs) are of high interest due to their key role in various biological processes and use as biomarkers. BNP size and composition are decisive for their functions, but simultaneous determination of both properties with high accuracy remains challenging. Optical microscopy allows precise determination of fluorescence/scattering intensity, but not the size of individual BNPs. The latter is better determined by tracking their random motion in bulk, but the limited illumination volume for tracking this motion impedes reliable intensity determination. Here, we show that by attaching BNPs to a supported lipid bilayer, subjecting them to hydrodynamic flows and tracking their motion via surface-sensitive optical imaging enable determination of their diffusion coefficients and flow-induced drifts, from which accurate quantification of both BNP size and emission intensity can be made. For vesicles, the accuracy of this approach is demonstrated by resolving the expected radius-squared dependence of their fluorescence intensity for radii down to 15 nm.

An integrative systems biology approach to understanding pulmonary diseases.

PubMed

Auffray, Charles; Adcock, Ian M; Chung, Kian Fan; Djukanovic, Ratko; Pison, Christophe; Sterk, Peter J

2010-06-01

Chronic inflammatory pulmonary diseases such as COPD and asthma are highly prevalent and associated with a major health burden worldwide. Despite a wealth of biologic and clinical information on normal and pathologic airway structure and function, the primary causes and mechanisms of disease remain to a large extent unknown, preventing the development of more efficient diagnosis and treatment. We propose to overcome these limitations through an integrative systems biology research strategy designed to identify the functional and regulatory pathways that play central roles in respiratory pathophysiology, starting with severe asthma. This approach relies on global genome, transcriptome, proteome, and metabolome data sets collected in cross-sectional patient cohorts with high-throughput measurement platforms and integrated with biologic and clinical data to inform predictive multiscale models ranging from the molecular to the organ levels. Working hypotheses formulated on the mechanisms and pathways involved in various disease states are tested through perturbation experiments using model simulation combined with targeted and global technologies in cellular and animal models. The responses observed are compared with those predicted by the initial models, which are refined to account better for the results. Novel perturbation experiments are designed and tested both computationally and experimentally to arbitrate between competing hypotheses. The process is iterated until the derived knowledge allows a better classification and subphenotyping of severe asthma using complex biomarkers, which will facilitate the development of novel diagnostic and therapeutic interventions targeting multiple components of the molecular and cellular pathways involved. This can be tested and validated in prospective clinical trials.

Systems Genetics Analysis of GWAS reveals Novel Associations between Key Biological Processes and Coronary Artery Disease

PubMed Central

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre FR; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2016-01-01

Objective Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Employing pathways (gene sets) from Reactome, we carried out a two-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CADGWAS data sets (9,889 cases/11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of 9 additional studies (15,502 cases/55,730 controls) from the CARDIoGRAM Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication p<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the TGF-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (e.g. semaphorin regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared to random networks (p<0.001). Network centrality analysis (‘degree’ and ‘betweenness’) further identified genes (e.g. NCAM1, FYN, FURIN etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. PMID:25977570

Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.

PubMed

Shih, Andrew J; Purvis, Jeremy; Radhakrishnan, Ravi

2008-12-01

The complexity in intracellular signaling mechanisms relevant for the conquest of many diseases resides at different levels of organization with scales ranging from the subatomic realm relevant to catalytic functions of enzymes to the mesoscopic realm relevant to the cooperative association of molecular assemblies and membrane processes. Consequently, the challenge of representing and quantifying functional or dysfunctional modules within the networks remains due to the current limitations in our understanding of mesoscopic biology, i.e., how the components assemble into functional molecular ensembles. A multiscale approach is necessary to treat a hierarchy of interactions ranging from molecular (nm, ns) to signaling (microm, ms) length and time scales, which necessitates the development and application of specialized modeling tools. Complementary to multiscale experimentation (encompassing structural biology, mechanistic enzymology, cell biology, and single molecule studies) multiscale modeling offers a powerful and quantitative alternative for the study of functional intracellular signaling modules. Here, we describe the application of a multiscale approach to signaling mediated by the ErbB1 receptor which constitutes a network hub for the cell's proliferative, migratory, and survival programs. Through our multiscale model, we mechanistically describe how point-mutations in the ErbB1 receptor can profoundly alter signaling characteristics leading to the onset of oncogenic transformations. Specifically, we describe how the point mutations induce cascading fragility mechanisms at the molecular scale as well as at the scale of the signaling network to preferentially activate the survival factor Akt. We provide a quantitative explanation for how the hallmark of preferential Akt activation in cell-lines harboring the constitutively active mutant ErbB1 receptors causes these cell-lines to be addicted to ErbB1-mediated generation of survival signals. Consequently, inhibition of ErbB1 activity leads to a remarkable therapeutic response in the addicted cell lines.

From Drosophila to humans: Reflections on the roles of the prolyl-isomerases and chaperones, cyclophilins, in cell function and disease

PubMed Central

Ferreira, Paulo A.; Orry, Andrew

2013-01-01

Despite remarkable advances in human genetics and other genetic model systems, the fruit fly, Drosophila melanogaster, remains a powerful experimental tool to probe with ease the inner workings of a myriad of biological and pathological processes, even when evolutionary forces impart apparent divergences to some of such processes. The understanding of such evolutionary differences provides mechanistic insights into genotype-phenotype correlations underpinning biological processes across metazoans. The pioneering work developed by the William Pak laboratory for the past four decades, and the work of others, epitomize the notion of how the Drosophila system breaks new fertile ground or complements research fields of high scientific and medical relevance. Among the three major genetic complementation groups produced by the Pak's laboratory and impairing distinct facets of photoreceptor neuronal function, the nina group (ninaA….J) selectively affects the biogenesis of G protein-coupled receptors (GPCR) mediating the photoconversion and transduction of light-stimuli. Among the nina genes identified, ninaA arguably assumes heightened significance for several reasons. First, it presents unique physiological selectivity toward the biogenesis of a subset of GPCRs, a standalone biological manifestation yet to be discerned for most mammalian homologues of NinaA. Second, NinaA belongs to a family of proteins, immunophilins, which are the primary targets for immunosuppressive drugs at the therapeutic forefront of a multitude of medical conditions. Third, NinaA closest homologue, cyclophilin-B (CyPB/PPIB), is an immunophilin whose loss-of-function was found recently to cause osteogenesis imperfecta in the human. This report highlights advances made by studies on some members of immunophilins, the cyclophilins. Finally, it re-examines critically data and dogmas derived from past and recent genetic, structural, biological and pathological studies on NinaA and few other cyclophilins that support some of such paradigms to be less than definite and advance our understanding of cyclophilins' roles in cell function, disease and therapeutic interventions. PMID:22332926

Neural Stem Cells (NSCs) and Proteomics.

PubMed

Shoemaker, Lorelei D; Kornblum, Harley I

2016-02-01

Neural stem cells (NSCs) can self-renew and give rise to the major cell types of the CNS. Studies of NSCs include the investigation of primary, CNS-derived cells as well as animal and human embryonic stem cell (ESC)-derived and induced pluripotent stem cell (iPSC)-derived sources. NSCs provide a means with which to study normal neural development, neurodegeneration, and neurological disease and are clinically relevant sources for cellular repair to the damaged and diseased CNS. Proteomics studies of NSCs have the potential to delineate molecules and pathways critical for NSC biology and the means by which NSCs can participate in neural repair. In this review, we provide a background to NSC biology, including the means to obtain them and the caveats to these processes. We then focus on advances in the proteomic interrogation of NSCs. This includes the analysis of posttranslational modifications (PTMs); approaches to analyzing different proteomic compartments, such the secretome; as well as approaches to analyzing temporal differences in the proteome to elucidate mechanisms of differentiation. We also discuss some of the methods that will undoubtedly be useful in the investigation of NSCs but which have not yet been applied to the field. While many proteomics studies of NSCs have largely catalogued the proteome or posttranslational modifications of specific cellular states, without delving into specific functions, some have led to understandings of functional processes or identified markers that could not have been identified via other means. Many challenges remain in the field, including the precise identification and standardization of NSCs used for proteomic analyses, as well as how to translate fundamental proteomics studies to functional biology. The next level of investigation will require interdisciplinary approaches, combining the skills of those interested in the biochemistry of proteomics with those interested in modulating NSC function. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Biological response to purification and acid functionalization of carbon nanotubes

NASA Astrophysics Data System (ADS)

Figarol, Agathe; Pourchez, Jérémie; Boudard, Delphine; Forest, Valérie; Tulliani, Jean-Marc; Lecompte, Jean-Pierre; Cottier, Michèle; Bernache-Assollant, Didier; Grosseau, Philippe

2014-07-01

Acid functionalization has been considered as an easy way to enhance the dispersion and biodegradation of carbon nanotubes (CNT). However, inconsistencies between toxicity studies of acid functionalized CNT remain unexplained. This could be due to a joint effect of the main physicochemical modifications resulting from an acid functionalization: addition of surface acid groups and purification from catalytic metallic impurities. In this study, the impact on CNT biotoxicity of these two physiochemical features was assessed separately. The in vitro biological response of RAW 264.7 macrophages was evaluated after exposure to 15-240 µg mL-1 of two types of multi-walled CNT. For each type of CNT (small: 20 nm diameter, and big: 90 nm diameter), three different surface chemical properties were studied (total of six CNT samples): pristine, acid functionalized and desorbed. Desorbed CNT were purified by the acid functionalization but presented a very low amount of surface acid groups due to a thermal treatment under vacuum. A Janus effect of acid functionalization with two opposite impacts is highlighted. The CNT purification decreased the overall toxicity, while the surface acid groups intensified it when present at a specific threshold. These acid groups especially amplified the pro-inflammatory response. The threshold mechanism which seemed to regulate the impact of acid groups should be further studied to determine its value and potential link to the other physicochemical state of the CNT. The results suggest that, for a safer-design approach, the benefit-risk balance of an acid functionalization has to be considered, depending on the CNT primary state of purification. Further research should be conducted in this direction.

Biochemical characterization of the selenoproteome in Gallus gallus via bioinformatics analysis: structure-function relationships and interactions of binding molecules.

PubMed

Zhu, Shi-Yong; Li, Xue-Nan; Sun, Xiao-Chen; Lin, Jia; Li, Wei; Zhang, Cong; Li, Jin-Long

2017-02-22

Knowledge about mammalian selenoproteins is increasing. However, the selenoproteome of birds remains considerably less understood, especially concerning its biochemical characterization, structure-function relationships and the interactions of binding molecules. In this work, the SECIS elements, subcellular localization, protein domains and interactions of binding molecules of the selenoproteome in Gallus gallus were analyzed using bioinformatics tools. We carried out comprehensive analyses of the structure-function relationships and interactions of the binding molecules of selenoproteins, to provide biochemical characterization of the selenoproteome in Gallus gallus. Our data provided a wealth of information on the biochemical functions of bird selenoproteins. Members of the selenoproteome were found to be involved in various biological processes in chickens, such as in antioxidants, maintenance of the redox balance, Se transport, and interactions with metals. Six membrane-bound selenoproteins (SelI, SelK, SelS, SelT, DIO1 and DIO3) played important roles in maintaining the membrane integrity. Chicken selenoproteins were classified according to their ligand binding sites as zinc-containing matrix metalloselenoproteins (Sep15, MsrB1, SelW and SelM), POP-containing selenoproteins (GPx1-4), FAD-interacting selenoproteins (TrxR1-3), secretory transport selenoproteins (GPx3 and SelPa) and other selenoproteins. The results of our study provided new evidence for the unknown biological functions of the selenoproteome in birds. Future research is required to confirm the novel biochemical functions of bird selenoproteins.

Discovery and Characterization of Chromatin States for Systematic Annotation of the Human Genome

NASA Astrophysics Data System (ADS)

Ernst, Jason; Kellis, Manolis

A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. Although individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use a multivariate Hidden Markov Model to reveal chromatin states in human T cells, based on recurrent and spatially coherent combinations of chromatin marks.We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, largescale repressed and repeat-associated states. Each chromatin state shows specific enrichments in functional annotations, sequence motifs and specific experimentally observed characteristics, suggesting distinct biological roles. This approach provides a complementary functional annotation of the human genome that reveals the genome-wide locations of diverse classes of epigenetic function.

Gene expression links functional networks across cortex and striatum.

PubMed

Anderson, Kevin M; Krienen, Fenna M; Choi, Eun Young; Reinen, Jenna M; Yeo, B T Thomas; Holmes, Avram J

2018-04-12

The human brain is comprised of a complex web of functional networks that link anatomically distinct regions. However, the biological mechanisms supporting network organization remain elusive, particularly across cortical and subcortical territories with vastly divergent cellular and molecular properties. Here, using human and primate brain transcriptional atlases, we demonstrate that spatial patterns of gene expression show strong correspondence with limbic and somato/motor cortico-striatal functional networks. Network-associated expression is consistent across independent human datasets and evolutionarily conserved in non-human primates. Genes preferentially expressed within the limbic network (encompassing nucleus accumbens, orbital/ventromedial prefrontal cortex, and temporal pole) relate to risk for psychiatric illness, chloride channel complexes, and markers of somatostatin neurons. Somato/motor associated genes are enriched for oligodendrocytes and markers of parvalbumin neurons. These analyses indicate that parallel cortico-striatal processing channels possess dissociable genetic signatures that recapitulate distributed functional networks, and nominate molecular mechanisms supporting cortico-striatal circuitry in health and disease.

From Embryonic Development to Human Diseases: The Functional Role of Caveolae/Caveolin

PubMed Central

Sohn, Jihee; Brick, Rachel M.; Tuan, Rocky S.

2017-01-01

Caveolae, an almost ubiquitous, structural component of the plasma membrane, play a critical role in many functions essential for proper cell function, including membrane trafficking, signal transduction, extracellular matrix remodeling, and tissue regeneration. Three main types of caveolin proteins have been identified from caveolae since the discovery of caveolin-1 in the early 1990s. All three (Cav-1, Cav-2, and Cav-3) play crucial roles in mammalian physiology, and can effect pathogenesis in a wide range of human diseases. While many biological activities of caveolins have been uncovered since its discovery, their role and regulation in embryonic develop remain largely poorly understood, although there is increasing evidence that caveolins may be linked to lung and brain birth defects. Further investigations are clearly needed to decipher how caveolae/caveolins mediate cellular functions and activities of normal embryogenesis and how their perturbations contribute to developmental disorders. PMID:26991990

Monotone viable trajectories for functional differential inclusions

NASA Astrophysics Data System (ADS)

Haddad, Georges

This paper is a study on functional differential inclusions with memory which represent the multivalued version of retarded functional differential equations. The main result gives a necessary and sufficient equations. The main result gives a necessary and sufficient condition ensuring the existence of viable trajectories; that means trajectories remaining in a given nonempty closed convex set defined by given constraints the system must satisfy to be viable. Some motivations for this paper can be found in control theory where F( t, φ) = { f( t, φ, u)} uɛU is the set of possible velocities of the system at time t, depending on the past history represented by the function φ and on a control u ranging over a set U of controls. Other motivations can be found in planning procedures in microeconomics and in biological evolutions where problems with memory do effectively appear in a multivalued version. All these models require viability constraints represented by a closed convex set.

Circular RNA: an emerging key player in RNA world.

PubMed

Meng, Xianwen; Li, Xue; Zhang, Peijing; Wang, Jingjing; Zhou, Yincong; Chen, Ming

2017-07-01

Insights into the circular RNA (circRNA) exploration have revealed that they are abundant in eukaryotic transcriptomes. Diverse genomic regions can generate different types of RNA circles, implying their diversity. Covalently closed loop structures elevate the stability of this new type of noncoding RNA. High-throughput sequencing analyses suggest that circRNAs exhibit tissue- and developmental-specific expression, indicating that they may play crucial roles in multiple cellular processes. Strikingly, several circRNAs could function as microRNA sponges and regulate gene transcription, highlighting a new class of important regulators. Here, we review the recent advances in knowledge of endogenous circRNA biogenesis, properties and functions. We further discuss the current findings about circRNAs in human diseases. In plants, the roles of circRNAs remain a mystery. Online resources and bioinformatics identification of circRNAs are essential for the analysis of circRNA biology, although different strategies yield divergent results. The understanding of circRNA functions remains limited; however, circRNAs are enriching the RNA world, acting as an emerging key player. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Strategies for regeneration of heart muscle.

PubMed

Guyette, Jacques P; Cohen, Ira S; Gaudette, Glenn R

2010-01-01

Regenerative medicine has emerged to the forefront of cardiac research, marrying discoveries in both basic science and engineering to develop viable therapeutic approaches for treating the diseased heart. Signifi cant advancements in gene therapy, stem cell biology, and cardiomyoplasty provide new optimism for regenerating damaged myocardium. Exciting new strategies for endogenous and exogenous regeneration have been proposed. However, questions remain as to whether these approaches can provide enough new myocyte mass to sufficiently restore mechanical function to the heart. In this article, we consider the mechanisms of endogenous cardiomyocyte regeneration and exogenous cell differentiation (with respect to myoblasts, stem cells, and induced pluripotent cells being researched for cell therapies). We begin by reviewing some of the cues that are being harnessed in strategies of gene/cell therapy for regenerating myocardium. We also consider some of the technical challenges that remain in determining new myocyte generation, tracking delivered cells in vivo, and correlating new myocyte contractility with cardiac function. Strategies for regenerating the heart are being realized as both animal and clinical trials suggest that these new approaches provide short-term improvement of cardiac function. However, a more complete understanding of the underlying mechanisms and applications is necessary to sustain longer-term therapeutic success.

Heparin functionalization increases retention of TGF-β2 and GDF5 on biphasic silk fibroin scaffolds for tendon/ligament-to-bone tissue engineering.

PubMed

Font Tellado, Sònia; Chiera, Silvia; Bonani, Walter; Poh, Patrina S P; Migliaresi, Claudio; Motta, Antonella; Balmayor, Elizabeth R; van Griensven, Martijn

2018-05-01

The tendon/ligament-to-bone transition (enthesis) is a highly specialized interphase tissue with structural gradients of extracellular matrix composition, collagen molecule alignment and mineralization. These structural features are essential for enthesis function, but are often not regenerated after injury. Tissue engineering is a promising strategy for enthesis repair. Engineering of complex tissue interphases such as the enthesis is likely to require a combination of biophysical, biological and chemical cues to achieve functional tissue regeneration. In this study, we cultured human primary adipose-derived mesenchymal stem cells (AdMCs) on biphasic silk fibroin scaffolds with integrated anisotropic (tendon/ligament-like) and isotropic (bone/cartilage like) pore alignment. We functionalized those scaffolds with heparin and explored their ability to deliver transforming growth factor β2 (TGF-β2) and growth/differentiation factor 5 (GDF5). Heparin functionalization increased the amount of TGF-β2 and GDF5 remaining attached to the scaffold matrix and resulted in biological effects at low growth factor doses. We analyzed the combined impact of pore alignment and growth factors on AdMSCs. TGF-β2 and pore anisotropy synergistically increased the expression of tendon/ligament markers and collagen I protein content. In addition, the combined delivery of TGF-β2 and GDF5 enhanced the expression of cartilage markers and collagen II protein content on substrates with isotropic porosity, whereas enthesis markers were enhanced in areas of mixed anisotropic/isotropic porosity. Altogether, the data obtained in this study improves current understanding on the combined effects of biological and structural cues on stem cell fate and presents a promising strategy for tendon/ligament-to-bone regeneration. Regeneration of the tendon/ligament-to-bone interphase (enthesis) is of significance in the repair of ruptured tendons/ligaments to bone to improve implant integration and clinical outcome. This study proposes a novel approach for enthesis regeneration based on a biomimetic and integrated tendon/ligament-to-bone construct, stem cells and heparin-based delivery of growth factors. We show that heparin can keep growth factors local and biologically active at low doses, which is critical to avoid supraphysiological doses and associated side effects. In addition, we identify synergistic effects of biological (growth factors) and structural (pore alignment) cues on stem cells. These results improve current understanding on the combined impact of biological and structural cues on the multi-lineage differentiation capacity of stem cells for regenerating complex tissue interphases. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Virtual anthropology.

PubMed

Weber, Gerhard W

2015-02-01

Comparative morphology, dealing with the diversity of form and shape, and functional morphology, the study of the relationship between the structure and the function of an organism's parts, are both important subdisciplines in biological research. Virtual anthropology (VA) contributes to comparative morphology by taking advantage of technological innovations, and it also offers new opportunities for functional analyses. It exploits digital technologies and pools experts from different domains such as anthropology, primatology, medicine, paleontology, mathematics, statistics, computer science, and engineering. VA as a technical term was coined in the late 1990s from the perspective of anthropologists with the intent of being mostly applied to biological questions concerning recent and fossil hominoids. More generally, however, there are advanced methods to study shape and size or to manipulate data digitally suitable for application to all kinds of primates, mammals, other vertebrates, and invertebrates or to issues regarding plants, tools, or other objects. In this sense, we could also call the field "virtual morphology." The approach yields permanently available virtual copies of specimens and data that comprehensively quantify geometry, including previously neglected anatomical regions. It applies advanced statistical methods, supports the reconstruction of specimens based on reproducible manipulations, and promotes the acquisition of larger samples by data sharing via electronic archives. Finally, it can help identify new, hidden traits, which is particularly important in paleoanthropology, where the scarcity of material demands extracting information from fragmentary remains. This contribution presents a current view of the six main work steps of VA: digitize, expose, compare, reconstruct, materialize, and share. The VA machinery has also been successfully used in biomechanical studies which simulate the stress and strains appearing in structures. Although methodological issues remain to be solved before results from the two domains can be fully integrated, the various overlaps and cross-fertilizations suggest the widespread appearance of a "virtual functional morphology" in the near future. © 2014 American Association of Physical Anthropologists.

Stallion sperm transcriptome comprises functionally coherent coding and regulatory RNAs as revealed by microarray analysis and RNA-seq.

PubMed

Das, Pranab J; McCarthy, Fiona; Vishnoi, Monika; Paria, Nandina; Gresham, Cathy; Li, Gang; Kachroo, Priyanka; Sudderth, A Kendrick; Teague, Sheila; Love, Charles C; Varner, Dickson D; Chowdhary, Bhanu P; Raudsepp, Terje

2013-01-01

Mature mammalian sperm contain a complex population of RNAs some of which might regulate spermatogenesis while others probably play a role in fertilization and early development. Due to this limited knowledge, the biological functions of sperm RNAs remain enigmatic. Here we report the first characterization of the global transcriptome of the sperm of fertile stallions. The findings improved understanding of the biological significance of sperm RNAs which in turn will allow the discovery of sperm-based biomarkers for stallion fertility. The stallion sperm transcriptome was interrogated by analyzing sperm and testes RNA on a 21,000-element equine whole-genome oligoarray and by RNA-seq. Microarray analysis revealed 6,761 transcripts in the sperm, of which 165 were sperm-enriched, and 155 were differentially expressed between the sperm and testes. Next, 70 million raw reads were generated by RNA-seq of which 50% could be aligned with the horse reference genome. A total of 19,257 sequence tags were mapped to all horse chromosomes and the mitochondrial genome. The highest density of mapped transcripts was in gene-rich ECA11, 12 and 13, and the lowest in gene-poor ECA9 and X; 7 gene transcripts originated from ECAY. Structural annotation aligned sperm transcripts with 4,504 known horse and/or human genes, rRNAs and 82 miRNAs, whereas 13,354 sequence tags remained anonymous. The data were aligned with selected equine gene models to identify additional exons and splice variants. Gene Ontology annotations showed that sperm transcripts were associated with molecular processes (chemoattractant-activated signal transduction, ion transport) and cellular components (membranes and vesicles) related to known sperm functions at fertilization, while some messenger and micro RNAs might be critical for early development. The findings suggest that the rich repertoire of coding and non-coding RNAs in stallion sperm is not a random remnant from spermatogenesis in testes but a selectively retained and functionally coherent collection of RNAs.

Stallion Sperm Transcriptome Comprises Functionally Coherent Coding and Regulatory RNAs as Revealed by Microarray Analysis and RNA-seq

PubMed Central

Das, Pranab J.; McCarthy, Fiona; Vishnoi, Monika; Paria, Nandina; Gresham, Cathy; Li, Gang; Kachroo, Priyanka; Sudderth, A. Kendrick; Teague, Sheila; Love, Charles C.; Varner, Dickson D.; Chowdhary, Bhanu P.; Raudsepp, Terje

2013-01-01

Mature mammalian sperm contain a complex population of RNAs some of which might regulate spermatogenesis while others probably play a role in fertilization and early development. Due to this limited knowledge, the biological functions of sperm RNAs remain enigmatic. Here we report the first characterization of the global transcriptome of the sperm of fertile stallions. The findings improved understanding of the biological significance of sperm RNAs which in turn will allow the discovery of sperm-based biomarkers for stallion fertility. The stallion sperm transcriptome was interrogated by analyzing sperm and testes RNA on a 21,000-element equine whole-genome oligoarray and by RNA-seq. Microarray analysis revealed 6,761 transcripts in the sperm, of which 165 were sperm-enriched, and 155 were differentially expressed between the sperm and testes. Next, 70 million raw reads were generated by RNA-seq of which 50% could be aligned with the horse reference genome. A total of 19,257 sequence tags were mapped to all horse chromosomes and the mitochondrial genome. The highest density of mapped transcripts was in gene-rich ECA11, 12 and 13, and the lowest in gene-poor ECA9 and X; 7 gene transcripts originated from ECAY. Structural annotation aligned sperm transcripts with 4,504 known horse and/or human genes, rRNAs and 82 miRNAs, whereas 13,354 sequence tags remained anonymous. The data were aligned with selected equine gene models to identify additional exons and splice variants. Gene Ontology annotations showed that sperm transcripts were associated with molecular processes (chemoattractant-activated signal transduction, ion transport) and cellular components (membranes and vesicles) related to known sperm functions at fertilization, while some messenger and micro RNAs might be critical for early development. The findings suggest that the rich repertoire of coding and non-coding RNAs in stallion sperm is not a random remnant from spermatogenesis in testes but a selectively retained and functionally coherent collection of RNAs. PMID:23409192

Evolving Relevance of Neuroproteomics in Alzheimer's Disease.

PubMed

Lista, Simone; Zetterberg, Henrik; O'Bryant, Sid E; Blennow, Kaj; Hampel, Harald

2017-01-01

Substantial progress in the understanding of the biology of Alzheimer's disease (AD) has been achieved over the past decades. The early detection and diagnosis of AD and other age-related neurodegenerative diseases, however, remain a challenging scientific frontier. Therefore, the comprehensive discovery (relating to all individual, converging or diverging biochemical disease mechanisms), development, validation, and qualification of standardized biological markers with diagnostic and prognostic functions with a precise performance profile regarding specificity, sensitivity, and positive and negative predictive value are warranted.Methodological innovations in the area of exploratory high-throughput technologies, such as sequencing, microarrays, and mass spectrometry-based analyses of proteins/peptides, have led to the generation of large global molecular datasets from a multiplicity of biological systems, such as biological fluids, cells, tissues, and organs. Such methodological progress has shifted the attention to the execution of hypothesis-independent comprehensive exploratory analyses (opposed to the classical hypothesis-driven candidate approach), with the aim of fully understanding the biological systems in physiology and disease as a whole. The systems biology paradigm integrates experimental biology with accurate and rigorous computational modelling to describe and foresee the dynamic features of biological systems. The use of dynamically evolving technological platforms, including mass spectrometry, in the area of proteomics has enabled to rush the process of biomarker discovery and validation for refining significantly the diagnosis of AD. Currently, proteomics-which is part of the systems biology paradigm-is designated as one of the dominant matured sciences needed for the effective exploratory discovery of prospective biomarker candidates expected to play an effective role in aiding the early detection, diagnosis, prognosis, and therapy development in AD.

From platelet-rich plasma to the reverse prosthesis: controversies in treating rotator cuff pathology.

PubMed

Craig, Edward V; Galatz, Leesa M; Sperling, John W

2014-01-01

Rotator cuff pathology and tearing remains a common cause of shoulder pain and disability. Although little controversy and disagreement exists regarding the treatment of small to moderate size tears in good quality tissue without retraction, there is difficulty in agreeing on the ideal treatment of the largest tears, particularly because those tears may be accompanied by widely variable levels of pain and function. Clinical decision making is made more difficult because of the variable presentations observed in patients with a documented full-thickness rotator cuff tear: some have good function and no pain, some have good function and pain, some have poor function and no pain, and some have both poor function and pain. The role of biologics as an adjunct in treating most rotator cuff tears remains unclear, with ongoing exploration of the roles of stem cells, growth factors, and platelet-rich plasma. In patients with unreconstructable tears with marked weakness in external rotation but good elevation, a latissimus transfer may restore rotation. Patches may play a role in partial repairs while serving as both a lattice for healing and a biomechanical anchoring point for sutures. In patients with massive tears and arthritis and in many who have rotator cuff insufficiency, pseudoparalysis, or anterosuperior escape without arthritis, reverse shoulder arthroplasty has led to improvements in pain and strength and revolutionized the treatment of rotator cuff tears.

Eat, breathe, ROS: controlling stem cell fate through metabolism.

PubMed

Kubli, Dieter A; Sussman, Mark A

2017-05-01

Research reveals cardiac regeneration exists at levels previously deemed unattainable. Clinical trials using stem cells demonstrate promising cardiomyogenic and regenerative potential but insufficient contractile recovery. Incomplete understanding of the biology of administered cells likely contributes to inconsistent patient outcomes. Metabolism is a core component of many well-characterized stem cell types, and metabolic changes fundamentally alter stem cell fate from self-renewal to lineage commitment, and vice versa. However, the metabolism of stem cells currently studied for cardiac regeneration remains incompletely understood. Areas covered: Key metabolic features of stem cells are reviewed and unique stem cell metabolic characteristics are discussed. Metabolic changes altering stem cell fate are considered from quiescence and self-renewal to lineage commitment. Key metabolic concepts are applied toward examining cardiac regeneration through stem cell-based approaches, and clinical implications of current cell therapies are evaluated to identify potential areas of improvement. Expert commentary: The metabolism and biology of stem cells used for cardiac therapy remain poorly characterized. A growing appreciation for the fundamental relationship between stem cell functionality and metabolic phenotype is developing. Future studies unraveling links between cardiac stem cell metabolism and regenerative potential may considerably improve treatment strategies and therapeutic outcomes.

Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models

PubMed Central

van Enkhuizen, Jordy; Geyer, Mark A.; Minassian, Arpi; Perry, William; Henry, Brook L.; Young, Jared W.

2015-01-01

Psychiatric patients with bipolar disorder suffer from states of depression and mania, during which a variety of symptoms are present. Current treatments are limited and neurocognitive deficits in particular often remain untreated. Targeted therapies based on the biological mechanisms of bipolar disorder could fill this gap and benefit patients and their families. Developing targeted therapies would benefit from appropriate animal models which are challenging to establish, but remain a vital tool. In this review, we summarize approaches to create a valid model relevant to bipolar disorder. We focus on studies that use translational tests of multivariate exploratory behavior, sensorimotor gating, decision-making under risk, and attentional functioning to discover profiles that are consistent between patients and rodent models. Using this battery of translational tests, similar behavior profiles in bipolar mania patients and mice with reduced dopamine transporter activity have been identified. Future investigations should combine other animal models that are biologically relevant to the neuropsychiatric disorder with translational behavioral assessment as outlined here. This methodology can be utilized to develop novel targeted therapies that relieve symptoms for more patients without common side effects caused by current treatments. PMID:26297513

Eat, breathe, ROS: controlling stem cell fate through metabolism

PubMed Central

Kubli, Dieter A.; Sussman, Mark A.

2017-01-01

Introduction Research reveals cardiac regeneration exists at levels previously deemed unattainable. Clinical trials using stem cells demonstrate promising cardiomyogenic and regenerative potential but insufficient contractile recovery. Incomplete understanding of the biology of administered cells likely contributes to inconsistent patient outcomes. Metabolism is a core component of many well-characterized stem cell types, and metabolic changes fundamentally alter stem cell fate from self-renewal to lineage commitment, and vice versa. However, the metabolism of stem cells currently studied for cardiac regeneration remains incompletely understood. Areas covered Key metabolic features of stem cells are reviewed and unique stem cell metabolic characteristics are discussed. Metabolic changes altering stem cell fate are considered from quiescence and self-renewal to lineage commitment. Key metabolic concepts are applied toward examining cardiac regeneration through stem cell-based approaches, and clinical implications of current cell therapies are evaluated to identify potential areas of improvement. Expert commentary The metabolism and biology of stem cells used for cardiac therapy remain poorly characterized. A growing appreciation for the fundamental relationship between stem cell functionality and metabolic phenotype is developing. Future studies unraveling links between cardiac stem cell metabolism and regenerative potential may considerably improve treatment strategies and therapeutic outcomes. PMID:28406333

Genome-wide Integration Study of Circulating miRNAs and Peripheral Whole-Blood mRNAs of Male Acute Ischemic Stroke Patients.

PubMed

Xue, Yang; Yin, Pengqi; Li, Guozhong; Zhong, Di

2018-06-01

Several circulating microRNAs (miRNAs) have been proved to serve as stable biomarkers in blood for acute ischemic stroke (AIS). However, the functions of these biomarkers remain elusive. By conducting the integration analysis of circulating miRNAs and peripheral whole-blood mRNAs using bioinformatics methods, we explored the biological role of these circulating markers in peripheral whole blood at the genome-wide level. Stroke-related circulating miRNA profile data (GSE86291) and peripheral whole-blood mRNA expression data (GSE16561) were collected from the Gene Expression Omnibus (GEO) datasets. We selected male patients to avoid any gender differences in stroke pathology. Male stroke-related miRNAs (M-miRNAs) and mRNAs (M-mRNAs) were detected using GEO2R. Nine M-miRNAs (five up- and four down-regulated) were applied to TargetScan to predict the possible target mRNAs. Next, we intersected these targets with the M-mRNAs (38 up- and three down-regulated) to obtain the male stroke-related overlapped mRNAs (Mo-mRNAs). Finally, we analyzed biological functions of Mo-mRNAs using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and constructed networks among the Mo-mRNAs, overlapped M-miRNAs (Mo-miRNAs), and their functions. The Mo-mRNAs were enriched in functions such as platelet degranulation, immune response, and pathways associated with phagosome biology and Staphylococcus aureus infection. This study provides an integrated view of interactions among circulating miRNAs and peripheral whole-blood mRNAs involved in the pathophysiological processes of male AIS. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Neural Stem Cells (NSCs) and Proteomics*

PubMed Central

Shoemaker, Lorelei D.; Kornblum, Harley I.

2016-01-01

Neural stem cells (NSCs) can self-renew and give rise to the major cell types of the CNS. Studies of NSCs include the investigation of primary, CNS-derived cells as well as animal and human embryonic stem cell (ESC)-derived and induced pluripotent stem cell (iPSC)-derived sources. NSCs provide a means with which to study normal neural development, neurodegeneration, and neurological disease and are clinically relevant sources for cellular repair to the damaged and diseased CNS. Proteomics studies of NSCs have the potential to delineate molecules and pathways critical for NSC biology and the means by which NSCs can participate in neural repair. In this review, we provide a background to NSC biology, including the means to obtain them and the caveats to these processes. We then focus on advances in the proteomic interrogation of NSCs. This includes the analysis of posttranslational modifications (PTMs); approaches to analyzing different proteomic compartments, such the secretome; as well as approaches to analyzing temporal differences in the proteome to elucidate mechanisms of differentiation. We also discuss some of the methods that will undoubtedly be useful in the investigation of NSCs but which have not yet been applied to the field. While many proteomics studies of NSCs have largely catalogued the proteome or posttranslational modifications of specific cellular states, without delving into specific functions, some have led to understandings of functional processes or identified markers that could not have been identified via other means. Many challenges remain in the field, including the precise identification and standardization of NSCs used for proteomic analyses, as well as how to translate fundamental proteomics studies to functional biology. The next level of investigation will require interdisciplinary approaches, combining the skills of those interested in the biochemistry of proteomics with those interested in modulating NSC function. PMID:26494823

Comparing sixteen scoring functions for predicting biological activities of ligands for protein targets.

PubMed

Xu, Weijun; Lucke, Andrew J; Fairlie, David P

2015-04-01

Accurately predicting relative binding affinities and biological potencies for ligands that interact with proteins remains a significant challenge for computational chemists. Most evaluations of docking and scoring algorithms have focused on enhancing ligand affinity for a protein by optimizing docking poses and enrichment factors during virtual screening. However, there is still relatively limited information on the accuracy of commercially available docking and scoring software programs for correctly predicting binding affinities and biological activities of structurally related inhibitors of different enzyme classes. Presented here is a comparative evaluation of eight molecular docking programs (Autodock Vina, Fitted, FlexX, Fred, Glide, GOLD, LibDock, MolDock) using sixteen docking and scoring functions to predict the rank-order activity of different ligand series for six pharmacologically important protein and enzyme targets (Factor Xa, Cdk2 kinase, Aurora A kinase, COX-2, pla2g2a, β Estrogen receptor). Use of Fitted gave an excellent correlation (Pearson 0.86, Spearman 0.91) between predicted and experimental binding only for Cdk2 kinase inhibitors. FlexX and GOLDScore produced good correlations (Pearson>0.6) for hydrophilic targets such as Factor Xa, Cdk2 kinase and Aurora A kinase. By contrast, pla2g2a and COX-2 emerged as difficult targets for scoring functions to predict ligand activities. Although possessing a high hydrophobicity in its binding site, β Estrogen receptor produced reasonable correlations using LibDock (Pearson 0.75, Spearman 0.68). These findings can assist medicinal chemists to better match scoring functions with ligand-target systems for hit-to-lead optimization using computer-aided drug design approaches. Copyright © 2015 Elsevier Inc. All rights reserved.

Modularity and evolutionary constraints in a baculovirus gene regulatory network

PubMed Central

2013-01-01

Background The structure of regulatory networks remains an open question in our understanding of complex biological systems. Interactions during complete viral life cycles present unique opportunities to understand how host-parasite network take shape and behave. The Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) is a large double-stranded DNA virus, whose genome may encode for 152 open reading frames (ORFs). Here we present the analysis of the ordered cascade of the AgMNPV gene expression. Results We observed an earlier onset of the expression than previously reported for other baculoviruses, especially for genes involved in DNA replication. Most ORFs were expressed at higher levels in a more permissive host cell line. Genes with more than one copy in the genome had distinct expression profiles, which could indicate the acquisition of new functionalities. The transcription gene regulatory network (GRN) for 149 ORFs had a modular topology comprising five communities of highly interconnected nodes that separated key genes that are functionally related on different communities, possibly maximizing redundancy and GRN robustness by compartmentalization of important functions. Core conserved functions showed expression synchronicity, distinct GRN features and significantly less genetic diversity, consistent with evolutionary constraints imposed in key elements of biological systems. This reduced genetic diversity also had a positive correlation with the importance of the gene in our estimated GRN, supporting a relationship between phylogenetic data of baculovirus genes and network features inferred from expression data. We also observed that gene arrangement in overlapping transcripts was conserved among related baculoviruses, suggesting a principle of genome organization. Conclusions Albeit with a reduced number of nodes (149), the AgMNPV GRN had a topology and key characteristics similar to those observed in complex cellular organisms, which indicates that modularity may be a general feature of biological gene regulatory networks. PMID:24006890

Molecular aspects of eye evolution and development: from the origin of retinal cells to the future of regenerative medicine.

PubMed

Ohuchi, Hideyo

2013-01-01

A central issue of evolutionary developmental biology is how the eye is diverged morphologically and functionally. However, the unifying mechanisms or schemes that govern eye diversification remain unsolved. In this review, I first introduce the concept of evolutionary developmental biology of the eye with a focus on photoreception, the fundamental property of retinal cells. Second, I summarize the early development of vertebrate eyes and the role of a homeobox gene, Lhx1, in subdivision of the retina into 2 domains, the neural retina and retinal pigmented epithelium of the optic primordium. The 2 retinal domains are essential components of the eye as they are found in such prototypic eyes as the extant planarian eye. Finally, I propose the presence of novel retinal cell subtypes with photosensory functions based on our recent work on atypical photopigments (opsins) in vertebrates. Since human diseases are attributable to the aberration of various types of cells due to alterations in gene expression, understanding the precise mechanisms of cellular diversification and unraveling the molecular profiles of cellular subtypes are essential to future regenerative medicine.

Microbial structural diversity estimated by dilution-extinction of phenotypic traits and T-RFLP analysis along a land-use intensification gradient

NASA Technical Reports Server (NTRS)

Gomez, Elena del V.; Garland, Jay L.; Roberts, Michael S.

2004-01-01

The present work tested whether the relationship between functional traits and inoculum density reflected structural diversity in bacterial communities from a land-use intensification gradient applying a mathematical model. Terminal restriction fragment length polymorphism (T-RFLP) analysis was also performed to provide an independent assessment of species richness. Successive 10-fold dilutions of a soil suspension were inoculated onto Biolog GN(R) microplates. Soil bacterial density was determined by total cell and plate counts. The relationship between phenotypic traits and inoculum density fit the model, allowing the estimation of maximal phenotypic potential (Rmax) and inoculum density (KI) at which Rmax will be half-reduced. Though Rmax decreased with time elapsed since clearing of native vegetation, KI remained high in two of the disturbed sites. The genetic pool of bacterial community did not experience a significant reduction, but the active fraction responding in the Biolog assay was adversely affected, suggesting a reduction in the functional potential. c2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.

Deciphering principles of transcription regulation in eukaryotic genomes

PubMed Central

Nguyen, Dat H; D'haeseleer, Patrik

2006-01-01

Transcription regulation has been responsible for organismal complexity and diversity in the course of biological evolution and adaptation, and it is determined largely by the context-dependent behavior of cis-regulatory elements (CREs). Therefore, understanding principles underlying CRE behavior in regulating transcription constitutes a fundamental objective of quantitative biology, yet these remain poorly understood. Here we present a deterministic mathematical strategy, the motif expression decomposition (MED) method, for deriving principles of transcription regulation at the single-gene resolution level. MED operates on all genes in a genome without requiring any a priori knowledge of gene cluster membership, or manual tuning of parameters. Applying MED to Saccharomyces cerevisiae transcriptional networks, we identified four functions describing four different ways that CREs can quantitatively affect gene expression levels. These functions, three of which have extrema in different positions in the gene promoter (short-, mid-, and long-range) whereas the other depends on the motif orientation, are validated by expression data. We illustrate how nature could use these principles as an additional dimension to amplify the combinatorial power of a small set of CREs in regulating transcription. PMID:16738557

Long non-coding RNA CASC2 regulates cell biological behaviour through the MAPK signalling pathway in hepatocellular carcinoma.

PubMed

Gan, Yuanyuan; Han, Nana; He, Xiaoqin; Yu, Jiajun; Zhang, Meixia; Zhou, Yujie; Liang, Huiling; Deng, Junjian; Zheng, Yongfa; Ge, Wei; Long, Zhixiong; Xu, Ximing

2017-06-01

Long non-coding RNAs have previously been demonstrated to play important roles in regulating human diseases, especially cancer. However, the biological functions and molecular mechanisms of long non-coding RNAs in hepatocellular carcinoma have not been extensively studied. The long non-coding RNA CASC2 (cancer susceptibility candidate 2) has been characterised as a tumour suppressor in endometrial cancer and gliomas. However, the role and function of CASC2 in hepatocellular carcinoma remain unknown. In this study, using quantitative real-time polymerase chain reaction, we confirmed that CASC2 expression was downregulated in 50 hepatocellular carcinoma cases (62%) and in hepatocellular carcinoma cell lines compared with the paired adjacent tissues and normal liver cells. In vitro experiments further demonstrated that overexpressed CASC2 decreased hepatocellular carcinoma cell proliferation, migration and invasion as well as promoted apoptosis via inactivating the mitogen-activated protein kinase signalling pathway. Our findings demonstrate that CASC2 could be a useful tumour suppressor factor and a promising therapeutic target for hepatocellular carcinoma.

Genetically encoded lipid-polypeptide hybrid biomaterials that exhibit temperature-triggered hierarchical self-assembly

NASA Astrophysics Data System (ADS)

Mozhdehi, Davoud; Luginbuhl, Kelli M.; Simon, Joseph R.; Dzuricky, Michael; Berger, Rüdiger; Varol, H. Samet; Huang, Fred C.; Buehne, Kristen L.; Mayne, Nicholas R.; Weitzhandler, Isaac; Bonn, Mischa; Parekh, Sapun H.; Chilkoti, Ashutosh

2018-05-01

Post-translational modification of proteins is a strategy widely used in biological systems. It expands the diversity of the proteome and allows for tailoring of both the function and localization of proteins within cells as well as the material properties of structural proteins and matrices. Despite their ubiquity in biology, with a few exceptions, the potential of post-translational modifications in biomaterials synthesis has remained largely untapped. As a proof of concept to demonstrate the feasibility of creating a genetically encoded biohybrid material through post-translational modification, we report here the generation of a family of three stimulus-responsive hybrid materials—fatty-acid-modified elastin-like polypeptides—using a one-pot recombinant expression and post-translational lipidation methodology. These hybrid biomaterials contain an amphiphilic domain, composed of a β-sheet-forming peptide that is post-translationally functionalized with a C14 alkyl chain, fused to a thermally responsive elastin-like polypeptide. They exhibit temperature-triggered hierarchical self-assembly across multiple length scales with varied structure and material properties that can be controlled at the sequence level.

Statistical Modeling of an Optically Trapped Cilium

NASA Astrophysics Data System (ADS)

Flaherty, Justin; Resnick, Andrew

We explore, analytically and experimentally, the stochastic dynamics of a biologically significant slender microcantilever, the primary cilium, held within an optical trap. Primary cilia are cellular organelles, present on most vertebrate cells, hypothesized to function as a fluid flow sensor. The mechanical properties of a cilium remain incompletely characterized. Optical trapping is an ideal method to probe the mechanical response of a cilium due to the spatial localization and non-contact nature of the applied force. However, analysis of an optically trapped cilium is complicated both by the geometry of a cilium and boundary conditions. Here, we present experimentally measured mean-squared displacement data of trapped cilia where the trapping force is oppositely directed to the elastic restoring force of the ciliary axoneme, analytical modeling results deriving the mean-squared displacement of a trapped cilium using the Langevin approach, and apply our analytical results to the experimental data. We demonstrate that mechanical properties of the cilium can be accurately determined and efficiently extracted from the data using our model. It is hoped that improved measurements will result in deeper understanding of the biological function of cellular flow sensing by this organelle.

Focus on Extracellular Vesicles: Physiological Role and Signalling Properties of Extracellular Membrane Vesicles

PubMed Central

Iraci, Nunzio; Leonardi, Tommaso; Gessler, Florian; Vega, Beatriz; Pluchino, Stefano

2016-01-01

Extracellular vesicles (EVs) are a heterogeneous population of secreted membrane vesicles, with distinct biogenesis routes, biophysical properties and different functions both in physiological conditions and in disease. The release of EVs is a widespread biological process, which is conserved across species. In recent years, numerous studies have demonstrated that several bioactive molecules are trafficked with(in) EVs, such as microRNAs, mRNAs, proteins and lipids. The understanding of their final impact on the biology of specific target cells remains matter of intense debate in the field. Also, EVs have attracted great interest as potential novel cell-free therapeutics. Here we describe the proposed physiological and pathological functions of EVs, with a particular focus on their molecular content. Also, we discuss the advances in the knowledge of the mechanisms regulating the secretion of EV-associated molecules and the specific pathways activated upon interaction with the target cell, highlighting the role of EVs in the context of the immune system and as mediators of the intercellular signalling in the brain. PMID:26861302

Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2.

PubMed

Wiemhoefer, Anne; Stargardt, Anita; van der Linden, Wouter A; Renner, Maria C; van Kesteren, Ronald E; Stap, Jan; Raspe, Marcel A; Tomkinson, Birgitta; Kessels, Helmut W; Ovaa, Huib; Overkleeft, Herman S; Florea, Bogdan; Reits, Eric A

2015-08-01

Tripeptidyl peptidase II (TPP2) is a serine peptidase involved in various biological processes, including antigen processing, cell growth, DNA repair, and neuropeptide mediated signaling. The underlying mechanisms of how a peptidase can influence this multitude of processes still remain unknown. We identified rapid proteomic changes in neuroblastoma cells following selective TPP2 inhibition using the known reversible inhibitor butabindide, as well as a new, more potent, and irreversible peptide phosphonate inhibitor. Our data show that TPP2 inhibition indirectly but rapidly decreases the levels of active, di-phosphorylated extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the nucleus, thereby down-regulating signal transduction downstream of growth factors and mitogenic stimuli. We conclude that TPP2 mediates many important cellular functions by controlling ERK1 and ERK2 phosphorylation. For instance, we show that TPP2 inhibition of neurons in the hippocampus leads to an excessive strengthening of synapses, indicating that TPP2 activity is crucial for normal brain function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Genome-wide identification and characterization of putative lncRNAs in the diamondback moth, Plutella xylostella (L.).

PubMed

Wang, Yue; Xu, Tingting; He, Weiyi; Shen, Xiujing; Zhao, Qian; Bai, Jianlin; You, Minsheng

2018-01-01

Long non-coding RNAs (lncRNAs) are of particular interest because of their contributions to many biological processes. Here, we present the genome-wide identification and characterization of putative lncRNAs in a global insect pest, Plutella xylostella. A total of 8096 lncRNAs were identified and classified into three groups. The average length of exons in lncRNAs was longer than that in coding genes and the GC content was lower than that in mRNAs. Most lncRNAs were flanked by canonical splice sites, similar to mRNAs. Expression profiling identified 114 differentially expressed lncRNAs during the DBM development and found that majority were temporally specific. While the biological functions of lncRNAs remain uncharacterized, many are microRNA precursors or competing endogenous RNAs involved in micro-RNA regulatory pathways. This work provides a valuable resource for further studies on molecular bases for development of DBM and lay the foundation for discovery of lncRNA functions in P. xylostella. Copyright © 2017 Elsevier Inc. All rights reserved.

OmicsNet: a web-based tool for creation and visual analysis of biological networks in 3D space.

PubMed

Zhou, Guangyan; Xia, Jianguo

2018-06-07

Biological networks play increasingly important roles in omics data integration and systems biology. Over the past decade, many excellent tools have been developed to support creation, analysis and visualization of biological networks. However, important limitations remain: most tools are standalone programs, the majority of them focus on protein-protein interaction (PPI) or metabolic networks, and visualizations often suffer from 'hairball' effects when networks become large. To help address these limitations, we developed OmicsNet - a novel web-based tool that allows users to easily create different types of molecular interaction networks and visually explore them in a three-dimensional (3D) space. Users can upload one or multiple lists of molecules of interest (genes/proteins, microRNAs, transcription factors or metabolites) to create and merge different types of biological networks. The 3D network visualization system was implemented using the powerful Web Graphics Library (WebGL) technology that works natively in most major browsers. OmicsNet supports force-directed layout, multi-layered perspective layout, as well as spherical layout to help visualize and navigate complex networks. A rich set of functions have been implemented to allow users to perform coloring, shading, topology analysis, and enrichment analysis. OmicsNet is freely available at http://www.omicsnet.ca.

Meta-analysis reveals complex marine biological responses to the interactive effects of ocean acidification and warming

PubMed Central

Harvey, Ben P; Gwynn-Jones, Dylan; Moore, Pippa J

2013-01-01

Ocean acidification and warming are considered two of the greatest threats to marine biodiversity, yet the combined effect of these stressors on marine organisms remains largely unclear. Using a meta-analytical approach, we assessed the biological responses of marine organisms to the effects of ocean acidification and warming in isolation and combination. As expected biological responses varied across taxonomic groups, life-history stages, and trophic levels, but importantly, combining stressors generally exhibited a stronger biological (either positive or negative) effect. Using a subset of orthogonal studies, we show that four of five of the biological responses measured (calcification, photosynthesis, reproduction, and survival, but not growth) interacted synergistically when warming and acidification were combined. The observed synergisms between interacting stressors suggest that care must be made in making inferences from single-stressor studies. Our findings clearly have implications for the development of adaptive management strategies particularly given that the frequency of stressors interacting in marine systems will be likely to intensify in the future. There is now an urgent need to move toward more robust, holistic, and ecologically realistic climate change experiments that incorporate interactions. Without them accurate predictions about the likely deleterious impacts to marine biodiversity and ecosystem functioning over the next century will not be possible. PMID:23610641

Meta-analysis reveals complex marine biological responses to the interactive effects of ocean acidification and warming.

PubMed

Harvey, Ben P; Gwynn-Jones, Dylan; Moore, Pippa J

2013-04-01

Ocean acidification and warming are considered two of the greatest threats to marine biodiversity, yet the combined effect of these stressors on marine organisms remains largely unclear. Using a meta-analytical approach, we assessed the biological responses of marine organisms to the effects of ocean acidification and warming in isolation and combination. As expected biological responses varied across taxonomic groups, life-history stages, and trophic levels, but importantly, combining stressors generally exhibited a stronger biological (either positive or negative) effect. Using a subset of orthogonal studies, we show that four of five of the biological responses measured (calcification, photosynthesis, reproduction, and survival, but not growth) interacted synergistically when warming and acidification were combined. The observed synergisms between interacting stressors suggest that care must be made in making inferences from single-stressor studies. Our findings clearly have implications for the development of adaptive management strategies particularly given that the frequency of stressors interacting in marine systems will be likely to intensify in the future. There is now an urgent need to move toward more robust, holistic, and ecologically realistic climate change experiments that incorporate interactions. Without them accurate predictions about the likely deleterious impacts to marine biodiversity and ecosystem functioning over the next century will not be possible.

Whipworm kinomes reflect a unique biology and adaptation to the host animal.

PubMed

Stroehlein, Andreas J; Young, Neil D; Korhonen, Pasi K; Chang, Bill C H; Nejsum, Peter; Pozio, Edoardo; La Rosa, Giuseppe; Sternberg, Paul W; Gasser, Robin B

2017-11-01

Roundworms belong to a diverse phylum (Nematoda) which is comprised of many parasitic species including whipworms (genus Trichuris). These worms have adapted to a biological niche within the host and exhibit unique morphological characteristics compared with other nematodes. Although these adaptations are known, the underlying molecular mechanisms remain elusive. The availability of genomes and transcriptomes of some whipworms now enables detailed studies of their molecular biology. Here, we defined and curated the full complement of an important class of enzymes, the protein kinases (kinomes) of two species of Trichuris, using an advanced and integrated bioinformatic pipeline. We investigated the transcription of Trichuris suis kinase genes across developmental stages, sexes and tissues, and reveal that selectively transcribed genes can be linked to central roles in developmental and reproductive processes. We also classified and functionally annotated the curated kinomes by integrating evidence from structural modelling and pathway analyses, and compared them with other curated kinomes of phylogenetically diverse nematode species. Our findings suggest unique adaptations in signalling processes governing worm morphology and biology, and provide an important resource that should facilitate experimental investigations of kinases and the biology of signalling pathways in nematodes. Copyright © 2017 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

A hybrid approach of gene sets and single genes for the prediction of survival risks with gene expression data.

PubMed

Seok, Junhee; Davis, Ronald W; Xiao, Wenzhong

2015-01-01

Accumulated biological knowledge is often encoded as gene sets, collections of genes associated with similar biological functions or pathways. The use of gene sets in the analyses of high-throughput gene expression data has been intensively studied and applied in clinical research. However, the main interest remains in finding modules of biological knowledge, or corresponding gene sets, significantly associated with disease conditions. Risk prediction from censored survival times using gene sets hasn't been well studied. In this work, we propose a hybrid method that uses both single gene and gene set information together to predict patient survival risks from gene expression profiles. In the proposed method, gene sets provide context-level information that is poorly reflected by single genes. Complementarily, single genes help to supplement incomplete information of gene sets due to our imperfect biomedical knowledge. Through the tests over multiple data sets of cancer and trauma injury, the proposed method showed robust and improved performance compared with the conventional approaches with only single genes or gene sets solely. Additionally, we examined the prediction result in the trauma injury data, and showed that the modules of biological knowledge used in the prediction by the proposed method were highly interpretable in biology. A wide range of survival prediction problems in clinical genomics is expected to benefit from the use of biological knowledge.

A Hybrid Approach of Gene Sets and Single Genes for the Prediction of Survival Risks with Gene Expression Data

PubMed Central

Seok, Junhee; Davis, Ronald W.; Xiao, Wenzhong

2015-01-01

Accumulated biological knowledge is often encoded as gene sets, collections of genes associated with similar biological functions or pathways. The use of gene sets in the analyses of high-throughput gene expression data has been intensively studied and applied in clinical research. However, the main interest remains in finding modules of biological knowledge, or corresponding gene sets, significantly associated with disease conditions. Risk prediction from censored survival times using gene sets hasn’t been well studied. In this work, we propose a hybrid method that uses both single gene and gene set information together to predict patient survival risks from gene expression profiles. In the proposed method, gene sets provide context-level information that is poorly reflected by single genes. Complementarily, single genes help to supplement incomplete information of gene sets due to our imperfect biomedical knowledge. Through the tests over multiple data sets of cancer and trauma injury, the proposed method showed robust and improved performance compared with the conventional approaches with only single genes or gene sets solely. Additionally, we examined the prediction result in the trauma injury data, and showed that the modules of biological knowledge used in the prediction by the proposed method were highly interpretable in biology. A wide range of survival prediction problems in clinical genomics is expected to benefit from the use of biological knowledge. PMID:25933378

The search for Pleiades in trait constellations: functional integration and phenotypic selection in the complex flowers of Morrenia brachystephana (Apocynaceae).

PubMed

Baranzelli, M C; Sérsic, A N; Cocucci, A A

2014-04-01

Pollinator-mediated natural selection on single traits, such as corolla tube or spur length, has been well documented. However, flower phenotypes are usually complex, and selection is expected to act on several traits that functionally interact rather than on a single isolated trait. Despite the fact that selection on complex phenotypes is expectedly widespread, multivariate selection modelling on such phenotypes still remains under-explored in plants. Species of the subfamily Asclepiadoideae (Apocynaceae) provide an opportunity to study such complex flower contrivances integrated by fine-scaled organs from disparate developmental origin. We studied the correlation structure among linear floral traits (i) by testing a priori morphological, functional or developmental hypotheses among traits and (ii) by exploring the organization of flower covariation, considering alternative expectations of modular organization or whole flower integration through conditional dependence analysis (CDA) and integration matrices. The phenotypic selection approach was applied to determine whether floral traits involved in the functioning of the pollination mechanism were affected by natural selection. Floral integration was low, suggesting that flowers are organized in more than just one correlation pleiad; our hypothetical functional correlation matrix was significantly correlated with the empirical matrix, and the CDA revealed three putative modules. Analyses of phenotypic selection showed significant linear and correlational gradients, lending support to expectations of functional interactions between floral traits. Significant correlational selection gradients found involved traits of different floral whorls, providing evidence for the existence of functional integration across developmental domains. © 2014 The Authors. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

Amino acid analysis

NASA Technical Reports Server (NTRS)

Winitz, M.; Graff, J. (Inventor)

1974-01-01

The process and apparatus for qualitative and quantitative analysis of the amino acid content of a biological sample are presented. The sample is deposited on a cation exchange resin and then is washed with suitable solvents. The amino acids and various cations and organic material with a basic function remain on the resin. The resin is eluted with an acid eluant, and the eluate containing the amino acids is transferred to a reaction vessel where the eluant is removed. Final analysis of the purified acylated amino acid esters is accomplished by gas-liquid chromatographic techniques.

New Statistics for Testing Differential Expression of Pathways from Microarray Data

NASA Astrophysics Data System (ADS)

Siu, Hoicheong; Dong, Hua; Jin, Li; Xiong, Momiao

Exploring biological meaning from microarray data is very important but remains a great challenge. Here, we developed three new statistics: linear combination test, quadratic test and de-correlation test to identify differentially expressed pathways from gene expression profile. We apply our statistics to two rheumatoid arthritis datasets. Notably, our results reveal three significant pathways and 275 genes in common in two datasets. The pathways we found are meaningful to uncover the disease mechanisms of rheumatoid arthritis, which implies that our statistics are a powerful tool in functional analysis of gene expression data.

Myeloid leukemia factor: a return ticket from human leukemia to fly hematopoiesis.

PubMed

Gobert, Vanessa; Haenlin, Marc; Waltzer, Lucas

2012-01-01

Even though deregulation of human MLF1, the founding member of the Myeloid Leukemia Factor family, has been associated with acute myeloid leukemia, the function and mode of action of this family of genes have remained rather mysterious. Yet, recent findings in Drosophila shed new light on their biological activity and suggest that they play an important role in hematopoiesis and leukemia, notably by regulating the stability of RUNX transcription factors, another family of conserved proteins with prominent roles in normal and malignant blood cell development.

Enabling systematic interrogation of protein-protein interactions in live cells with a versatile ultra-high-throughput biosensor platform | Office of Cancer Genomics

Cancer.gov

The vast datasets generated by next generation gene sequencing and expression profiling have transformed biological and translational research. However, technologies to produce large-scale functional genomics datasets, such as high-throughput detection of protein-protein interactions (PPIs), are still in early development. While a number of powerful technologies have been employed to detect PPIs, a singular PPI biosensor platform featured with both high sensitivity and robustness in a mammalian cell environment remains to be established.

GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2).

PubMed

Crawford, Terry D; Audia, James E; Bellon, Steve; Burdick, Daniel J; Bommi-Reddy, Archana; Côté, Alexandre; Cummings, Richard T; Duplessis, Martin; Flynn, E Megan; Hewitt, Michael; Huang, Hon-Ren; Jayaram, Hariharan; Jiang, Ying; Joshi, Shivangi; Kiefer, James R; Murray, Jeremy; Nasveschuk, Christopher G; Neiss, Arianne; Pardo, Eneida; Romero, F Anthony; Sandy, Peter; Sims, Robert J; Tang, Yong; Taylor, Alexander M; Tsui, Vickie; Wang, Jian; Wang, Shumei; Wang, Yongyun; Xu, Zhaowu; Zawadzke, Laura; Zhu, Xiaoqin; Albrecht, Brian K; Magnuson, Steven R; Cochran, Andrea G

2017-07-13

The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.

Size Matters: Developing Design Rules to Engineer Nanoparticles for Solid Tumour Targeting

NASA Astrophysics Data System (ADS)

Sykes, Edward Alexander

Nanotechnology enables the design of highly customizable platforms for producing minimally invasive and programmable strategies for cancer diagnosis and treatment. Advances in this field have demonstrated that nanoparticles can enhance specificity of anti-cancer agents, respond to tumour-specific cues, and direct the visualization of biological targets in vivo. . Nanoparticles can be synthesized within the 1 to 100 nm range to achieve different electromagnetic properties and specifically interact with biological tissues by tuning their size, shape, and surface chemistry. However, it remains unclear which physicochemical parameters are critical for delivering nanomaterials to the tumour site. With less than 5% of administered nanoparticles reaching the tumour, engineering of nanoparticles for effective delivery to solid tumours remains a critical challenge to cancer nanomedicine. A more comprehensive understanding of the interplay between the nanomaterial physicochemical properties and biological systems is necessary to enhance the efficacy of nanoparticle tumour targeting. This thesis explores how nanoparticle size and functionalization with cancer cell specific agents impact nanoparticle delivery to tumours. Furthermore, this doctoral work (i) discusses how tumour structure evolves with growth, (ii) elucidates how such changes modulate nanoparticle accumulation, and (iii) identifies how the skin serves as a significant off-target site for nanoparticle uptake. This thesis also demonstrates the utility of empirically-derived parametric models, Monte Carlo simulations, and decision matrices for mechanistically understanding and predicting the impact of nanomaterial features and tumour biology on nanoparticle fate in vivo. These topics establish key design considerations to tailor nanoparticles for enhanced tumour targeting. Collectively, the concepts presented herein form a fundamental framework for the development of personalized nanomedicine and nano-diagnostic agents in the future.

Chemical, biological, radiological, and nuclear decontamination: Recent trends and future perspective

PubMed Central

Kumar, Vinod; Goel, Rajeev; Chawla, Raman; Silambarasan, M.; Sharma, Rakesh Kumar

2010-01-01

Chemical, biological, radiological, and nuclear (CBRN) decontamination is the removal of CBRN material from equipment or humans. The objective of the decontamination is to reduce radiation burden, salvage equipment, and materials, remove loose CBRN contaminants, and fix the remaining in place in preparation for protective storage or permanent disposal work activities. Decontamination may be carried out using chemical, electrochemical, and mechanical means. Like materials, humans may also be contaminated with CBRN contamination. Changes in cellular function can occur at lower radiation doses and exposure to chemicals. At high dose, cell death may take place. Therefore, decontamination of humans at the time of emergency while generating bare minimum waste is an enormous task requiring dedication of large number of personnel and large amount of time. General principles of CBRN decontamination are discussed in this review with emphasis on radiodecontamination. PMID:21829318

Natural product synthesis at the interface of chemistry and biology.

PubMed

Hong, Jiyong

2014-08-11

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Thymomodulin: biological properties and clinical applications.

PubMed

Kouttab, N M; Prada, M; Cazzola, P

1989-01-01

Thymomodulin (Ellem Industria Farmaceutica s.p.a., Milan, Italy) is a calf thymus acid lysate derivative, composed of several peptides with a molecular weight range of 1-10 kD. Thymomodulin did not exhibit any mutagenic effect. Furthermore, thymomodulin used in animal studies showed no toxicity even when used at high concentrations. Of major significance are the observations in murine and human systems that thymomodulin remains active when administered orally. In vitro and in vivo administered thymomodulin was able to induce the maturation of T-lymphocytes. Additionally, studies in vitro showed that this thymic derivative can enhance the functions of mature T-lymphocytes with cascading effects on B-cell and macrophage functions. Extensive human clinical trials with thymomodulin showed that this agent can improve the clinical symptoms observed with various disease processes, including infections, allergies and malignancies, and can improve immunological functions during ageing.

Regulation of metabolism by the Mediator complex.

PubMed

Youn, Dou Yeon; Xiaoli, Alus M; Pessin, Jeffrey E; Yang, Fajun

2016-01-01

The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals.

A PR-1-like Protein of Fusarium oxysporum Functions in Virulence on Mammalian Hosts*

PubMed Central

Prados-Rosales, Rafael C.; Roldán-Rodríguez, Raquel; Serena, Carolina; López-Berges, Manuel S.; Guarro, Josep; Martínez-del-Pozo, Álvaro; Di Pietro, Antonio

2012-01-01

The pathogenesis-related PR-1-like protein family comprises secreted proteins from the animal, plant, and fungal kingdoms whose biological function remains poorly understood. Here we have characterized a PR-1-like protein, Fpr1, from Fusarium oxysporum, an ubiquitous fungal pathogen that causes vascular wilt disease on a wide range of plant species and can produce life-threatening infections in immunocompromised humans. Fpr1 is secreted and proteolytically processed by the fungus. The fpr1 gene is required for virulence in a disseminated immunodepressed mouse model, and its function depends on the integrity of the proposed active site of PR-1-like proteins. Fpr1 belongs to a gene family that has expanded in plant pathogenic Sordariomycetes. These results suggest that secreted PR-1-like proteins play important roles in fungal pathogenicity. PMID:22553200

Removal design report for the 108-F Biological Laboratory

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1997-09-01

Most of the 100-F facilities were deactivated with the reactor and have since been demolished. Of the dozen or so reactor-related structures, only the 105-F Reactor Building and the 108-F Biology Laboratory remain standing today. The 108-F Biology Laboratory was intended to be used as a facility for the mixing and addition of chemicals used in the treatment of the reactor cooling water. Shortly after F Reactor began operation, it was determined that the facility was not needed for this purpose. In 1949, the building was converted for use as a biological laboratory. In 1962, the lab was expanded bymore » adding a three-story annex to the original four-story structure. The resulting lab had a floor area of approximately 2,883 m{sup 2} (main building and annex) that operated until 1973. The building contained 47 laboratories, a number of small offices, a conference room, administrative section, lunch and locker rooms, and a heavily shielded, high-energy exposure cell. The purpose of this removal design report is to establish the methods of decontamination and decommissioning and the supporting functions associated with facility removal and disposal.« less

Extended Kalman Filter for Estimation of Parameters in Nonlinear State-Space Models of Biochemical Networks

PubMed Central

Sun, Xiaodian; Jin, Li; Xiong, Momiao

2008-01-01

It is system dynamics that determines the function of cells, tissues and organisms. To develop mathematical models and estimate their parameters are an essential issue for studying dynamic behaviors of biological systems which include metabolic networks, genetic regulatory networks and signal transduction pathways, under perturbation of external stimuli. In general, biological dynamic systems are partially observed. Therefore, a natural way to model dynamic biological systems is to employ nonlinear state-space equations. Although statistical methods for parameter estimation of linear models in biological dynamic systems have been developed intensively in the recent years, the estimation of both states and parameters of nonlinear dynamic systems remains a challenging task. In this report, we apply extended Kalman Filter (EKF) to the estimation of both states and parameters of nonlinear state-space models. To evaluate the performance of the EKF for parameter estimation, we apply the EKF to a simulation dataset and two real datasets: JAK-STAT signal transduction pathway and Ras/Raf/MEK/ERK signaling transduction pathways datasets. The preliminary results show that EKF can accurately estimate the parameters and predict states in nonlinear state-space equations for modeling dynamic biochemical networks. PMID:19018286

LateBiclustering: Efficient Heuristic Algorithm for Time-Lagged Bicluster Identification.

PubMed

Gonçalves, Joana P; Madeira, Sara C

2014-01-01

Identifying patterns in temporal data is key to uncover meaningful relationships in diverse domains, from stock trading to social interactions. Also of great interest are clinical and biological applications, namely monitoring patient response to treatment or characterizing activity at the molecular level. In biology, researchers seek to gain insight into gene functions and dynamics of biological processes, as well as potential perturbations of these leading to disease, through the study of patterns emerging from gene expression time series. Clustering can group genes exhibiting similar expression profiles, but focuses on global patterns denoting rather broad, unspecific responses. Biclustering reveals local patterns, which more naturally capture the intricate collaboration between biological players, particularly under a temporal setting. Despite the general biclustering formulation being NP-hard, considering specific properties of time series has led to efficient solutions for the discovery of temporally aligned patterns. Notably, the identification of biclusters with time-lagged patterns, suggestive of transcriptional cascades, remains a challenge due to the combinatorial explosion of delayed occurrences. Herein, we propose LateBiclustering, a sensible heuristic algorithm enabling a polynomial rather than exponential time solution for the problem. We show that it identifies meaningful time-lagged biclusters relevant to the response of Saccharomyces cerevisiae to heat stress.

Automated glycopeptide analysis—review of current state and future directions

PubMed Central

Dallas, David C.; Martin, William F.; Hua, Serenus

2013-01-01

Glycosylation of proteins is involved in immune defense, cell–cell adhesion, cellular recognition and pathogen binding and is one of the most common and complex post-translational modifications. Science is still struggling to assign detailed mechanisms and functions to this form of conjugation. Even the structural analysis of glycoproteins—glycoproteomics—remains in its infancy due to the scarcity of high-throughput analytical platforms capable of determining glycopeptide composition and structure, especially platforms for complex biological mixtures. Glycopeptide composition and structure can be determined with high mass-accuracy mass spectrometry, particularly when combined with chromatographic separation, but the sheer volume of generated data necessitates computational software for interpretation. This review discusses the current state of glycopeptide assignment software—advances made to date and issues that remain to be addressed. The various software and algorithms developed so far provide important insights into glycoproteomics. However, there is currently no freely available software that can analyze spectral data in batch and unambiguously determine glycopeptide compositions for N- and O-linked glycopeptides from relevant biological sources such as human milk and serum. Few programs are capable of aiding in structural determination of the glycan component. To significantly advance the field of glycoproteomics, analytical software and algorithms are required that: (i) solve for both N- and O-linked glycopeptide compositions, structures and glycosites in biological mixtures; (ii) are high-throughput and process data in batches; (iii) can interpret mass spectral data from a variety of sources and (iv) are open source and freely available. PMID:22843980

Genes Responsive to Low-Intensity Pulsed Ultrasound in MC3T3-E1 Preosteoblast Cells

PubMed Central

Tabuchi, Yoshiaki; Sugahara, Yuuki; Ikegame, Mika; Suzuki, Nobuo; Kitamura, Kei-ichiro; Kondo, Takashi

2013-01-01

Although low-intensity pulsed ultrasound (LIPUS) has been shown to enhance bone fracture healing, the underlying mechanism of LIPUS remains to be fully elucidated. Here, to better understand the molecular mechanism underlying cellular responses to LIPUS, we investigated gene expression profiles in mouse MC3T3-E1 preosteoblast cells exposed to LIPUS using high-density oligonucleotide microarrays and computational gene expression analysis tools. Although treatment of the cells with a single 20-min LIPUS (1.5 MHz, 30 mW/cm2) did not affect the cell growth or alkaline phosphatase activity, the treatment significantly increased the mRNA level of Bglap. Microarray analysis demonstrated that 38 genes were upregulated and 37 genes were downregulated by 1.5-fold or more in the cells at 24-h post-treatment. Ingenuity pathway analysis demonstrated that the gene network U (up) contained many upregulated genes that were mainly associated with bone morphology in the category of biological functions of skeletal and muscular system development and function. Moreover, the biological function of the gene network D (down), which contained downregulated genes, was associated with gene expression, the cell cycle and connective tissue development and function. These results should help to further clarify the molecular basis of the mechanisms of the LIPUS response in osteoblast cells. PMID:24252911

Myoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes.

PubMed

Blomme, Arnaud; Fahmy, Karim; Peulen, Olivier; Costanza, Brunella; Fontaine, Marie; Struman, Ingrid; Baiwir, Dominique; de Pauw, Edwin; Thiry, Marc; Bellahcène, Akeila; Castronovo, Vincent; Turtoi, Andrei

2016-12-13

Exosomes are communication mediators participating in the intercellular exchange of proteins, metabolites and nucleic acids. Recent studies have demonstrated that exosomes are characterized by a unique proteomic composition that is distinct from the cellular one. The mechanisms responsible for determining the proteome content of the exosomes remain however obscure. In the current study we employ ultrastructural approach to validate a novel exosomal protein myoferlin. This is a multiple C2-domain containing protein, known for its conserved physiological function in endocytosis and vesicle fusion biology. Emerging studies demonstrate that myoferlin is frequently overexpressed in cancer, where it promotes cancer cell migration and invasion. Our data expand these findings by showing that myoferlin is a general component of cancer cell derived exosomes from different breast and pancreatic cancer cell lines. Using proteomic analysis, we demonstrate for the first time that myoferlin depletion in cancer cells leads to a significantly modulated exosomal protein load. Such myoferlin-depleted exosomes were also functionally deficient as shown by their reduced capacity to transfer nucleic acids to human endothelial cells (HUVEC). Beyond this, myoferlin-depleted cancer exosomes also had a significantly reduced ability to induce migration and proliferation of HUVEC. The present study highlights myoferlin as a new functional player in exosome biology, calling for novel strategies to target this emerging oncogene in human cancer.

Genetic framework for GATA factor function in vascular biology.

PubMed

Linnemann, Amelia K; O'Geen, Henriette; Keles, Sunduz; Farnham, Peggy J; Bresnick, Emery H

2011-08-16

Vascular endothelial dysfunction underlies the genesis and progression of numerous diseases. Although the GATA transcription factor GATA-2 is expressed in endothelial cells and is implicated in coronary heart disease, it has been studied predominantly as a master regulator of hematopoiesis. Because many questions regarding GATA-2 function in the vascular biology realm remain unanswered, we used ChIP sequencing and loss-of-function strategies to define the GATA-2-instigated genetic network in human endothelial cells. In contrast to erythroid cells, GATA-2 occupied a unique target gene ensemble consisting of genes encoding key determinants of endothelial cell identity and inflammation. GATA-2-occupied sites characteristically contained motifs that bind activator protein-1 (AP-1), a pivotal regulator of inflammatory genes. GATA-2 frequently occupied the same chromatin sites as c-JUN and c-FOS, heterodimeric components of AP-1. Although all three components were required for maximal AP-1 target gene expression, GATA-2 was not required for AP-1 chromatin occupancy. GATA-2 conferred maximal phosphorylation of chromatin-bound c-JUN at Ser-73, which stimulates AP-1-dependent transactivation, in a chromosomal context-dependent manner. This work establishes a link between a GATA factor and inflammatory genes, mechanistic insights underlying GATA-2-AP-1 cooperativity and a rigorous genetic framework for understanding GATA-2 function in normal and pathophysiological vascular states.

Exploration of Uncharted Regions of the Protein Universe

PubMed Central

Jaroszewski, Lukasz; Li, Zhanwen; Krishna, S. Sri; Bakolitsa, Constantina; Wooley, John; Deacon, Ashley M.; Wilson, Ian A.; Godzik, Adam

2009-01-01

The genome projects have unearthed an enormous diversity of genes of unknown function that are still awaiting biological and biochemical characterization. These genes, as most others, can be grouped into families based on sequence similarity. The PFAM database currently contains over 2,200 such families, referred to as domains of unknown function (DUF). In a coordinated effort, the four large-scale centers of the NIH Protein Structure Initiative have determined the first three-dimensional structures for more than 250 of these DUF families. Analysis of the first 248 reveals that about two thirds of the DUF families likely represent very divergent branches of already known and well-characterized families, which allows hypotheses to be formulated about their biological function. The remainder can be formally categorized as new folds, although about one third of these show significant substructure similarity to previously characterized folds. These results infer that, despite the enormous increase in the number and the diversity of new genes being uncovered, the fold space of the proteins they encode is gradually becoming saturated. The previously unexplored sectors of the protein universe appear to be primarily shaped by extreme diversification of known protein families, which then enables organisms to evolve new functions and adapt to particular niches and habitats. Notwithstanding, these DUF families still constitute the richest source for discovery of the remaining protein folds and topologies. PMID:19787035

Hierarchical Structure Controls Nanomechanical Properties of Vimentin Intermediate Filaments

PubMed Central

Qin, Zhao; Kreplak, Laurent; Buehler, Markus J.

2009-01-01

Intermediate filaments (IFs), in addition to microtubules and microfilaments, are one of the three major components of the cytoskeleton in eukaryotic cells, playing a vital role in mechanotransduction and in providing mechanical stability to cells. Despite the importance of IF mechanics for cell biology and cell mechanics, the structural basis for their mechanical properties remains unknown. Specifically, our understanding of fundamental filament properties, such as the basis for their great extensibility, stiffening properties, and their exceptional mechanical resilience remains limited. This has prevented us from answering fundamental structure-function relationship questions related to the biomechanical role of intermediate filaments, which is crucial to link structure and function in the protein material's biological context. Here we utilize an atomistic-level model of the human vimentin dimer and tetramer to study their response to mechanical tensile stress, and describe a detailed analysis of the mechanical properties and associated deformation mechanisms. We observe a transition from alpha-helices to beta-sheets with subsequent interdimer sliding under mechanical deformation, which has been inferred previously from experimental results. By upscaling our results we report, for the first time, a quantitative comparison to experimental results of IF nanomechanics, showing good agreement. Through the identification of links between structures and deformation mechanisms at distinct hierarchical levels, we show that the multi-scale structure of IFs is crucial for their characteristic mechanical properties, in particular their ability to undergo severe deformation of ≈300% strain without breaking, facilitated by a cascaded activation of a distinct deformation mechanisms operating at different levels. This process enables IFs to combine disparate properties such as mechanosensitivity, strength and deformability. Our results enable a new paradigm in studying biological and mechanical properties of IFs from an atomistic perspective, and lay the foundation to understanding how properties of individual protein molecules can have profound effects at larger length-scales. PMID:19806221

Hierarchical structure controls nanomechanical properties of vimentin intermediate filaments.

PubMed

Qin, Zhao; Kreplak, Laurent; Buehler, Markus J

2009-10-06

Intermediate filaments (IFs), in addition to microtubules and microfilaments, are one of the three major components of the cytoskeleton in eukaryotic cells, playing a vital role in mechanotransduction and in providing mechanical stability to cells. Despite the importance of IF mechanics for cell biology and cell mechanics, the structural basis for their mechanical properties remains unknown. Specifically, our understanding of fundamental filament properties, such as the basis for their great extensibility, stiffening properties, and their exceptional mechanical resilience remains limited. This has prevented us from answering fundamental structure-function relationship questions related to the biomechanical role of intermediate filaments, which is crucial to link structure and function in the protein material's biological context. Here we utilize an atomistic-level model of the human vimentin dimer and tetramer to study their response to mechanical tensile stress, and describe a detailed analysis of the mechanical properties and associated deformation mechanisms. We observe a transition from alpha-helices to beta-sheets with subsequent interdimer sliding under mechanical deformation, which has been inferred previously from experimental results. By upscaling our results we report, for the first time, a quantitative comparison to experimental results of IF nanomechanics, showing good agreement. Through the identification of links between structures and deformation mechanisms at distinct hierarchical levels, we show that the multi-scale structure of IFs is crucial for their characteristic mechanical properties, in particular their ability to undergo severe deformation of approximately 300% strain without breaking, facilitated by a cascaded activation of a distinct deformation mechanisms operating at different levels. This process enables IFs to combine disparate properties such as mechanosensitivity, strength and deformability. Our results enable a new paradigm in studying biological and mechanical properties of IFs from an atomistic perspective, and lay the foundation to understanding how properties of individual protein molecules can have profound effects at larger length-scales.

A method to identify differential expression profiles of time-course gene data with Fourier transformation.

PubMed

Kim, Jaehee; Ogden, Robert Todd; Kim, Haseong

2013-10-18

Time course gene expression experiments are an increasingly popular method for exploring biological processes. Temporal gene expression profiles provide an important characterization of gene function, as biological systems are both developmental and dynamic. With such data it is possible to study gene expression changes over time and thereby to detect differential genes. Much of the early work on analyzing time series expression data relied on methods developed originally for static data and thus there is a need for improved methodology. Since time series expression is a temporal process, its unique features such as autocorrelation between successive points should be incorporated into the analysis. This work aims to identify genes that show different gene expression profiles across time. We propose a statistical procedure to discover gene groups with similar profiles using a nonparametric representation that accounts for the autocorrelation in the data. In particular, we first represent each profile in terms of a Fourier basis, and then we screen out genes that are not differentially expressed based on the Fourier coefficients. Finally, we cluster the remaining gene profiles using a model-based approach in the Fourier domain. We evaluate the screening results in terms of sensitivity, specificity, FDR and FNR, compare with the Gaussian process regression screening in a simulation study and illustrate the results by application to yeast cell-cycle microarray expression data with alpha-factor synchronization.The key elements of the proposed methodology: (i) representation of gene profiles in the Fourier domain; (ii) automatic screening of genes based on the Fourier coefficients and taking into account autocorrelation in the data, while controlling the false discovery rate (FDR); (iii) model-based clustering of the remaining gene profiles. Using this method, we identified a set of cell-cycle-regulated time-course yeast genes. The proposed method is general and can be potentially used to identify genes which have the same patterns or biological processes, and help facing the present and forthcoming challenges of data analysis in functional genomics.

Telomerase and the search for the end of cancer.

PubMed

Mocellin, Simone; Pooley, Karen A; Nitti, Donato

2013-02-01

Many of the fundamental molecular mechanisms underlying tumor biology remain elusive and, thus, developing specific anticancer therapies remains a challenge. The recently discovered relationships identified among telomeres, telomerase, aging, and cancer have opened a new avenue in tumor biology research that may revolutionize anticancer therapy. This review summarizes the critical aspects of telomerase biology that underpin the development of novel telomerase-targeting therapies for malignant diseases, and special regard is given to the aspects of telomerase that make it such an appealing target, such as the widespread expression of telomerase in cancers. Despite significant progress, issues remain to be addressed before telomerase-based therapies are truly effective and we include critical discussion of the results obtained thus far. Copyright © 2012 Elsevier Ltd. All rights reserved.

Multiple retentive means for prosthetic restoration of a large facial defect - a case report.

PubMed

Abdulhadi, Laith Mahmoud

2010-01-01

A 70-year-old man who suffered from extensive extra and intraoral defects was rehabilitated with a prosthesis using multiple retaining means. The treatment was performed in two parts: externally involving the construction of an episthesis supported only by the remaining intact boundaries of the defect and retained by mini-dental implants and spectacle frame with a modified ear hook; and intraorally by an acrylic resin obturator to restore the function of the hemi-sectioned hard and soft palate. The episthesis was securely retained with minimal movement and/or dislodgment of the prosthesis during function. Multiple retentive techniques may be used to fix heavy external prostheses as an alternative to conventional implants or biological adhesives.

The biology and function of exosomes in cancer.

PubMed

Kalluri, Raghu

2016-04-01

Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40-150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes can be used as liquid biopsies and noninvasive biomarkers for early detection, diagnosis, and treatment of cancer patients.

The Ecology of Seamounts: Structure, Function, and Human Impacts

NASA Astrophysics Data System (ADS)

Clark, Malcolm R.; Rowden, Ashley A.; Schlacher, Thomas; Williams, Alan; Consalvey, Mireille; Stocks, Karen I.; Rogers, Alex D.; O'Hara, Timothy D.; White, Martin; Shank, Timothy M.; Hall-Spencer, Jason M.

2010-01-01

In this review of seamount ecology, we address a number of key scientific issues concerning the structure and function of benthic communities, human impacts, and seamount management and conservation. We consider whether community composition and diversity differ between seamounts and continental slopes, how important dispersal capabilities are in seamount connectivity, what environmental factors drive species composition and diversity, whether seamounts are centers of enhanced biological productivity, and whether they have unique trophic architecture. We discuss how vulnerable seamount communities are to fishing and mining, and how we can balance exploitation of resources and conservation of habitat. Despite considerable advances in recent years, there remain many questions about seamount ecosystems that need closer integration of molecular, oceanographic, and ecological research.

Enzymatically Active Microgels from Self-Assembling Protein Nanofibrils for Microflow Chemistry

PubMed Central

2015-01-01

Amyloid fibrils represent a generic class of protein structure associated with both pathological states and with naturally occurring functional materials. This class of protein nanostructure has recently also emerged as an excellent foundation for sophisticated functional biocompatible materials including scaffolds and carriers for biologically active molecules. Protein-based materials offer the potential advantage that additional functions can be directly incorporated via gene fusion producing a single chimeric polypeptide that will both self-assemble and display the desired activity. To succeed, a chimeric protein system must self-assemble without the need for harsh triggering conditions which would damage the appended functional protein molecule. However, the micrometer to nanoscale patterning and morphological control of protein-based nanomaterials has remained challenging. This study demonstrates a general approach for overcoming these limitations through the microfluidic generation of enzymatically active microgels that are stabilized by amyloid nanofibrils. The use of scaffolds formed from biomaterials that self-assemble under mild conditions enables the formation of catalytic microgels while maintaining the integrity of the encapsulated enzyme. The enzymatically active microgel particles show robust material properties and their porous architecture allows diffusion in and out of reactants and products. In combination with microfluidic droplet trapping approaches, enzymatically active microgels illustrate the potential of self-assembling materials for enzyme immobilization and recycling, and for biological flow-chemistry. These design principles can be adopted to create countless other bioactive amyloid-based materials with diverse functions. PMID:26030507

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

PubMed

Adams, Hieab H H; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura M E; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; Braber, Anouk Den; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco J C; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, W T; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic J A; Van Duijn, Cornelia M; Van Haren, Neeltje E M; Van T Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton J M; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

2016-12-01

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Novel genetic loci underlying human intracranial volume identified through genome-wide association

PubMed Central

Adams, Hieab HH; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura ME; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher RK; Cuellar-Partida, Gabriel; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David CM; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Olde Loohuis, Loes M; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein MJ; Van Eijk, Kristel R; Van Erp, Theo GM; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco JC; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald HH; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, WT; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda WJH; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Valdés Hernández, Maria C; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic JA; Van Duijn, Cornelia M; Van Haren, Neeltje EM; Van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton JM; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

2016-01-01

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth. PMID:27694991

Integrating functional genomics to accelerate mechanistic personalized medicine.

PubMed

Tyner, Jeffrey W

2017-03-01

The advent of deep sequencing technologies has resulted in the deciphering of tremendous amounts of genetic information. These data have led to major discoveries, and many anecdotes now exist of individual patients whose clinical outcomes have benefited from novel, genetically guided therapeutic strategies. However, the majority of genetic events in cancer are currently undrugged, leading to a biological gap between understanding of tumor genetic etiology and translation to improved clinical approaches. Functional screening has made tremendous strides in recent years with the development of new experimental approaches to studying ex vivo and in vivo drug sensitivity. Numerous discoveries and anecdotes also exist for translation of functional screening into novel clinical strategies; however, the current clinical application of functional screening remains largely confined to small clinical trials at specific academic centers. The intersection between genomic and functional approaches represents an ideal modality to accelerate our understanding of drug sensitivities as they relate to specific genetic events and further understand the full mechanisms underlying drug sensitivity patterns.

SIRT3 functions as a tumor suppressor in hepatocellular carcinoma.

PubMed

Zeng, Xianchun; Wang, Nanzhu; Zhai, Hui; Wang, Rongpin; Wu, Jiahong; Pu, Wei

2017-03-01

Hepatocellular carcinoma is one of the leading causes for cancer-related mortality worldwide. SIRT3 may function as either oncogene or tumor suppressor in a panel of cancers; however, the role of SIRT3 in hepatocellular carcinoma remains unclear. In this study, we assayed the expression level of SIRT3 in hepatocellular carcinoma tissues by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. A loss-of-function approach was used to examine the effects of SIRT3 on biological activity, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of SIRT3 protein in hepatocellular carcinoma tissues were significantly downregulated compared with those in adjacent non-cancerous tissues. Furthermore, SIRT3 could decrease cell proliferation and inhibit cell migration/invasion in hepatocellular carcinoma cell line. Taken together, these results elucidated the function of SIRT3 in hepatocellular carcinoma development and suggested that SIRT3 might function as tumor suppressor in hepatocellular carcinoma by targeting PI3K/Akt pathway.

Human endogenous retrovirus HERV-K(HML-2) encodes a stable signal peptide with biological properties distinct from Rec

PubMed Central

Ruggieri, Alessia; Maldener, Esther; Sauter, Marlies; Mueller-Lantzsch, Nikolaus; Meese, Eckart; Fackler, Oliver T; Mayer, Jens

2009-01-01

Background The human endogenous retrovirus HERV-K(HML-2) family is associated with testicular germ cell tumors (GCT). Various HML-2 proviruses encode viral proteins such as Env and Rec. Results We describe here that HML-2 Env gives rise to a 13 kDa signal peptide (SP) that harbors a different C-terminus compared to Rec. Subsequent to guiding Env to the endoplasmatic reticulum (ER), HML-2 SP is released into the cytosol. Biochemical analysis and confocal microscopy demonstrated that similar to Rec, SP efficiently translocates to the granular component of nucleoli. Unlike Rec, SP does not shuttle between nucleus and cytoplasm. SP is less stable than Rec as it is subjected to proteasomal degradation. Moreover, SP lacks export activity towards HML-2 genomic RNA, the main function of Rec in the original viral context, and SP does not interfere with Rec's RNA export activity. Conclusion SP is a previously unrecognized HML-2 protein that, besides targeting and translocation of Env into the ER lumen, may exert biological functions distinct from Rec. HML-2 SP represents another functional similarity with the closely related Mouse Mammary Tumor Virus that encodes an Env-derived SP named p14. Our findings furthermore support the emerging concept of bioactive SPs as a conserved retroviral strategy to modulate their host cell environment, evidenced here by a "retroviral fossil". While the specific role of HML-2 SP remains to be elucidated in the context of human biology, we speculate that it may be involved in immune evasion of GCT cells or tumorigenesis. PMID:19220907

Models of Acetylcholine and Dopamine Signals Differentially Improve Neural Representations

PubMed Central

Holca-Lamarre, Raphaël; Lücke, Jörg; Obermayer, Klaus

2017-01-01

Biological and artificial neural networks (ANNs) represent input signals as patterns of neural activity. In biology, neuromodulators can trigger important reorganizations of these neural representations. For instance, pairing a stimulus with the release of either acetylcholine (ACh) or dopamine (DA) evokes long lasting increases in the responses of neurons to the paired stimulus. The functional roles of ACh and DA in rearranging representations remain largely unknown. Here, we address this question using a Hebbian-learning neural network model. Our aim is both to gain a functional understanding of ACh and DA transmission in shaping biological representations and to explore neuromodulator-inspired learning rules for ANNs. We model the effects of ACh and DA on synaptic plasticity and confirm that stimuli coinciding with greater neuromodulator activation are over represented in the network. We then simulate the physiological release schedules of ACh and DA. We measure the impact of neuromodulator release on the network's representation and on its performance on a classification task. We find that ACh and DA trigger distinct changes in neural representations that both improve performance. The putative ACh signal redistributes neural preferences so that more neurons encode stimulus classes that are challenging for the network. The putative DA signal adapts synaptic weights so that they better match the classes of the task at hand. Our model thus offers a functional explanation for the effects of ACh and DA on cortical representations. Additionally, our learning algorithm yields performances comparable to those of state-of-the-art optimisation methods in multi-layer perceptrons while requiring weaker supervision signals and interacting with synaptically-local weight updates. PMID:28690509

Prediction of allosteric sites on protein surfaces with an elastic-network-model-based thermodynamic method.

PubMed

Su, Ji Guo; Qi, Li Sheng; Li, Chun Hua; Zhu, Yan Ying; Du, Hui Jing; Hou, Yan Xue; Hao, Rui; Wang, Ji Hua

2014-08-01

Allostery is a rapid and efficient way in many biological processes to regulate protein functions, where binding of an effector at the allosteric site alters the activity and function at a distant active site. Allosteric regulation of protein biological functions provides a promising strategy for novel drug design. However, how to effectively identify the allosteric sites remains one of the major challenges for allosteric drug design. In the present work, a thermodynamic method based on the elastic network model was proposed to predict the allosteric sites on the protein surface. In our method, the thermodynamic coupling between the allosteric and active sites was considered, and then the allosteric sites were identified as those where the binding of an effector molecule induces a large change in the binding free energy of the protein with its ligand. Using the proposed method, two proteins, i.e., the 70 kD heat shock protein (Hsp70) and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, were studied and the allosteric sites on the protein surface were successfully identified. The predicted results are consistent with the available experimental data, which indicates that our method is a simple yet effective approach for the identification of allosteric sites on proteins.

The in vitro effects of advanced glycation end products on basophil functions.

PubMed

Han, Kaiyu; Suzukawa, Maho; Yamaguchi, Masao; Sugimoto, Naoya; Nakase, Yuko; Toda, Takako; Nagase, Hiroyuki; Ohta, Ken

2011-01-01

Basophils are thought to play pivotal roles in the pathogenesis of allergic reactions, but their roles in inflammation associated with systemic abnormalities such as metabolic disorders remain largely unknown. Advanced glycation end products (AGEs) are potentially important substances produced in high-glucose disease conditions. In this in vitro study, we investigated whether the biological functions of human basophils can be influenced by AGEs. We analyzed the effects of AGEs on various functions and markers of human basophils, including CD11b expression, apoptosis, degranulation, and cytokine production. Flow cytometric analysis indicated that the level of the receptor for AGEs (RAGE) on the surface of freshly isolated basophils was very low but was clearly upregulated by IL-3. Apoptosis of basophils was induced by high concentrations of glycated albumin. Although glycated albumin failed to affect the level of surface CD11b expression or to trigger degranulation or production of IL-4 and IL-13 in basophils, it dose-dependently induced IL-6 and IL-8 secretion. AGEs seem to act on human basophils; they suppress the cells' longevity but elicit secretion of inflammatory cytokines. Through these biological changes, basophils might play some roles in inflammatory conditions associated with metabolic disorders presenting elevated levels of AGEs. Copyright © 2011 S. Karger AG, Basel.

Engineering functional inorganic-organic hybrid systems: advances in siRNA therapeutics.

PubMed

Shen, Jianliang; Zhang, Wei; Qi, Ruogu; Mao, Zong-Wan; Shen, Haifa

2018-03-21

Cancer treatment still faces a lot of obstacles such as tumor heterogeneity, drug resistance and systemic toxicities. Beyond the traditional treatment modalities, exploitation of RNA interference (RNAi) as an emerging approach has immense potential for the treatment of various gene-caused diseases including cancer. The last decade has witnessed enormous research and achievements focused on RNAi biotechnology. However, delivery of small interference RNA (siRNA) remains a key challenge in the development of clinical RNAi therapeutics. Indeed, functional nanomaterials play an important role in siRNA delivery, which could overcome a wide range of sequential physiological and biological obstacles. Nanomaterial-formulated siRNA systems have potential applications in protection of siRNA from degradation, improving the accumulation in the target tissues, enhancing the siRNA therapy and reducing the side effects. In this review, we explore and summarize the role of functional inorganic-organic hybrid systems involved in the siRNA therapeutic advancements. Additionally, we gather the surface engineering strategies of hybrid systems to optimize for siRNA delivery. Major progress in the field of inorganic-organic hybrid platforms including metallic/non-metallic cores modified with organic shells or further fabrication as the vectors for siRNA delivery is discussed to give credit to the interdisciplinary cooperation between chemistry, pharmacy, biology and medicine.

Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism

PubMed Central

Watanabe, Takamitsu; Otowa, Takeshi; Abe, Osamu; Kuwabara, Hitoshi; Aoki, Yuta; Natsubori, Tatsunobu; Takao, Hidemasa; Kakiuchi, Chihiro; Kondo, Kenji; Ikeda, Masashi; Iwata, Nakao; Kasai, Kiyoto; Sasaki, Tsukasa

2017-01-01

Abstract Oxytocin appears beneficial for autism spectrum disorder (ASD), and more than 20 single-nucleotide polymorphisms (SNPs) in oxytocin receptor (OXTR) are relevant to ASD. However, neither biological functions of OXTR SNPs in ASD nor critical OXTR SNPs that determine oxytocin’s effects on ASD remains known. Here, using a machine-learning algorithm that was designed to evaluate collective effects of multiple SNPs and automatically identify most informative SNPs, we examined relationships between 27 representative OXTR SNPs and six types of behavioral/neural response to oxytocin in ASD individuals. The oxytocin effects were extracted from our previous placebo-controlled within-participant clinical trial administering single-dose intranasal oxytocin to 38 high-functioning adult Japanese ASD males. Consequently, we identified six different SNP sets that could accurately predict the six different oxytocin efficacies, and confirmed the robustness of these SNP selections against variations of the datasets and analysis parameters. Moreover, major alleles of several prominent OXTR SNPs—including rs53576 and rs2254298—were found to have dissociable effects on the oxytocin efficacies. These findings suggest biological functions of the OXTR SNP variants on autistic oxytocin responses, and implied that clinical oxytocin efficacy may be genetically predicted before its actual administration, which would contribute to establishment of future precision medicines for ASD. PMID:27798253

Construction of human induced pluripotent stem cell-derived oriented bone matrix microstructure by using in vitro engineered anisotropic culture model.

PubMed

Ozasa, Ryosuke; Matsugaki, Aira; Isobe, Yoshihiro; Saku, Taro; Yun, Hui-Suk; Nakano, Takayoshi

2018-02-01

Bone tissue has anisotropic microstructure based on collagen/biological apatite orientation, which plays essential roles in the mechanical and biological functions of bone. However, obtaining an appropriate anisotropic microstructure during the bone regeneration process remains a great challenging. A powerful strategy for the control of both differentiation and structural development of newly-formed bone is required in bone tissue engineering, in order to realize functional bone tissue regeneration. In this study, we developed a novel anisotropic culture model by combining human induced pluripotent stem cells (hiPSCs) and artificially-controlled oriented collagen scaffold. The oriented collagen scaffold allowed hiPSCs-derived osteoblast alignment and further construction of anisotropic bone matrix which mimics the bone tissue microstructure. To the best of our knowledge, this is the first report showing the construction of bone mimetic anisotropic bone matrix microstructure from hiPSCs. Moreover, we demonstrated for the first time that the hiPSCs-derived osteoblasts possess a high level of intact functionality to regulate cell alignment. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 360-369, 2018. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc.

Prediction of allosteric sites on protein surfaces with an elastic-network-model-based thermodynamic method

NASA Astrophysics Data System (ADS)

Su, Ji Guo; Qi, Li Sheng; Li, Chun Hua; Zhu, Yan Ying; Du, Hui Jing; Hou, Yan Xue; Hao, Rui; Wang, Ji Hua

2014-08-01

Allostery is a rapid and efficient way in many biological processes to regulate protein functions, where binding of an effector at the allosteric site alters the activity and function at a distant active site. Allosteric regulation of protein biological functions provides a promising strategy for novel drug design. However, how to effectively identify the allosteric sites remains one of the major challenges for allosteric drug design. In the present work, a thermodynamic method based on the elastic network model was proposed to predict the allosteric sites on the protein surface. In our method, the thermodynamic coupling between the allosteric and active sites was considered, and then the allosteric sites were identified as those where the binding of an effector molecule induces a large change in the binding free energy of the protein with its ligand. Using the proposed method, two proteins, i.e., the 70 kD heat shock protein (Hsp70) and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, were studied and the allosteric sites on the protein surface were successfully identified. The predicted results are consistent with the available experimental data, which indicates that our method is a simple yet effective approach for the identification of allosteric sites on proteins.

Novel functional Renilla luciferase mutant provides long-term serum stability and high luminescence activity.

PubMed

Song, Woo Chul; Sung, Hye-Jin; Park, Kyung Soo; Choi, Jeong-Woo; Cho, Je-Yeol; Um, Soong Ho

2013-10-01

Fluorescent and luminescent chemical probes are essential in recent medical diagnostics. However, the use of these probes in vivo has raised concerns due to their low sensitivity, background signal interference, and non-biocompatibility. Therefore, biological chromophores have received much attention as new alternatives. In particular, luciferase, a class of oxidative enzyme with bioluminescence, has emerged as a promising fluorophore due to its improved biocompatibility. However, the enzyme usually possesses weaker luminescence and stability relative to its chemically-based competitors. Here, we report a novel functional mutant luciferase with both enhanced luminescence and long-term serum stability. For the preparation of the modified Renilla luciferase, a new bacterial subcloning design was established. The luciferase coding DNA sequence was redesigned so that mutant luciferase could be easily expressed in an Escherichia coli system. The mutant Renilla luciferase, which we called "m-Rluc," demonstrated characteristic enzymatic functions and showed a 5.6-fold increase in luminescence activity. In addition, the enzyme's physiological stability remained >80% for more than 5days, in contrast to conventional luciferase, termed "hrluc," which disappeared within a few hours. We suggest that this novel biological luciferase probe may be a great tool for both in vitro and in vivo medical diagnostics. Copyright © 2013 Elsevier Inc. All rights reserved.

Bayesian spatiotemporal analysis of zero-inflated biological population density data by a delta-normal spatiotemporal additive model.

PubMed

Arcuti, Simona; Pollice, Alessio; Ribecco, Nunziata; D'Onghia, Gianfranco

2016-03-01

We evaluate the spatiotemporal changes in the density of a particular species of crustacean known as deep-water rose shrimp, Parapenaeus longirostris, based on biological sample data collected during trawl surveys carried out from 1995 to 2006 as part of the international project MEDITS (MEDiterranean International Trawl Surveys). As is the case for many biological variables, density data are continuous and characterized by unusually large amounts of zeros, accompanied by a skewed distribution of the remaining values. Here we analyze the normalized density data by a Bayesian delta-normal semiparametric additive model including the effects of covariates, using penalized regression with low-rank thin-plate splines for nonlinear spatial and temporal effects. Modeling the zero and nonzero values by two joint processes, as we propose in this work, allows to obtain great flexibility and easily handling of complex likelihood functions, avoiding inaccurate statistical inferences due to misclassification of the high proportion of exact zeros in the model. Bayesian model estimation is obtained by Markov chain Monte Carlo simulations, suitably specifying the complex likelihood function of the zero-inflated density data. The study highlights relevant nonlinear spatial and temporal effects and the influence of the annual Mediterranean oscillations index and of the sea surface temperature on the distribution of the deep-water rose shrimp density. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Magnetic Resonance Imaging Revealed Splenic Targeting of Canine Parvovirus Capsid Protein VP2

NASA Astrophysics Data System (ADS)

Ma, Yufei; Wang, Haiming; Yan, Dan; Wei, Yanquan; Cao, Yuhua; Yi, Peiwei; Zhang, Hailu; Deng, Zongwu; Dai, Jianwu; Liu, Xiangtao; Luo, Jianxun; Zhang, Zhijun; Sun, Shiqi; Guo, Huichen

2016-03-01

Canine parvovirus (CPV) is a highly contagious infectious virus, whose infectious mechanism remains unclear because of acute gastroenteritis and the lack of an efficient tool to visualize the virus in real time during virology research. In this study, we developed an iron oxide nanoparticle supported by graphene quantum dots (GQD), namely, FeGQD. In this composite material, GQD acts as a stabilizer; thus, vacancies are retained on the surface for further physical adsorption of the CPV VP2 protein. The FeGQD@VP2 nanocomposite product showed largely enhanced colloidal stability in comparison with bare FeGQD, as well as negligible toxicity both in vitro and in vivo. The composite displayed high uptake into transferrin receptor (TfR) positive cells, which are distinguishable from FeGQD or TfR negative cells. In addition, the composite developed a significant accumulation in spleen rather than in liver, where bare FeGQD or most iron oxide nanoparticles gather. As these evident targeting abilities of FeGQD@VP2 strongly suggested, the biological activity of CPV VP2 was retained in our study, and its biological functions might correspond to CPV when the rare splenic targeting ability is considered. This approach can be applied to numerous other biomedical studies that require a simple yet efficient approach to track proteins in vivo while retaining biological function and may facilitate virus-related research.

Magnetic Resonance Imaging Revealed Splenic Targeting of Canine Parvovirus Capsid Protein VP2

PubMed Central

Ma, Yufei; Wang, Haiming; Yan, Dan; Wei, Yanquan; Cao, Yuhua; Yi, Peiwei; Zhang, Hailu; Deng, Zongwu; Dai, Jianwu; Liu, Xiangtao; Luo, Jianxun; Zhang, Zhijun; Sun, Shiqi; Guo, Huichen

2016-01-01

Canine parvovirus (CPV) is a highly contagious infectious virus, whose infectious mechanism remains unclear because of acute gastroenteritis and the lack of an efficient tool to visualize the virus in real time during virology research. In this study, we developed an iron oxide nanoparticle supported by graphene quantum dots (GQD), namely, FeGQD. In this composite material, GQD acts as a stabilizer; thus, vacancies are retained on the surface for further physical adsorption of the CPV VP2 protein. The FeGQD@VP2 nanocomposite product showed largely enhanced colloidal stability in comparison with bare FeGQD, as well as negligible toxicity both in vitro and in vivo. The composite displayed high uptake into transferrin receptor (TfR) positive cells, which are distinguishable from FeGQD or TfR negative cells. In addition, the composite developed a significant accumulation in spleen rather than in liver, where bare FeGQD or most iron oxide nanoparticles gather. As these evident targeting abilities of FeGQD@VP2 strongly suggested, the biological activity of CPV VP2 was retained in our study, and its biological functions might correspond to CPV when the rare splenic targeting ability is considered. This approach can be applied to numerous other biomedical studies that require a simple yet efficient approach to track proteins in vivo while retaining biological function and may facilitate virus-related research. PMID:26996514

Long noncoding RNA, tissue differentiation-inducing nonprotein coding RNA is upregulated and promotes development of esophageal squamous cell carcinoma.

PubMed

Xu, Y; Qiu, M; Chen, Y; Wang, J; Xia, W; Mao, Q; Yang, L; Li, M; Jiang, F; Xu, L; Yin, R

2016-11-01

Esophageal squamous cell carcinoma (ESCC) is one of the major causes of cancer death worldwide, especially in Eastern Asia. Due to the poor prognosis, it is necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recently, studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Increasing evidence indicates that some lncRNAs are widely involved in the development and progression of ESCC, such as HOTAIR, SPRY4-IT1 and POU3F3. An emerging lncRNA, tissue differentiation-inducing nonprotein coding RNA (TINCR), has been studied in human cutaneous squamous cell carcinoma and has critical biological function, but its role in ESCC remains unknown. Here, we evaluated the expression profile of TINCR and its biological function in ESCC. In a cohort of 56 patients, TINCR was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues. Further, in vitro silencing TINCR via small interfering RNA (siRNA) inhibited the proliferation, migration and invasion of ESCC cells. Meantime, siRNA treatment induced apoptosis and blocked the progression of cell cycle. Taken together, our study suggests that TINCR promotes proliferation, migration and invasion of ESCC cells, acting as a potential oncogene of ESCC. © 2016 International Society for Diseases of the Esophagus.

Novel, customizable scoring functions, parameterized using N-PLS, for structure-based drug discovery.

PubMed

Catana, Cornel; Stouten, Pieter F W

2007-01-01

The ability to accurately predict biological affinity on the basis of in silico docking to a protein target remains a challenging goal in the CADD arena. Typically, "standard" scoring functions have been employed that use the calculated docking result and a set of empirical parameters to calculate a predicted binding affinity. To improve on this, we are exploring novel strategies for rapidly developing and tuning "customized" scoring functions tailored to a specific need. In the present work, three such customized scoring functions were developed using a set of 129 high-resolution protein-ligand crystal structures with measured Ki values. The functions were parametrized using N-PLS (N-way partial least squares), a multivariate technique well-known in the 3D quantitative structure-activity relationship field. A modest correlation between observed and calculated pKi values using a standard scoring function (r2 = 0.5) could be improved to 0.8 when a customized scoring function was applied. To mimic a more realistic scenario, a second scoring function was developed, not based on crystal structures but exclusively on several binding poses generated with the Flo+ docking program. Finally, a validation study was conducted by generating a third scoring function with 99 randomly selected complexes from the 129 as a training set and predicting pKi values for a test set that comprised the remaining 30 complexes. Training and test set r2 values were 0.77 and 0.78, respectively. These results indicate that, even without direct structural information, predictive customized scoring functions can be developed using N-PLS, and this approach holds significant potential as a general procedure for predicting binding affinity on the basis of in silico docking.

Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity.

PubMed

Xu, Xiang; Zhao, Jingyue; Xu, Zhen; Peng, Baozhen; Huang, Qiuhua; Arnold, Eddy; Ding, Jianping

2004-08-06

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, and regulation of the enzymatic activity of IDHs is crucial for their biological functions. Bacterial IDHs are reversibly regulated by phosphorylation of a strictly conserved serine residue at the active site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse important biological functions; however, their regulatory mechanism remains unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically relevant conformational states of the enzyme that differ substantially in the structure of the active site and in the overall structure. A structural segment at the active site that forms a conserved alpha-helix in all known NADP-IDH structures assumes a loop conformation in the open, inactive form of HcIDH; a partially unraveled alpha-helix in the semi-open, intermediate form; and an alpha-helix in the closed, active form. The side chain of Asp279 of this segment occupies the isocitrate-binding site and forms hydrogen bonds with Ser94 (the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the metal ion in the active form. The structural data led us to propose a novel self-regulatory mechanism for HcIDH that mimics the phosphorylation mechanism used by the bacterial homologs, consistent with biochemical and biological data. This mechanism might be applicable to other eukaryotic NADP-IDHs. The results also provide insights into the recognition and specificity of substrate and cofactor by eukaryotic NADP-IDHs.

Molecular Architecture of Full-length TRF1 Favors Its Interaction with DNA.

PubMed

Boskovic, Jasminka; Martinez-Gago, Jaime; Mendez-Pertuz, Marinela; Buscato, Alberto; Martinez-Torrecuadrada, Jorge Luis; Blasco, Maria A

2016-10-07

Telomeres are specific DNA-protein structures found at both ends of eukaryotic chromosomes that protect the genome from degradation and from being recognized as double-stranded breaks. In vertebrates, telomeres are composed of tandem repeats of the TTAGGG sequence that are bound by a six-subunit complex called shelterin. Molecular mechanisms of telomere functions remain unknown in large part due to lack of structural data on shelterins, shelterin complex, and its interaction with the telomeric DNA repeats. TRF1 is one of the best studied shelterin components; however, the molecular architecture of the full-length protein remains unknown. We have used single-particle electron microscopy to elucidate the structure of TRF1 and its interaction with telomeric DNA sequence. Our results demonstrate that full-length TRF1 presents a molecular architecture that assists its interaction with telometic DNA and at the same time makes TRFH domains accessible to other TRF1 binding partners. Furthermore, our studies suggest hypothetical models on how other proteins as TIN2 and tankyrase contribute to regulate TRF1 function. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Bottom-up synthetic biology: modular design for making artificial platelets

NASA Astrophysics Data System (ADS)

Majumder, Sagardip; Liu, Allen P.

2018-01-01

Engineering artificial cells to mimic one or multiple fundamental cell biological functions is an emerging area of synthetic biology. Reconstituting functional modules from biological components in vitro is a challenging yet an important essence of bottom-up synthetic biology. Here we describe the concept of building artificial platelets using bottom-up synthetic biology and the four functional modules that together could enable such an ambitious effort.

Does changing pain-related knowledge reduce pain and improve function through changes in catastrophizing?

PubMed

Lee, Hopin; McAuley, James H; Hübscher, Markus; Kamper, Steven J; Traeger, Adrian C; Moseley, G Lorimer

2016-04-01

Evidence from randomized controlled studies shows that reconceptualizing pain improves patients' knowledge of pain biology, reduces catastrophizing thoughts, and improves pain and function. However, causal relationships between these variables remain untested. It is hypothesized that reductions in catastrophizing could mediate the relationship between improvements in pain knowledge and improvements in pain and function. To test this causal mechanism, we conducted longitudinal mediation analyses on a cohort of 799 patients who were exposed to a pain education intervention. Patients provided responses to the neurophysiology of pain questionnaire, catastrophic thoughts about pain scale, visual analogue pain scale, and the patient specific functional scale, at baseline, 1-month, 6-month, and 12-month follow-up. With adjustment for potential confounding variables, an improvement in pain biology knowledge was significantly associated with a reduction in pain intensity (total effect = -2.20, 95% confidence interval [CI] = -2.96 to -1.44). However, this effect was not mediated by a reduction in catastrophizing (indirect effect = -0.16, 95% CI = -0.36 to 0.02). This might be due to a weak, nonsignificant relationship between changes in catastrophizing and pain intensity (path b = 0.19, 95% CI = -0.03 to 0.41). Similar trends were found in models with function as the outcome. Our findings indicate that change in catastrophizing did not mediate the effect of pain knowledge acquisition on change in pain or function. The strength of this conclusion is moderated, however, if patient-clinician relational factors are conceptualized as a consequence of catastrophizing, rather than a cause.

Genetics of Sleep and Sleep disorders

PubMed Central

Sehgal, Amita; Mignot, Emmanuel

2011-01-01

Sleep remains one of the least understood phenomena in biology – even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association (GWA) studies have uncovered ~14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. PMID:21784243

Quantitative proteomic characterization of redox-dependent post-translational modifications on protein cysteines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, Jicheng; Gaffrey, Matthew J.; Qian, Wei-Jun

Protein cysteine thiols play a crucial role in redox signaling, regulation of enzymatic activity and protein function, and maintaining redox homeostasis in living systems. The unique chemical reactivity of thiol groups makes cysteine susceptible to oxidative modifications by reactive oxygen and nitrogen species to form a broad array of reversible and irreversible protein post-translational modifications (PTMs). The reversible modifications in particular are one of the major components of redox signaling and are involved in regulation of various cellular processes under physiological and pathological conditions. The biological significance of these redox PTMs in health and diseases has been increasingly recognized. Herein,more » we review the recent advances of quantitative proteomic approaches for investigating redox PTMs in complex biological systems, including the general considerations of sample processing, various chemical or affinity enrichment strategies, and quantitative approaches. We also highlight a number of redox proteomic approaches that enable effective profiling of redox PTMs for addressing specific biological questions. Although some technological limitations remain, redox proteomics is paving the way towards a better understanding of redox signaling and regulation in human health and diseases.« less

Biological effects of direct and indirect manipulation of the fascial system. Narrative review.

PubMed

Parravicini, Giovanni; Bergna, Andrea

2017-04-01

Osteopathic Manipulative Treatment (OMT) is effective in improving function, movement and restoring pain conditions. Despite clinical results, the mechanisms of how OMT achieves its' effects remain unclear. The fascial system is described as a tensional network that envelops the human body. Direct or indirect manipulations of the fascial system are a distinctive part of OMT. This review describes the biological effects of direct and indirect manipulation of the fascial system. Literature search was performed in February 2016 in the electronic databases: Cochrane, Medline, Scopus, Ostmed, Pedro and authors' publications relative to Fascia Research Congress Website. Manipulation of the fascial system seems to interfere with some cellular processes providing various pro-inflammatory and anti-inflammatory cells and molecules. Despite growing research in the osteopathic field, biological effects of direct or indirect manipulation of the fascial system are not conclusive. To elevate manual medicine as a primary intervention in clinical settings, it's necessary to clarify how OMT modalities work in order to underpin their clinical efficacies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Understanding the Mechanism of Translocation of Adenylate Cyclase Toxin across Biological Membranes

PubMed Central

Ostolaza, Helena; Martín, César; González-Bullón, David; Uribe, Kepa B.; Etxaniz, Asier

2017-01-01

Adenylate cyclase toxin (ACT) is one of the principal virulence factors secreted by the whooping cough causative bacterium Bordetella pertussis, and it has a critical role in colonization of the respiratory tract and establishment of the disease. ACT targets phagocytes via binding to the CD11b/CD18 integrin and delivers its N-terminal adenylate cyclase (AC) domain directly to the cell cytosol, where it catalyzes unregulated conversion of cytosolic ATP into cAMP upon activation by binding to cellular calmodulin. High cAMP levels disrupt bactericidal functions of the immune cells, ultimately leading to cell death. In spite of its relevance in the ACT biology, the mechanism by which its ≈400 amino acid-long AC domain is transported through the target plasma membrane, and is released into the target cytosol, remains enigmatic. This article is devoted to refresh our knowledge on the mechanism of AC translocation across biological membranes. Two models, the so-called “two-step model” and the recently-proposed “toroidal pore model”, will be considered. PMID:28934133

Developmental biology, the stem cell of biological disciplines.

PubMed

Gilbert, Scott F

2017-12-01

Developmental biology (including embryology) is proposed as "the stem cell of biological disciplines." Genetics, cell biology, oncology, immunology, evolutionary mechanisms, neurobiology, and systems biology each has its ancestry in developmental biology. Moreover, developmental biology continues to roll on, budding off more disciplines, while retaining its own identity. While its descendant disciplines differentiate into sciences with a restricted set of paradigms, examples, and techniques, developmental biology remains vigorous, pluripotent, and relatively undifferentiated. In many disciplines, especially in evolutionary biology and oncology, the developmental perspective is being reasserted as an important research program.

Functions in Biological Kind Classification

ERIC Educational Resources Information Center

Lombrozo, Tania; Rehder, Bob

2012-01-01

Biological traits that serve functions, such as a zebra's coloration (for camouflage) or a kangaroo's tail (for balance), seem to have a special role in conceptual representations for biological kinds. In five experiments, we investigate whether and why functional features are privileged in biological kind classification. Experiment 1…

Discretization of Gene Expression Data Unmasks Molecular Subgroups Recurring in Different Human Cancer Types.

PubMed

Beleut, Manfred; Soeldner, Robert; Egorov, Mark; Guenther, Rolf; Dehler, Silvia; Morys-Wortmann, Corinna; Moch, Holger; Henco, Karsten; Schraml, Peter

2016-01-01

Despite the individually different molecular alterations in tumors, the malignancy associated biological traits are strikingly similar. Results of a previous study using renal cell carcinoma (RCC) as a model pointed towards cancer-related features, which could be visualized as three groups by microarray based gene expression analysis. In this study, we used a mathematic model to verify the presence of these groups in RCC as well as in other cancer types. We developed an algorithm for gene-expression deviation profiling for analyzing gene expression data of a total of 8397 patients with 13 different cancer types and normal tissues. We revealed three common Cancer Transcriptomic Profiles (CTPs) which recurred in all investigated tumors. Additionally, CTPs remained robust regardless of the functions or numbers of genes analyzed. CTPs may represent common genetic fingerprints, which potentially reflect the closely related biological traits of human cancers.

Over Expression of Long Non-Coding RNA PANDA Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8.

PubMed

Peng, Chuanhui; Hu, Wendi; Weng, Xiaoyu; Tong, Rongliang; Cheng, Shaobing; Ding, Chaofeng; Xiao, Heng; Lv, Zhen; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

2017-06-23

It has been reported that long non-coding RNA PANDA was disregulated in varieties types of tumor, but its expression level and biological role in hepatocellular carcinoma (HCC) remains contradictory. We detected PANDA expression in two independent cohorts (48 HCC patients following liver transplantation and 84 HCC patients following liver resection), and found that PANDA was down-regulated in HCC. Thereafter we explored its function in cancer biology by inversing its low expression. Surprisingly, overexpression of PANDA promoted HCC proliferation and carcinogenesis in vitro and in vivo. Mechanistically, PANDA repressed transcriptional activity of senescence associated inflammatory factor IL8, which leaded to inhibition of cellular senescence. Therefore, our research help to better understand the complex role of PANDA in HCC, and suggest more thoughtful strategies should be applied before it can be treated as a potential therapeutic target.

Molecular Precision at Micrometer Length Scales: Hierarchical Assembly of DNA-Protein Nanostructures.

PubMed

Schiffels, Daniel; Szalai, Veronika A; Liddle, J Alexander

2017-07-25

Robust self-assembly across length scales is a ubiquitous feature of biological systems but remains challenging for synthetic structures. Taking a cue from biology-where disparate molecules work together to produce large, functional assemblies-we demonstrate how to engineer microscale structures with nanoscale features: Our self-assembly approach begins by using DNA polymerase to controllably create double-stranded DNA (dsDNA) sections on a single-stranded template. The single-stranded DNA (ssDNA) sections are then folded into a mechanically flexible skeleton by the origami method. This process simultaneously shapes the structure at the nanoscale and directs the large-scale geometry. The DNA skeleton guides the assembly of RecA protein filaments, which provides rigidity at the micrometer scale. We use our modular design strategy to assemble tetrahedral, rectangular, and linear shapes of defined dimensions. This method enables the robust construction of complex assemblies, greatly extending the range of DNA-based self-assembly methods.

Self-interference 3D super-resolution microscopy for deep tissue investigations.

PubMed

Bon, Pierre; Linarès-Loyez, Jeanne; Feyeux, Maxime; Alessandri, Kevin; Lounis, Brahim; Nassoy, Pierre; Cognet, Laurent

2018-06-01

Fluorescence localization microscopy has achieved near-molecular resolution capable of revealing ultra-structures, with a broad range of applications, especially in cellular biology. However, it remains challenging to attain such resolution in three dimensions and inside biological tissues beyond the first cell layer. Here we introduce SELFI, a framework for 3D single-molecule localization within multicellular specimens and tissues. The approach relies on self-interference generated within the microscope's point spread function (PSF) to simultaneously encode equiphase and intensity fluorescence signals, which together provide the 3D position of an emitter. We combined SELFI with conventional localization microscopy to visualize F-actin 3D filament networks and reveal the spatial distribution of the transcription factor OCT4 in human induced pluripotent stem cells at depths up to 50 µm inside uncleared tissue spheroids. SELFI paves the way to nanoscale investigations of native cellular processes in intact tissues.

Lectins from Mycelia of Basidiomycetes

PubMed Central

Nikitina, Valentina E.; Loshchinina, Ekaterina A.; Vetchinkina, Elena P.

2017-01-01

Lectins are proteins of a nonimmunoglobulin nature that are capable of specific recognition of and reversible binding to the carbohydrate moieties of complex carbohydrates, without altering the covalent structure of any of the recognized glycosyl ligands. They have a broad range of biological activities important for the functioning of the cell and the whole organism and, owing to the high specificity of reversible binding to carbohydrates, are valuable tools used widely in biology and medicine. Lectins can be produced by many living organisms, including basidiomycetes. Whereas lectins from the fruit bodies of basidiomycetes have been studied sufficiently well, mycelial lectins remain relatively unexplored. Here, we review and comparatively analyze what is currently known about lectins isolated from the vegetative mycelium of macrobasidiomycetes, including their localization, properties, and carbohydrate specificities. Particular attention is given to the physiological role of mycelial lectins in fungal growth and development. PMID:28640205

Salt marsh vegetation promotes efficient tidal channel networks

PubMed Central

Kearney, William S.; Fagherazzi, Sergio

2016-01-01

Tidal channel networks mediate the exchange of water, nutrients and sediment between an estuary and marshes. Biology feeds back into channel morphodynamics through the influence of vegetation on both flow and the cohesive strength of channel banks. Determining how vegetation affects channel networks is essential in understanding the biological functioning of intertidal ecosystems and their ecosystem services. However, the processes that control the formation of an efficient tidal channel network remain unclear. Here we compare the channel networks of vegetated salt marshes in Massachusetts and the Venice Lagoon to unvegetated systems in the arid environments of the Gulf of California and Yemen. We find that the unvegetated systems are dissected by less efficient channel networks than the vegetated salt marshes. These differences in network geometry reflect differences in the branching and meandering of the channels in the network, characteristics that are related to the density of vegetation on the marsh. PMID:27430165

Biological substrates of schizophrenia.

PubMed

Kovelman, J A; Scheibel, A B

1986-01-01

Schizophrenia is increasingly believed to represent a group of organic disorders which primarily, although not exclusively, affect the central nervous system. Our purpose is to review a representative sample of twentieth-century literature which speaks to the biological substrates of the syndrome. Subjects reviewed include genetic and environmental contributions to the onset of illness, early and recent findings of gross structural anomalies, and apparent histopathological alterations in cerebral cortex, cerebellar vermis, limbic system, and brain stem, as well as problems of cerebral asymmetry. Data from a diverse group of electrophysiological studies reveal several promising correlates of these areas of investigation. Despite the inconsistent nature of the findings to date, several themes have begun to emerge, including patterns of hypofrontal/hyperparietal regional cerebral flow and glucose utilization, left hemispheric dysfunction, and deficits of interhemispheric information processing. The interpretation and significance of these emerging patterns remains unclear and must await more profound insights into the nature of normal and abnormal cerebral function.

Total synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units

NASA Astrophysics Data System (ADS)

Wu, Yong; Xiong, De-Cai; Chen, Si-Cong; Wang, Yong-Shi; Ye, Xin-Shan

2017-03-01

Carbohydrates are diverse bio-macromolecules with highly complex structures that are involved in numerous biological processes. Well-defined carbohydrates obtained by chemical synthesis are essential to the understanding of their functions. However, synthesis of carbohydrates is greatly hampered by its insufficient efficiency. So far, assembly of long carbohydrate chains remains one of the most challenging tasks for synthetic chemists. Here we describe a highly efficient assembly of a 92-mer polysaccharide by the preactivation-based one-pot glycosylation protocol. Several linear and branched oligosaccharide/polysaccharide fragments ranging from 5-mer to 31-mer in length have been rapidly constructed in one-pot manner, which enables the first total synthesis of a biologically important mycobacterial arabinogalactan through a highly convergent [31+31+30] coupling reaction. Our results show that the preactivation-based one-pot glycosylation protocol may provide access to the construction of long and complicated carbohydrate chains.

RNA Characterization by Solid-State NMR Spectroscopy.

PubMed

Yang, Yufei; Wang, Shenlin

2018-06-21

The structures of RNAs, which play critical roles in various biological processes, provide important clues and insights into the biological functions of these molecules. However, RNA structure determination remains a challenging topic. In recent years, magic-angle-spinning solid-state NMR (MAS SSNMR) has emerged as an alternative technique for structural and dynamic characterization of RNA. MAS SSNMR has been successfully applied to provide atomic-level structural information about several RNA molecules and RNA-protein complexes. In this Minireview, we give an overview of recent progress in the field of MAS SSNMR based RNA structural characterization, and introduce sample preparation strategies and SSNMR spectroscopic techniques that have been incorporated to identify RNA structural elements. We also highlight a few impressive examples of RNAs that have been investigated extensively by SSNMR. Finally, we briefly discuss future technical trends in the use of MAS SSNMR to facilitate RNA structure determination. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention.

PubMed

Ornelas, Argentina; Zacharias-Millward, Niki; Menter, David G; Davis, Jennifer S; Lichtenberger, Lenard; Hawke, David; Hawk, Ernest; Vilar, Eduardo; Bhattacharya, Pratip; Millward, Steven

2017-06-01

After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

Dinosaur peptides suggest mechanisms of protein survival.

PubMed

San Antonio, James D; Schweitzer, Mary H; Jensen, Shane T; Kalluri, Raghu; Buckley, Michael; Orgel, Joseph P R O

2011-01-01

Eleven collagen peptide sequences recovered from chemical extracts of dinosaur bones were mapped onto molecular models of the vertebrate collagen fibril derived from extant taxa. The dinosaur peptides localized to fibril regions protected by the close packing of collagen molecules, and contained few acidic amino acids. Four peptides mapped to collagen regions crucial for cell-collagen interactions and tissue development. Dinosaur peptides were not represented in more exposed parts of the collagen fibril or regions mediating intermolecular cross-linking. Thus functionally significant regions of collagen fibrils that are physically shielded within the fibril may be preferentially preserved in fossils. These results show empirically that structure-function relationships at the molecular level could contribute to selective preservation in fossilized vertebrate remains across geological time, suggest a 'preservation motif', and bolster current concepts linking collagen structure to biological function. This non-random distribution supports the hypothesis that the peptides are produced by the extinct organisms and suggests a chemical mechanism for survival.

Personal reflections on a galvanizing trail.

PubMed

O'Dell, B L

1998-01-01

This article encompasses my perception of, and experience in, an exciting segment of the trace element era in nutrition research: the role of zinc in the nutrition of animals and humans. Zinc has been a major player on the stage of trace element research, and it has left a trail that galvanized the attention of many researchers, including myself. It is ubiquitous in biological systems, and it plays a multitude of physiologic and biochemical functions. A brief historical overview is followed by a discussion of the contributions the work done in my laboratory has made toward understanding the physiological and biochemical functions of zinc. The effort of 40 years has led to the belief that one of zinc's major roles, and perhaps its first limiting role, is to preserve plasma-membrane function as regards ion channels and signal transduction. Although substantial knowledge has been gained relating to the importance of zinc in nutrition, much remains to be discovered.

Solution Exchange Lithography: A Versatile Tool for Sequential Surface Engineering

NASA Astrophysics Data System (ADS)

Pester, Christian; Mattson, Kaila; Bothman, David; Klinger, Daniel; Lee, Kenneth; Discekici, Emre; Narupai, Benjaporn; Hawker, Craig

The covalent attachment of polymers has emerged as a viable strategy for the preparation of multi-functional surfaces. Patterned, surface-grafted polymer brushes provide spatial control over wetting, mechanical, biological or electronic properties, and allow fabrication of `intelligent' substrates which selectively adapt to their environment. However, the route towards patterned polymer brush surfaces often remains challenging, creating a demand for more efficient and less complicated fabrication strategies. We describe the design and application of a novel experimental setup to combine light-mediated and flow chemistry for the fabrication of hierarchical surface-grafted polymer brushes. Using light-mediated, surface initiated controlled radical polymerization and post-functionalization via well-established, and highly efficient chemistries, polymer brush films of previously unimaginable complexity are now shown to be accessible. This methodology allows full flexibility to exchange both lithographic photomasks and chemical environments in-situ, readily affording multidimensional thin film architectures, all from uniformly functionalized substrates.

The Landscape of long non-coding RNA classification

PubMed Central

St Laurent, Georges; Wahlestedt, Claes; Kapranov, Philipp

2015-01-01

Advances in the depth and quality of transcriptome sequencing have revealed many new classes of long non-coding RNAs (lncRNAs). lncRNA classification has mushroomed to accommodate these new findings, even though the real dimensions and complexity of the non-coding transcriptome remain unknown. Although evidence of functionality of specific lncRNAs continues to accumulate, conflicting, confusing, and overlapping terminology has fostered ambiguity and lack of clarity in the field in general. The lack of fundamental conceptual un-ambiguous classification framework results in a number of challenges in the annotation and interpretation of non-coding transcriptome data. It also might undermine integration of the new genomic methods and datasets in an effort to unravel function of lncRNA. Here, we review existing lncRNA classifications, nomenclature, and terminology. Then we describe the conceptual guidelines that have emerged for their classification and functional annotation based on expanding and more comprehensive use of large systems biology-based datasets. PMID:25869999

Protein prenylation: a new mode of host-pathogen interaction.

PubMed

Amaya, Moushimi; Baranova, Ancha; van Hoek, Monique L

2011-12-09

Post translational modifications are required for proteins to be fully functional. The three step process, prenylation, leads to farnesylation or geranylgeranylation, which increase the hydrophobicity of the prenylated protein for efficient anchoring into plasma membranes and/or organellar membranes. Prenylated proteins function in a number of signaling and regulatory pathways that are responsible for basic cell operations. Well characterized prenylated proteins include Ras, Rac and Rho. Recently, pathogenic prokaryotic proteins, such as SifA and AnkB, have been shown to be prenylated by eukaryotic host cell machinery, but their functions remain elusive. The identification of other bacterial proteins undergoing this type of host-directed post-translational modification shows promise in elucidating host-pathogen interactions to develop new therapeutics. This review incorporates new advances in the study of protein prenylation into a broader aspect of biology with a focus on host-pathogen interaction. Copyright © 2011 Elsevier Inc. All rights reserved.

FUN-L: gene prioritization for RNAi screens.

PubMed

Lees, Jonathan G; Hériché, Jean-Karim; Morilla, Ian; Fernández, José M; Adler, Priit; Krallinger, Martin; Vilo, Jaak; Valencia, Alfonso; Ellenberg, Jan; Ranea, Juan A; Orengo, Christine

2015-06-15

Most biological processes remain only partially characterized with many components still to be identified. Given that a whole genome can usually not be tested in a functional assay, identifying the genes most likely to be of interest is of critical importance to avoid wasting resources. Given a set of known functionally related genes and using a state-of-the-art approach to data integration and mining, our Functional Lists (FUN-L) method provides a ranked list of candidate genes for testing. Validation of predictions from FUN-L with independent RNAi screens confirms that FUN-L-produced lists are enriched in genes with the expected phenotypes. In this article, we describe a website front end to FUN-L. The website is freely available to use at http://funl.org © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.

PubMed

Wang, Liqun; Xia, Jing; Li, Jonathan; Hagemann, Tracy L; Jones, Jeffrey R; Fraenkel, Ernest; Weitz, David A; Zhang, Su-Chun; Messing, Albee; Feany, Mel B

2018-05-15

Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.

FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis?

PubMed

Ren, Bin

2018-04-24

FoxO1 has emerged as an important regulator of angiogenesis. Recent work published in this Journal shows that FoxO1 regulates VEGF expression in keratinocytes and is required for angiogenesis in wound healing. Since FoxO1 also regulates CD36 transcription, and endothelial cell differentiation and vascular maturation, this transcription factor may be essential for the formation of functional vascular networks via coupling the regulation of CD36 in vascular endothelial cells under physiological and pathological conditions. Although many outstanding questions remain to be answered, the mechanisms by which FoxO1 regulates VEGF in keratinocytes provide insight into the development of functional angiogenesis and further our understanding of vascular biology. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Extensive gene content variation in the Brachypodium distachyon pan-genome correlates with population structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gordon, Sean P.; Contreras-Moreira, Bruno; Woods, Daniel P.

While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely tomore » be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution.« less

Probing Functional Heteromeric Chemokine Protein-Protein Interactions through Conformation-Assisted Oxime Ligation.

PubMed

Agten, Stijn M; Koenen, Rory R; Ippel, Hans; Eckardt, Veit; von Hundelshausen, Philipp; Mayo, Kevin H; Weber, Christian; Hackeng, Tilman M

2016-11-21

Protein-protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially involved in pathological disorders such as cancer, atherosclerosis, and HIV. It remains unclear whether this functional modulation is mediated by heterodimer formation or by the additive effects of mixed chemokines on their respective receptors. To address this issue, we report the synthesis of a covalent RANTES-PF4 heterodimer (termed OPRAH) by total chemical synthesis and oxime ligation, with an acceleration of the final ligation step driven by PPIs between RANTES and PF4. Compared to mixed separate chemokines, OPRAH exhibited increased biological activity, thus providing evidence that physical formation of the heterodimer indeed mediates enhanced function. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Probing Functional Heteromeric Chemokine Protein–Protein Interactions through Conformation‐Assisted Oxime Ligation

PubMed Central

Agten, Stijn M.; Koenen, Rory R.; Ippel, Hans; Eckardt, Veit; von Hundelshausen, Philipp; Mayo, Kevin H.; Weber, Christian

2016-01-01

Abstract Protein–protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially involved in pathological disorders such as cancer, atherosclerosis, and HIV. It remains unclear whether this functional modulation is mediated by heterodimer formation or by the additive effects of mixed chemokines on their respective receptors. To address this issue, we report the synthesis of a covalent RANTES‐PF4 heterodimer (termed OPRAH) by total chemical synthesis and oxime ligation, with an acceleration of the final ligation step driven by PPIs between RANTES and PF4. Compared to mixed separate chemokines, OPRAH exhibited increased biological activity, thus providing evidence that physical formation of the heterodimer indeed mediates enhanced function. PMID:27785869

Extensive gene content variation in the Brachypodium distachyon pan-genome correlates with population structure.

PubMed

Gordon, Sean P; Contreras-Moreira, Bruno; Woods, Daniel P; Des Marais, David L; Burgess, Diane; Shu, Shengqiang; Stritt, Christoph; Roulin, Anne C; Schackwitz, Wendy; Tyler, Ludmila; Martin, Joel; Lipzen, Anna; Dochy, Niklas; Phillips, Jeremy; Barry, Kerrie; Geuten, Koen; Budak, Hikmet; Juenger, Thomas E; Amasino, Richard; Caicedo, Ana L; Goodstein, David; Davidson, Patrick; Mur, Luis A J; Figueroa, Melania; Freeling, Michael; Catalan, Pilar; Vogel, John P

2017-12-19

While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely to be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution.

Apoptotic transition of senescent cells accompanied with mitochondrial hyper-function

PubMed Central

Wang, Danli; Liu, Yang; Zhang, Rui; Zhang, Fen; Sui, Weihao; Chen, Li; Zheng, Ran; Chen, Xiaowen; Wen, Feiqiu; Ouyang, Hong-Wei; Ji, Junfeng

2016-01-01

Defined as stable cell-cycle arrest, cellular senescence plays an important role in diverse biological processes including tumorigenesis, organismal aging, and embryonic development. Although increasing evidence has documented the metabolic changes in senescent cells, mitochondrial function and its potential contribution to the fate of senescent cells remain largely unknown. Here, using two in vitro models of cellular senescence induced by doxorubicin treatment and prolonged passaging of neonatal human foreskin fibroblasts, we report that senescent cells exhibited high ROS level and augmented glucose metabolic rate concomitant with both morphological and quantitative changes of mitochondria. Furthermore, mitochondrial membrane potential depolarized at late stage of senescent cells which eventually led to apoptosis. Our study reveals that mitochondrial hyper-function contributes to the implementation of cellular senescence and we propose a model in which the mitochondrion acts as the key player in promoting fate-determination in senescent cells. PMID:27056883

Chia Oil Extraction Coproduct as a Potential New Ingredient for the Food Industry: Chemical, Physicochemical, Techno-Functional and Antioxidant Properties.

PubMed

Fernández-López, Juana; Lucas-González, Raquel; Viuda-Martos, Manuel; Sayas-Barberá, Estrella; Pérez-Alvarez, José Angel

2018-06-01

The aim of this work was to characterize the coproduct obtained from chia oil production (cold-pressing) with a view to its possible application in new food product development. For this characterization, the following determinations were made: proximate composition, physicochemical analysis, techno-functional properties, total phenolic and flavonoid content, polyphenolic profile and antioxidant capacity (using four different methods). Chia coproduct showed significantly higher levels of proteins and total dietary fiber and lower levels of fats than chia seeds, pointing to the promising nature of this coproduct as an ingredient of food formulations since it remains a source of high biological value proteins and total dietary fiber (as chia seeds themselves) but with a lower energy value. This chia coproduct presents similar techno-functional properties to the original chia seeds and significantly higher levels of polyphenolic compounds and, consequently, higher antioxidant activity.

RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response.

PubMed

Lee, Yuan-Cho; Zhou, Qing; Chen, Junjie; Yuan, Jingsong

2016-12-19

ETAA1 (Ewing tumor-associated antigen 1), also known as ETAA16, was identified as a tumor-specific antigen in the Ewing family of tumors. However, the biological function of this protein remains unknown. Here, we report the identification of ETAA1 as a DNA replication stress response protein. ETAA1 specifically interacts with RPA (Replication protein A) via two conserved RPA-binding domains and is therefore recruited to stalled replication forks. Interestingly, further analysis of ETAA1 function revealed that ETAA1 participates in the activation of ATR signaling pathway via a conserved ATR-activating domain (AAD) located near its N terminus. Importantly, we demonstrate that both RPA binding and ATR activation are required for ETAA1 function at stalled replication forks to maintain genome stability. Therefore, our data suggest that ETAA1 is a new ATR activator involved in replication checkpoint control. Copyright © 2016 Elsevier Ltd. All rights reserved.

Virus-Based MicroRNA Silencing in Plants1[C][W][OPEN

PubMed Central

Sha, Aihua; Zhao, Jinping; Yin, Kangquan; Tang, Yang; Wang, Yan; Wei, Xiang; Hong, Yiguo; Liu, Yule

2014-01-01

MicroRNAs (miRNAs) play pivotal roles in various biological processes across kingdoms. Many plant miRNAs have been experimentally identified or predicted by bioinformatics mining of small RNA databases. However, the functions of these miRNAs remain largely unknown due to the lack of effective genetic tools. Here, we report a virus-based microRNA silencing (VbMS) system that can be used for functional analysis of plant miRNAs. VbMS is performed through tobacco rattle virus-based expression of miRNA target mimics to silence endogenous miRNAs. VbMS of either miR172 or miR165/166 caused developmental defects in Nicotiana benthamiana. VbMS of miR319 reduced the complexity of tomato (Solanum lycopersicum) compound leaves. These results demonstrate that tobacco rattle virus-based VbMS is a powerful tool to silence endogenous miRNAs and to dissect their functions in different plant species. PMID:24296072

Extensive gene content variation in the Brachypodium distachyon pan-genome correlates with population structure

DOE PAGES

Gordon, Sean P.; Contreras-Moreira, Bruno; Woods, Daniel P.; ...

2017-12-19

While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely tomore » be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution.« less

Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase.

PubMed

Tang, Jing; Vernekar, Sanjeev Kumar V; Chen, Yue-Lei; Miller, Lena; Huber, Andrew D; Myshakina, Nataliya; Sarafianos, Stefan G; Parniak, Michael A; Wang, Zhengqiang

2017-06-16

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Seeking the chemical roots of darwinism: bridging between chemistry and biology.

PubMed

Pross, Addy

2009-08-24

Chemistry and biology are intimately connected sciences yet the chemistry-biology interface remains problematic and central issues regarding the very essence of living systems remain unresolved. In this essay we build on a kinetic theory of replicating systems that encompasses the idea that there are two distinct kinds of stability in nature-thermodynamic stability, associated with "regular" chemical systems, and dynamic kinetic stability, associated with replicating systems. That fundamental distinction is utilized to bridge between chemistry and biology by demonstrating that within the parallel world of replicating systems there is a second law analogue to the second law of thermodynamics, and that Darwinian theory may, through scientific reductionism, be related to that second law analogue. Possible implications of these ideas to the origin of life problem and the relationship between chemical emergence and biological evolution are discussed.

Structural and Functional Loss in Restored Wetland Ecosystems

PubMed Central

Moreno-Mateos, David; Power, Mary E.; Comín, Francisco A.; Yockteng, Roxana

2012-01-01

Wetlands are among the most productive and economically valuable ecosystems in the world. However, because of human activities, over half of the wetland ecosystems existing in North America, Europe, Australia, and China in the early 20th century have been lost. Ecological restoration to recover critical ecosystem services has been widely attempted, but the degree of actual recovery of ecosystem functioning and structure from these efforts remains uncertain. Our results from a meta-analysis of 621 wetland sites from throughout the world show that even a century after restoration efforts, biological structure (driven mostly by plant assemblages), and biogeochemical functioning (driven primarily by the storage of carbon in wetland soils), remained on average 26% and 23% lower, respectively, than in reference sites. Either recovery has been very slow, or postdisturbance systems have moved towards alternative states that differ from reference conditions. We also found significant effects of environmental settings on the rate and degree of recovery. Large wetland areas (>100 ha) and wetlands restored in warm (temperate and tropical) climates recovered more rapidly than smaller wetlands and wetlands restored in cold climates. Also, wetlands experiencing more (riverine and tidal) hydrologic exchange recovered more rapidly than depressional wetlands. Restoration performance is limited: current restoration practice fails to recover original levels of wetland ecosystem functions, even after many decades. If restoration as currently practiced is used to justify further degradation, global loss of wetland ecosystem function and structure will spread. PMID:22291572

Measuring job stress among hospital nurses: an attempt to identify biological markers.

PubMed

Kawaguchi, Yoshichika; Toyomasu, Kouji; Yoshida, Noriko; Baba, Kaori; Uemoto, Masaharu; Minota, Shoichi

2007-02-01

The purpose of this study was to identify biological markers corresponding to job stress among hospital nurses. The subjects of this study were 128 nurses working at a university hospital. The NIOSH job stress questionnaire and the Miki Nurse Stressor 35-item Scale measured their job stress levels. The GHQ28 was also used to measure the subjects' general mental health status. Blood analyses for neuroendocrine function and immunity reaction were performed in order to identify biological markers of job stress. Stress is related to the plasma levels of catecholamine, cortisol, adrenocorticotrophic hormone, and natural killer cell activity, therefore these factors were measured accordingly. In consideration to circadian rhythms, blood was collected from the subjects prior to the start of the day shift. The nurses filled out the questionnaires on the day of the blood tests. In order to investigate the correlation between job stress reactions indicated by the questionnaires and the results of the blood tests, we utilized Pearson's correlation coefficient and partial correlation coefficient for which other affected items were controlled. In this study, significant correlations were found between job stress and biological factors; however, the correlations were not strong. Thus, it can be said that the biological markers associated with a specific kind of job stress remain unclear. In the future, rather than implementing a simple cross-sectional study, a longitudinal study including follow-up research will be more effective in establishing biological markers for job stress.

Surface tension in human pathophysiology and its application as a medical diagnostic tool

PubMed Central

Fathi-Azarbayjani, Anahita; Jouyban, Abolghasem

2015-01-01

Introduction: Pathological features of disease appear to be quite different. Despite this diversity, the common feature of various disorders underlies physicochemical and biochemical factors such as surface tension. Human biological fluids comprise various proteins and phospholipids which are capable of adsorption at fluid interfaces and play a vital role in the physiological function of human organs. Surface tension of body fluids correlates directly to the development of pathological states. Methods: In this review, the variety of human diseases mediated by the surface tension changes of biological phenomena and the failure of biological fluids to remain in their native state are discussed. Results: Dynamic surface tension measurements of human biological fluids depend on various parameters such as sex, age and changes during pregnancy or certain disease. It is expected that studies of surface tension behavior of human biological fluids will provide additional information and might become useful in medical practice. Theoretical background on surface tension measurement and surface tension values of reference fluids obtained from healthy and sick patients are depicted. Conclusion: It is well accepted that no single biomarker will be effective in clinical diagnosis. The surface tension measurement combined with routine lab tests may be a novel non-invasive method which can not only facilitate the discovery of diagnostic models for various diseases and its severity, but also be a useful tool for monitoring treatment efficacy. We therefore expect that studies of surface tension behavior of human biological fluids will provide additional useful information in medical practice. PMID:25901295

Integrated assessment of oil pollution using biological monitoring and chemical fingerprinting.

PubMed

Lewis, Ceri; Guitart, Carlos; Pook, Chris; Scarlett, Alan; Readman, James W; Galloway, Tamara S

2010-06-01

A full assessment of the impact of oil and chemical spills at sea requires the identification of both the polluting chemicals and the biological effects they cause. Here, a combination of chemical fingerprinting of surface oils, tissue residue analysis, and biological effects measures was used to explore the relationship between spilled oil and biological impact following the grounding of the MSC Napoli container ship in Lyme Bay, England in January 2007. Initially, oil contamination remained restricted to a surface slick in the vicinity of the wreck, and there was no chemical evidence to link biological impairment of animals (the common limpet, Patella vulgata) on the shore adjacent to the oil spill. Secondary oil contamination associated with salvage activities in July 2007 was also assessed. Chemical analyses of aliphatic hydrocarbons and terpanes in shell swabs taken from limpet shells provided an unequivocal match with the fuel oil carried by the ship. Corresponding chemical analysis of limpet tissues revealed increased concentrations of polycyclic aromatic hydrocarbons (PAHs) dominated by phenanthrene and C1 to C3 phenanthrenes with smaller contributions from heavier molecular weight PAHs. Concurrent ecotoxicological tests indicated impairment of cellular viability (p < 0.001), reduced immune function (p < 0.001), and damage to DNA (Comet assay, p < 0.001) in these animals, whereas antioxidant defenses were elevated relative to un-oiled animals. These results illustrate the value of combining biological monitoring with chemical fingerprinting for the rapid identification of spilled oils and their sublethal impacts on biota in situ. Copyright 2010 SETAC.

Reading about the actions of others: biological motion imagery and action congruency influence brain activity.

PubMed

Deen, Ben; McCarthy, Gregory

2010-05-01

Prior neuroimaging research has implicated regions within and near the posterior superior temporal sulcus (pSTS) in the visual processing of biological motion and of the intentions implied by specific movements. However, it is unknown whether this region is engaged during the processing of human motion at a conceptual level, such as during story comprehension. Here, we obtained functional magnetic resonance images from subjects reading brief stories that described a human character's background and then concluded with an action or decision made by the character. Half of the stories contained incidental descriptions of biological motion (such as the character's walking or grasping) while the remaining half did not. As a second factor, the final action of the story was either congruent or incongruent with the character's background and implied goals and intentions. Stories that contained biological motion strongly activated the pSTS bilaterally, along with ventral temporal areas, premotor cortex, left motor cortex, and the precuneus. Active regions of pSTS in individual subjects closely overlapped with regions identified with a separate biological motion localizer (point-light display) task. Reading incongruent versus congruent stories activated dorsal anterior cingulate cortex and bilateral anterior insula. These results support the hypothesis that reading can engage higher visual cortex in a content-specific manner, and suggest that the presence of biological motion should be controlled as a potential confound in fMRI studies using story comprehension tasks. 2010. Published by Elsevier Ltd.

Biological life-support systems

NASA Technical Reports Server (NTRS)

Shepelev, Y. Y.

1975-01-01

The establishment of human living environments by biologic methods, utilizing the appropriate functions of autotrophic and heterotrophic organisms is examined. Natural biologic systems discussed in terms of modeling biologic life support systems (BLSS), the structure of biologic life support systems, and the development of individual functional links in biologic life support systems are among the factors considered. Experimental modeling of BLSS in order to determine functional characteristics, mechanisms by which stability is maintained, and principles underlying control and regulation is also discussed.

Biological effects due to weak magnetic field on plants

NASA Astrophysics Data System (ADS)

Belyavskaya, N. A.

2004-01-01

Throughout the evolution process, Earth's magnetic field (MF, about 50 μT) was a natural component of the environment for living organisms. Biological objects, flying on planned long-term interplanetary missions, would experience much weaker magnetic fields, since galactic MF is known to be 0.1-1 nT. However, the role of weak magnetic fields and their influence on functioning of biological organisms are still insufficiently understood, and is actively studied. Numerous experiments with seedlings of different plant species placed in weak magnetic field have shown that the growth of their primary roots is inhibited during early germination stages in comparison with control. The proliferative activity and cell reproduction in meristem of plant roots are reduced in weak magnetic field. Cell reproductive cycle slows down due to the expansion of G 1 phase in many plant species (and of G 2 phase in flax and lentil roots), while other phases of cell cycle remain relatively stabile. In plant cells exposed to weak magnetic field, the functional activity of genome at early pre-replicate period is shown to decrease. Weak magnetic field causes intensification of protein synthesis and disintegration in plant roots. At ultrastructural level, changes in distribution of condensed chromatin and nucleolus compactization in nuclei, noticeable accumulation of lipid bodies, development of a lytic compartment (vacuoles, cytosegresomes and paramural bodies), and reduction of phytoferritin in plastids in meristem cells were observed in pea roots exposed to weak magnetic field. Mitochondria were found to be very sensitive to weak magnetic field: their size and relative volume in cells increase, matrix becomes electron-transparent, and cristae reduce. Cytochemical studies indicate that cells of plant roots exposed to weak magnetic field show Ca 2+ over-saturation in all organelles and in cytoplasm unlike the control ones. The data presented suggest that prolonged exposures of plants to weak magnetic field may cause different biological effects at the cellular, tissue and organ levels. They may be functionally related to systems that regulate plant metabolism including the intracellular Ca 2+ homeostasis. However, our understanding of very complex fundamental mechanisms and sites of interactions between weak magnetic fields and biological systems is still incomplete and still deserve strong research efforts.

Integrin-Linked Kinase Is Indispensable for Keratinocyte Differentiation and Epidermal Barrier Function.

PubMed

Sayedyahossein, Samar; Rudkouskaya, Alena; Leclerc, Valerie; Dagnino, Lina

2016-02-01

A functional permeability barrier is essential to prevent the passage of water and electrolytes, macromolecules, and pathogens through the epidermis. This is accomplished in terminally differentiated keratinocytes through formation of a cornified envelope and the assembly of tight intercellular junctions. Integrin-linked kinase (ILK) is a scaffold protein essential for hair follicle morphogenesis and epidermal attachment to the basement membrane. However, the biological functions of ILK in differentiated keratinocytes remain poorly understood. Furthermore, whether ILK is implicated in keratinocyte differentiation and intercellular junction formation has remained an unresolved issue. Here we describe a pivotal role for ILK in keratinocyte differentiation responses to increased extracellular Ca(2+), regulation of adherens and tight junction assembly, and the formation of an outside-in permeability barrier toward macromolecules. In the absence of ILK, the calcium sensing receptor, E-cadherin, and ZO-1 fail to translocate to the cell membrane, through mechanisms that involve abnormalities in microtubules and in RhoA activation. In situ, ILK-deficient epidermis exhibits reduced tight junction formation and increased outside-in permeability to a dextran tracer, indicating reduced barrier properties toward macromolecules. Therefore, ILK is an essential component of keratinocyte differentiation programs that contribute to epidermal integrity and the establishment of its barrier properties. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Long Noncoding RNAs in Lung Cancer.

PubMed

Roth, Anna; Diederichs, Sven

2016-01-01

Despite great progress in research and treatment options, lung cancer remains the leading cause of cancer-related deaths worldwide. Oncogenic driver mutations in protein-encoding genes were defined and allow for personalized therapies based on genetic diagnoses. Nonetheless, diagnosis of lung cancer mostly occurs at late stages, and chronic treatment is followed by a fast onset of chemoresistance. Hence, there is an urgent need for reliable biomarkers and alternative treatment options. With the era of whole genome and transcriptome sequencing technologies, long noncoding RNAs emerged as a novel class of versatile, functional RNA molecules. Although for most of them the mechanism of action remains to be defined, accumulating evidence confirms their involvement in various aspects of lung tumorigenesis. They are functional on the epigenetic, transcriptional, and posttranscriptional level and are regulators of pathophysiological key pathways including cell growth, apoptosis, and metastasis. Long noncoding RNAs are gaining increasing attention as potential biomarkers and a novel class of druggable molecules. It has become clear that we are only beginning to understand the complexity of tumorigenic processes. The clinical integration of long noncoding RNAs in terms of prognostic and predictive biomarker signatures and additional cancer targets could provide a chance to increase the therapeutic benefit. Here, we review the current knowledge about the expression, regulation, biological function, and clinical relevance of long noncoding RNAs in lung cancer.

Co-occurrence of linguistic and biological diversity in biodiversity hotspots and high biodiversity wilderness areas

PubMed Central

Gorenflo, L. J.; Romaine, Suzanne; Mittermeier, Russell A.; Walker-Painemilla, Kristen

2012-01-01

As the world grows less biologically diverse, it is becoming less linguistically and culturally diverse as well. Biologists estimate annual loss of species at 1,000 times or more greater than historic rates, and linguists predict that 50–90% of the world’s languages will disappear by the end of this century. Prior studies indicate similarities in the geographic arrangement of biological and linguistic diversity, although conclusions have often been constrained by use of data with limited spatial precision. Here we use greatly improved datasets to explore the co-occurrence of linguistic and biological diversity in regions containing many of the Earth’s remaining species: biodiversity hotspots and high biodiversity wilderness areas. Results indicate that these regions often contain considerable linguistic diversity, accounting for 70% of all languages on Earth. Moreover, the languages involved are frequently unique (endemic) to particular regions, with many facing extinction. Likely reasons for co-occurrence of linguistic and biological diversity are complex and appear to vary among localities, although strong geographic concordance between biological and linguistic diversity in many areas argues for some form of functional connection. Languages in high biodiversity regions also often co-occur with one or more specific conservation priorities, here defined as endangered species and protected areas, marking particular localities important for maintaining both forms of diversity. The results reported in this article provide a starting point for focused research exploring the relationship between biological and linguistic–cultural diversity, and for developing integrated strategies designed to conserve species and languages in regions rich in both. PMID:22566626

Co-occurrence of linguistic and biological diversity in biodiversity hotspots and high biodiversity wilderness areas.

PubMed

Gorenflo, L J; Romaine, Suzanne; Mittermeier, Russell A; Walker-Painemilla, Kristen

2012-05-22

As the world grows less biologically diverse, it is becoming less linguistically and culturally diverse as well. Biologists estimate annual loss of species at 1,000 times or more greater than historic rates, and linguists predict that 50-90% of the world's languages will disappear by the end of this century. Prior studies indicate similarities in the geographic arrangement of biological and linguistic diversity, although conclusions have often been constrained by use of data with limited spatial precision. Here we use greatly improved datasets to explore the co-occurrence of linguistic and biological diversity in regions containing many of the Earth's remaining species: biodiversity hotspots and high biodiversity wilderness areas. Results indicate that these regions often contain considerable linguistic diversity, accounting for 70% of all languages on Earth. Moreover, the languages involved are frequently unique (endemic) to particular regions, with many facing extinction. Likely reasons for co-occurrence of linguistic and biological diversity are complex and appear to vary among localities, although strong geographic concordance between biological and linguistic diversity in many areas argues for some form of functional connection. Languages in high biodiversity regions also often co-occur with one or more specific conservation priorities, here defined as endangered species and protected areas, marking particular localities important for maintaining both forms of diversity. The results reported in this article provide a starting point for focused research exploring the relationship between biological and linguistic-cultural diversity, and for developing integrated strategies designed to conserve species and languages in regions rich in both.

Pharmacotherapy for the soul and psychotherapy for the body.

PubMed

Groleger, Urban

2007-09-01

The "mind-body" dualism has shaped the development of psychiatry. At the very beginning psychiatry was related to the mind and the rest of the medicine to the body. The main reasons for such division were lack of biological evidence for psychiatric disorders and wrong beliefs about demonic origins of "lunacy". But although the development of science offered more than enough biological evidence to understand brain as an organ of origin for psychiatric disorders, the dualism of mind and body remained alive even in the modern classification systems. One of the consequences was another dualism that differ biological (e.g. pharmacotherapy) from psychological therapy (e.g. psychotherapy) as completely different approaches. The purpose of this article is to offer enough evidence to reframe the existing dualisms into a different paradigm. In every illness both mind and body can be affected to a different extent. Which part of an illness is body and which part is mind is often difficult to differentiate even when we compare a person with broken leg with a person with acute stress reaction. For that reason it might be an over-simplification to differentiate sharply between biological and psychological therapies. The evidence show that psychotherapy influences biology of the brain and that pharmacotherapy influences psychological, social and developmental dimensions of the diseased person as well as overall well-being and functionality. In the era where medicine discovered psychology and psychiatry discovered biology, the debates and divisions that steam out of past dualisms should end. Every practising physician regardless of the medical discipline uses in everyday practice both biological and psychological approaches to help the patient successfully.

Constructing New Bioorthogonal Reagents and Reactions.

PubMed

Row, R David; Prescher, Jennifer A

2018-05-15

Chemical tools are transforming our understanding of biomolecules and living systems. Included in this group are bioorthogonal reagents-functional groups that are inert to most biological species, but can be selectively ligated with complementary probes, even in live cells and whole organisms. Applications of these tools have revealed fundamental new insights into biomolecule structure and function-information often beyond the reach of genetic approaches. In many cases, the knowledge gained from bioorthogonal probes has enabled new questions to be asked and innovative research to be pursued. Thus, the continued development and application of these tools promises to both refine our view of biological systems and facilitate new discoveries. Despite decades of achievements in bioorthogonal chemistry, limitations remain. Several reagents are too large or insufficiently stable for use in cellular environments. Many bioorthogonal groups also cross-react with one another, restricting them to singular tasks. In this Account, we describe our work to address some of the voids in the bioorthogonal toolbox. Our efforts to date have focused on small reagents with a high degree of tunability: cyclopropenes, triazines, and cyclopropenones. These motifs react selectively with complementary reagents, and their unique features are enabling new pursuits in biology. The Account is organized by common themes that emerged in our development of novel bioorthogonal reagents and reactions. First, natural product structures can serve as valuable starting points for probe design. Cyclopropene, triazine, and cyclopropenone motifs are all found in natural products, suggesting that they would be metabolically stable and compatible with a variety of living systems. Second, fine-tuning bioorthogonal reagents is essential for their successful translation to biological systems. Different applications demand different types of probes; thus, generating a collection of tools that span a continuum of reactivities and stabilities remains an important goal. We have used both computational analyses and mechanistic studies to guide the optimization of various cyclopropene and triazine probes. Along the way, we identified reagents that are chemoselective but best suited for in vitro work. Others are selective and robust enough for use in living organisms. The last section of this Account highlights the need for the continued pursuit of new reagents and reactions. Challenges exist when bioorthogonal chemistries must be used in concert, given that many exploit similar mechanisms and cannot be used simultaneously. Such limitations have precluded certain multicomponent labeling studies and other biological applications. We have relied on mechanistic and computational insights to identify mutually orthogonal sets of reactions, in addition to exploring unique genres of reactivity. The continued development of mechanistically distinct, biocompatible reactions will further diversify the bioorthogonal reaction portfolio for examining biomolecules.

Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease.

PubMed

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre F R; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2015-07-01

Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. © 2015 American Heart Association, Inc.

Insights into Hox protein function from a large scale combinatorial analysis of protein domains.

PubMed

Merabet, Samir; Litim-Mecheri, Isma; Karlsson, Daniel; Dixit, Richa; Saadaoui, Mehdi; Monier, Bruno; Brun, Christine; Thor, Stefan; Vijayraghavan, K; Perrin, Laurent; Pradel, Jacques; Graba, Yacine

2011-10-01

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.

Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains

PubMed Central

Karlsson, Daniel; Dixit, Richa; Saadaoui, Mehdi; Monier, Bruno; Brun, Christine; Thor, Stefan; Vijayraghavan, K.; Perrin, Laurent; Pradel, Jacques; Graba, Yacine

2011-01-01

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences. PMID:22046139

The Ufm1 Cascade

PubMed Central

Daniel, Jens; Liebau, Eva

2014-01-01

The ubiquitin-fold modifier 1 (Ufm1) is a posttranslational modifier that belongs to the ubiquitin-like protein (UBL) family. Ufm1 is present in nearly all eukaryotic organisms, with the exception of fungi. It resembles ubiquitin in its ability to be ligated to other proteins, as well as in the mechanism of ligation. While the Ufm1 cascade has been implicated in endoplasmic reticulum functions and cell cycle control, its biological role still remains poorly understood. In this short review, we summarize the current state of Ufm1 research and its potential role in human diseases, like diabetes, ischemic heart disease and cancer. PMID:24921187

The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies.

PubMed

Kang, Chang Moo; Babicky, Michele L; Lowy, Andrew M

2014-03-01

Pancreatic cancer remains a devastating disease with a mortality rate that has not changed substantially in decades. Novel therapies are therefore desperately needed. The RON receptor tyrosine kinase has been identified as an important mediator of KRAS oncogene addiction and is overexpressed in the majority of pancreatic cancers. Preclinical studies show that inhibition of RON function decreases pancreatic cancer cell migration, invasion, and survival and can sensitize pancreatic cancer cells to chemotherapy. This article reviews the current state of knowledge regarding RON biology and pancreatic cancer and discusses its potential as a therapeutic target.

Bioluminescence in the Ocean: Origins of Biological, Chemical, and Ecological Diversity

NASA Astrophysics Data System (ADS)

Widder, E. A.

2010-05-01

From bacteria to fish, a remarkable variety of marine life depends on bioluminescence (the chemical generation of light) for finding food, attracting mates, and evading predators. Disparate biochemical systems and diverse phylogenetic distribution patterns of light-emitting organisms highlight the ecological benefits of bioluminescence, with biochemical and genetic analyses providing new insights into the mechanisms of its evolution. The origins and functions of some bioluminescent systems, however, remain obscure. Here, I review recent advances in understanding bioluminescence in the ocean and highlight future research efforts that will unite molecular details with ecological and evolutionary relationships.

Detection of Bacillus spores within 15 minutes by surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Shende, Chetan; Inscore, Frank; Huang, Hermes; Farquharson, Stuart; Sengupta, Atanu

2012-06-01

Since the distribution of Bacillus anthracis causing spores through the US Postal System, there has been a persistent fear that biological warfare agents (BWAs) will be used by terrorists against our military abroad and our civilians at home. Despite the substantial effort to develop BWA analyzers, they remain either too slow, produce high falsealarm rates, lack sensitivity, or cannot be fielded. Consequently there remains a need for a portable analyzer that can overcome these limitations as expressed at the 2011 Biological Weapons Convention. To meet this need we have been developing a sample system that selectively binds BWAs and produce surface-enhanced Raman (SER) spectra using portable Raman spectrometers. Here we describe the use of a short peptide ligand functionalized on silver nanoparticles to selectively capture Bacillus cereus spores (a surrogate of B. anthracis) and their subsequent detection by SER spectroscopy. This technique was used to specifically detect B. cereus spores over closely related species like B. subtilis belonging to the same genus within 15 minutes. Sensitivity of the method was demonstrated by detecting 104 B. cereus spores/mL of water. The technology, once developed should prove invaluable for rapid monitoring of BWAs, which will immensely help first responders and emergency personnel in implementing appropriate counter measures.

Platelet-rich plasma for regeneration of neural feedback pathways around dental implants: a concise review and outlook on future possibilities

PubMed Central

Huang, Yan; Bornstein, Michael M; Lambrichts, Ivo; Yu, Hai-Yang; Politis, Constantinus; Jacobs, Reinhilde

2017-01-01

Along with the development of new materials, advanced medical imaging and surgical techniques, osseointegrated dental implants are considered a successful and constantly evolving treatment modality for the replacement of missing teeth in patients with complete or partial edentulism. The importance of restoring the peripheral neural feedback pathway and thus repairing the lack of periodontal mechanoreceptors after tooth extraction has been highlighted in the literature. Nevertheless, regenerating the nerve fibers and reconstructing the neural feedback pathways around osseointegrated implants remain a challenge. Recent studies have provided evidence that platelet-rich plasma (PRP) therapy is a promising treatment for musculoskeletal injuries. Because of its high biological safety, convenience and usability, PRP therapy has gradually gained popularity in the clinical field. Although much remains to be learned, the growth factors from PRP might play key roles in peripheral nerve repair mechanisms. This review presents known growth factors contributing to the biological efficacy of PRP and illustrates basic and (pre-)clinical evidence regarding the use of PRP and its relevant products in peripheral nerve regeneration. In addition, the potential of local application of PRP for structural and functional recovery of injured peripheral nerves around dental implants is discussed. PMID:28282030

Interleukin-35: Expanding Its Job Profile

PubMed Central

Sawant, Deepali V.; Hamilton, Kristia

2015-01-01

Counter-regulation afforded by specialized regulatory cell populations and immunosuppressive cytokines is critical for balancing immune outcome. The inhibitory potential of the established suppressive cytokines, IL-10 and TGFβ, has been well elucidated in diverse inflammatory scenarios in conjunction with their key roles in Treg development and function. Despite the early predictions for an immunomodulatory role for the Ebi3/p35 heterodimer in placental trophoblasts, IL-35 biology remained elusive until 2007 when it was established as a Treg-restricted inhibitory cytokine. Since then, Treg-derived IL-35 has been shown to exhibit its suppressive activities in a range of autoimmune diseases and cancer models. Recent studies are beginning to explore other cellular sources of IL-35, such as Bregs and CD8+ Tregs. Despite these new cellular sources and targets, the mode of IL-35 suppression remains restricted to inhibition of proliferation and induction of an IL-35-producing induced regulatory T cell population referred to as iTr35. In this review, we explore the early beginnings, status quo, and future prospects of IL-35 biology. The unparalleled opportunity of targeting multiple immunosuppressive populations (Tregs, Bregs, CD8+ Tregs) through IL-35 is highly exciting and offers tremendous promise from a translational standpoint, particularly for cancer immunotherapies. PMID:25919641

pH-Sensitive polymer assisted self-aggregation of bis(pyrene) in living cells in situ with turn-on fluorescence

NASA Astrophysics Data System (ADS)

Duan, Zhongyu; Gao, Yu-Juan; Qiao, Zeng-Ying; Qiao, Shenglin; Wang, Yongmei; Hou, Chunyuan; Wang, Lei; Wang, Hao

2015-09-01

Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self-aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future.

Survivorship analysis when cure is a possibility: a Monte Carlo study.

PubMed

Goldman, A I

1984-01-01

Parametric survivorship analyses of clinical trials commonly involves the assumption of a hazard function constant with time. When the empirical curve obviously levels off, one can modify the hazard function model by use of a Gompertz or Weibull distribution with hazard decreasing over time. Some cancer treatments are thought to cure some patients within a short time of initiation. Then, instead of all patients having the same hazard, decreasing over time, a biologically more appropriate model assumes that an unknown proportion (1 - pi) have constant high risk whereas the remaining proportion (pi) have essentially no risk. This paper discusses the maximum likelihood estimation of pi and the power curves of the likelihood ratio test. Monte Carlo studies provide results for a variety of simulated trials; empirical data illustrate the methods.

The biology and function of exosomes in cancer

PubMed Central

Kalluri, Raghu

2016-01-01

Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40–150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes can be used as liquid biopsies and noninvasive biomarkers for early detection, diagnosis, and treatment of cancer patients. PMID:27035812

Goblet Cells of the Conjunctiva: A Review of Recent Findings

PubMed Central

Gipson, Ilene K

2016-01-01

Goblet cells within the conjunctival epithelium are specialized cells that secrete mucins onto the surface of the eye. Recent research has demonstrated new characteristics of the cells, including factors influencing their differentiation, their gene products and their functions at the ocular surface. The following review summarizes the newly discovered aspects of the role of Spdef, a member of the Ets transcription factor family in conjunctival goblet cell differentiation, the newly discovered goblet cell products including claudin2, the Wnt inhibitor Frzb, and the transmembrane mucin Muc16. The current concepts of conjunctival goblet cell function, including debris removal and immune surveillance are reviewed, as are changes in the goblet cell population in ocular surface diseases. Major remaining questions regarding conjunctival cell biology are discussed. PMID:27091323

Plant diversity and root traits benefit physical properties key to soil function in grasslands.

PubMed

Gould, Iain J; Quinton, John N; Weigelt, Alexandra; De Deyn, Gerlinde B; Bardgett, Richard D

2016-09-01

Plant diversity loss impairs ecosystem functioning, including important effects on soil. Most studies that have explored plant diversity effects belowground, however, have largely focused on biological processes. As such, our understanding of how plant diversity impacts the soil physical environment remains limited, despite the fundamental role soil physical structure plays in ensuring soil function and ecosystem service provision. Here, in both a glasshouse and a long-term field study, we show that high plant diversity in grassland systems increases soil aggregate stability, a vital structural property of soil, and that root traits play a major role in determining diversity effects. We also reveal that the presence of particular plant species within mixed communities affects an even wider range of soil physical processes, including hydrology and soil strength regimes. Our results indicate that alongside well-documented effects on ecosystem functioning, plant diversity and root traits also benefit essential soil physical properties. © 2016 The Authors Ecology Letters published by CNRS and John Wiley & Sons Ltd.

[Fine mapping of complex disease susceptibility loci].

PubMed

Song, Qingfeng; Zhang, Hongxing; Ma, Yilong; Zhou, Gangqiao

2014-01-01

Genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) markers have identified more than 3800 susceptibility loci for more than 660 diseases or traits. However, the most significantly associated variants or causative variants in these loci and their biological functions have remained to be clarified. These causative variants can help to elucidate the pathogenesis and discover new biomarkers of complex diseases. One of the main goals in the post-GWAS era is to identify the causative variants and susceptibility genes, and clarify their functional aspects by fine mapping. For common variants, imputation or re-sequencing based strategies were implemented to increase the number of analyzed variants and help to identify the most significantly associated variants. In addition, functional element, expression quantitative trait locus (eQTL) and haplotype analyses were performed to identify functional common variants and susceptibility genes. For rare variants, fine mapping was carried out by re-sequencing, rare haplotype analysis, family-based analysis, burden test, etc.This review summarizes the strategies and problems for fine mapping.

Regulation of T-cell receptor signalling by membrane microdomains

PubMed Central

Razzaq, Tahir M; Ozegbe, Patricia; Jury, Elizabeth C; Sembi, Phupinder; Blackwell, Nathan M; Kabouridis, Panagiotis S

2004-01-01

There is now considerable evidence suggesting that the plasma membrane of mammalian cells is compartmentalized by functional lipid raft microdomains. These structures are assemblies of specialized lipids and proteins and have been implicated in diverse biological functions. Analysis of their protein content using proteomics and other methods revealed enrichment of signalling proteins, suggesting a role for these domains in intracellular signalling. In T lymphocytes, structure/function experiments and complementary pharmacological studies have shown that raft microdomains control the localization and function of proteins which are components of signalling pathways regulated by the T-cell antigen receptor (TCR). Based on these studies, a model for TCR phosphorylation in lipid rafts is presented. However, despite substantial progress in the field, critical questions remain. For example, it is unclear if membrane rafts represent a homogeneous population and if their structure is modified upon TCR stimulation. In the future, proteomics and the parallel development of complementary analytical methods will undoubtedly contribute in further delineating the role of lipid rafts in signal transduction mechanisms. PMID:15554919

Can We Define and Characterize the Aging Lower Urinary Tract?—ICI-RS 2015

PubMed Central

Vahabi, Bahareh; Wagg, Adrian S.; Rosier, Peter F.W.M.; Rademakers, Kevin L.J.; Denys, Marie-Astrid; Pontari, Michel; Lovick, Thelma; Valentini, Francoise A.; Nelson, Pierre P.; Andersson, Karl-Erik; Fry, Christopher H.

2017-01-01

The prevalence of lower urinary tract (LUT) symptoms increases with age but the etiology is unknown. This article aims to identify research directions that clarify the basis of this association. The initial question is whether biological age is the variable of interest or a time-dependent accumulation of factors that impact on LUT function at rates that differ between individuals. In particular, the accumulation of conditions or agents due to inflammatory states or tissue ischemia is important. Much of the above has been concerned with changes to bladder function and morphology. However, the outflow tract function is also affected, in particular changes to the function of external sphincter skeletal muscle and associated sacral motor nerve control. Nocturia is a cardinal symptom of LUT dysfunction and is more prevalent with aging. Urine production is determined by diurnal changes to the production of certain hormones as well as arterial blood pressure and such diurnal rhythms are blunted in subjects with nocturia, but the causal links remain to be elucidated. Changes to the central nervous control of LUT function with age are also increasingly recognized, whether in mid-brain/ brainstem regions that directly affect LUT function or in higher centers that determine psychosocial and emotional factors impinging on the LUT. In particular, the linkage between increasing white matter hyperintensities and LUT dysfunction during aging is recognized but not understood. Overall, a more rational approach is being developed to link LUT dysfunction with factors that accumulate with age, however, the precise causal pathways remain to be characterized. PMID:28444710

The relativity of biological function.

PubMed

Laubichler, Manfred D; Stadler, Peter F; Prohaska, Sonja J; Nowick, Katja

2015-12-01

Function is a central concept in biological theories and explanations. Yet discussions about function are often based on a narrow understanding of biological systems and processes, such as idealized molecular systems or simple evolutionary, i.e., selective, dynamics. Conflicting conceptions of function continue to be used in the scientific literature to support certain claims, for instance about the fraction of "functional DNA" in the human genome. Here we argue that all biologically meaningful interpretations of function are necessarily context dependent. This implies that they derive their meaning as well as their range of applicability only within a specific theoretical and measurement context. We use this framework to shed light on the current debate about functional DNA and argue that without considering explicitly the theoretical and measurement contexts all attempts to integrate biological theories are prone to fail.

Exploring Mouse Protein Function via Multiple Approaches.

PubMed

Huang, Guohua; Chu, Chen; Huang, Tao; Kong, Xiangyin; Zhang, Yunhua; Zhang, Ning; Cai, Yu-Dong

2016-01-01

Although the number of available protein sequences is growing exponentially, functional protein annotations lag far behind. Therefore, accurate identification of protein functions remains one of the major challenges in molecular biology. In this study, we presented a novel approach to predict mouse protein functions. The approach was a sequential combination of a similarity-based approach, an interaction-based approach and a pseudo amino acid composition-based approach. The method achieved an accuracy of about 0.8450 for the 1st-order predictions in the leave-one-out and ten-fold cross-validations. For the results yielded by the leave-one-out cross-validation, although the similarity-based approach alone achieved an accuracy of 0.8756, it was unable to predict the functions of proteins with no homologues. Comparatively, the pseudo amino acid composition-based approach alone reached an accuracy of 0.6786. Although the accuracy was lower than that of the previous approach, it could predict the functions of almost all proteins, even proteins with no homologues. Therefore, the combined method balanced the advantages and disadvantages of both approaches to achieve efficient performance. Furthermore, the results yielded by the ten-fold cross-validation indicate that the combined method is still effective and stable when there are no close homologs are available. However, the accuracy of the predicted functions can only be determined according to known protein functions based on current knowledge. Many protein functions remain unknown. By exploring the functions of proteins for which the 1st-order predicted functions are wrong but the 2nd-order predicted functions are correct, the 1st-order wrongly predicted functions were shown to be closely associated with the genes encoding the proteins. The so-called wrongly predicted functions could also potentially be correct upon future experimental verification. Therefore, the accuracy of the presented method may be much higher in reality.

Exploring Mouse Protein Function via Multiple Approaches

PubMed Central

Huang, Tao; Kong, Xiangyin; Zhang, Yunhua; Zhang, Ning

2016-01-01

Although the number of available protein sequences is growing exponentially, functional protein annotations lag far behind. Therefore, accurate identification of protein functions remains one of the major challenges in molecular biology. In this study, we presented a novel approach to predict mouse protein functions. The approach was a sequential combination of a similarity-based approach, an interaction-based approach and a pseudo amino acid composition-based approach. The method achieved an accuracy of about 0.8450 for the 1st-order predictions in the leave-one-out and ten-fold cross-validations. For the results yielded by the leave-one-out cross-validation, although the similarity-based approach alone achieved an accuracy of 0.8756, it was unable to predict the functions of proteins with no homologues. Comparatively, the pseudo amino acid composition-based approach alone reached an accuracy of 0.6786. Although the accuracy was lower than that of the previous approach, it could predict the functions of almost all proteins, even proteins with no homologues. Therefore, the combined method balanced the advantages and disadvantages of both approaches to achieve efficient performance. Furthermore, the results yielded by the ten-fold cross-validation indicate that the combined method is still effective and stable when there are no close homologs are available. However, the accuracy of the predicted functions can only be determined according to known protein functions based on current knowledge. Many protein functions remain unknown. By exploring the functions of proteins for which the 1st-order predicted functions are wrong but the 2nd-order predicted functions are correct, the 1st-order wrongly predicted functions were shown to be closely associated with the genes encoding the proteins. The so-called wrongly predicted functions could also potentially be correct upon future experimental verification. Therefore, the accuracy of the presented method may be much higher in reality. PMID:27846315

In situ Proteomic Profiling of Curcumin Targets in HCT116 Colon Cancer Cell Line.

PubMed

Wang, Jigang; Zhang, Jianbin; Zhang, Chong-Jing; Wong, Yin Kwan; Lim, Teck Kwang; Hua, Zi-Chun; Liu, Bin; Tannenbaum, Steven R; Shen, Han-Ming; Lin, Qingsong

2016-02-26

To date, the exact targets and mechanism of action of curcumin, a natural product with anti-inflammatory and anti-cancer properties, remain elusive. Here we synthesized a cell permeable curcumin probe (Cur-P) with an alkyne moiety, which can be tagged with biotin for affinity enrichment, or with a fluorescent dye for visualization of the direct-binding protein targets of curcumin in situ. iTRAQ(TM) quantitative proteomics approach was applied to distinguish the specific binding targets from the non-specific ones. In total, 197 proteins were confidently identified as curcumin binding targets from HCT116 colon cancer cell line. Gene Ontology analysis showed that the targets are broadly distributed and enriched in the nucleus, mitochondria and plasma membrane, and they are involved in various biological functions including metabolic process, regulation, response to stimulus and cellular process. Ingenuity Pathway Analysis(TM) (IPA) suggested that curcumin may exert its anticancer effects over multiple critical biological pathways including the EIF2, eIF4/p70S6K, mTOR signaling and mitochondrial dysfunction pathways. Functional validations confirmed that curcumin downregulates cellular protein synthesis, and induces autophagy, lysosomal activation and increased ROS production, thus leading to cell death.

In situ Proteomic Profiling of Curcumin Targets in HCT116 Colon Cancer Cell Line

PubMed Central

Wang, Jigang; Zhang, Jianbin; Zhang, Chong-Jing; Wong, Yin Kwan; Lim, Teck Kwang; Hua, Zi-Chun; Liu, Bin; Tannenbaum, Steven R.; Shen, Han-Ming; Lin, Qingsong

2016-01-01

To date, the exact targets and mechanism of action of curcumin, a natural product with anti-inflammatory and anti-cancer properties, remain elusive. Here we synthesized a cell permeable curcumin probe (Cur-P) with an alkyne moiety, which can be tagged with biotin for affinity enrichment, or with a fluorescent dye for visualization of the direct-binding protein targets of curcumin in situ. iTRAQTM quantitative proteomics approach was applied to distinguish the specific binding targets from the non-specific ones. In total, 197 proteins were confidently identified as curcumin binding targets from HCT116 colon cancer cell line. Gene Ontology analysis showed that the targets are broadly distributed and enriched in the nucleus, mitochondria and plasma membrane, and they are involved in various biological functions including metabolic process, regulation, response to stimulus and cellular process. Ingenuity Pathway AnalysisTM (IPA) suggested that curcumin may exert its anticancer effects over multiple critical biological pathways including the EIF2, eIF4/p70S6K, mTOR signaling and mitochondrial dysfunction pathways. Functional validations confirmed that curcumin downregulates cellular protein synthesis, and induces autophagy, lysosomal activation and increased ROS production, thus leading to cell death. PMID:26915414

Predicting Protein Relationships to Human Pathways through a Relational Learning Approach Based on Simple Sequence Features.

PubMed

García-Jiménez, Beatriz; Pons, Tirso; Sanchis, Araceli; Valencia, Alfonso

2014-01-01

Biological pathways are important elements of systems biology and in the past decade, an increasing number of pathway databases have been set up to document the growing understanding of complex cellular processes. Although more genome-sequence data are becoming available, a large fraction of it remains functionally uncharacterized. Thus, it is important to be able to predict the mapping of poorly annotated proteins to original pathway models. We have developed a Relational Learning-based Extension (RLE) system to investigate pathway membership through a function prediction approach that mainly relies on combinations of simple properties attributed to each protein. RLE searches for proteins with molecular similarities to specific pathway components. Using RLE, we associated 383 uncharacterized proteins to 28 pre-defined human Reactome pathways, demonstrating relative confidence after proper evaluation. Indeed, in specific cases manual inspection of the database annotations and the related literature supported the proposed classifications. Examples of possible additional components of the Electron transport system, Telomere maintenance and Integrin cell surface interactions pathways are discussed in detail. All the human predicted proteins in the 2009 and 2012 releases 30 and 40 of Reactome are available at http://rle.bioinfo.cnio.es.

An Update on Cellular MicroRNA Expression in Human Papillomavirus-Associated Head and Neck Squamous Cell Carcinoma.

PubMed

Emmett, Sarah; Whiteman, David C; Panizza, Benedict J; Antonsson, Annika

2018-06-19

Squamous cell carcinoma of mucosal sites in the head and neck (HNSCC) is the sixth most common cause of cancer worldwide, and despite advances in conventional management, it still has significant morbidity and mortality associated with both diagnosis and treatment. Advances in our understanding of the biological mechanisms underlying this disease have demonstrated a significant difference between human papillomavirus (HPV)-associated, HPV and tobacco associated, and HPV-negative disease. It remains important to further elucidate the biologic and genetic differences between HPV-associated and tobacco-associated disease, with the aim of earlier diagnosis through screening, and advances in management including the development of novel therapeutic agents. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression, and have effects on almost every cellular function, and have potentially important applications to diagnosis, management and prognosis in HNSCC. Establishing a cellular miRNA expression profile for HPV-associated disease may therefore have important implications for the screening and treatment of this disease. This review summarises the current findings regarding miRNA expression in mucosal HNSCC, and focuses particularly on miRNA expression in HPV-associated tumours. © 2018 S. Karger AG, Basel.

Artificial specific binders directly recovered from chemically modified nucleic acid libraries.

PubMed

Kasahara, Yuuya; Kuwahara, Masayasu

2012-01-01

Specific binders comprised of nucleic acids, that is, RNA/DNA aptamers, are attractive functional biopolymers owing to their potential broad application in medicine, food hygiene, environmental analysis, and biological research. Despite the large number of reports on selection of natural DNA/RNA aptamers, there are not many examples of direct screening of chemically modified nucleic acid aptamers. This is because of (i) the inferior efficiency and accuracy of polymerase reactions involving transcription/reverse-transcription of modified nucleotides compared with those of natural nucleotides, (ii) technical difficulties and additional time and effort required when using modified nucleic acid libraries, and (iii) ambiguous efficacies of chemical modifications in binding properties until recently; in contrast, the effects of chemical modifications on biostability are well studied using various nucleotide analogs. Although reports on the direct screening of a modified nucleic acid library remain in the minority, chemical modifications would be essential when further functional expansion of nucleic acid aptamers, in particular for medical and biological uses, is considered. This paper focuses on enzymatic production of chemically modified nucleic acids and their application to random screenings. In addition, recent advances and possible future research are also described.

Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics.

PubMed

Ding, Wei; Palaiokostas, Michail; Wang, Wen; Orsi, Mario

2015-12-10

Biological bilayer membranes typically contain varying amounts of lamellar and nonlamellar lipids. Lamellar lipids, such as dioleoylphosphatidylcholine (DOPC), are defined by their tendency to form the lamellar phase, ubiquitous in biology. Nonlamellar lipids, such as dioleoylphosphatidylethanolamine (DOPE), prefer instead to form nonlamellar phases, which are mostly nonbiological. However, nonlamellar lipids mix with lamellar lipids in biomembrane structures that remain overall lamellar. Importantly, changes in the lamellar vs nonlamellar lipid composition are believed to affect membrane function and modulate membrane proteins. In this work, we employ atomistic molecular dynamics simulations to quantify how a range of bilayer properties are altered by variations in the lamellar vs nonlamellar lipid composition. Specifically, we simulate five DOPC/DOPE bilayers at mixing ratios of 1/0, 3/1, 1/1, 1/3, and 0/1. We examine properties including lipid area and bilayer thickness, as well as the transmembrane profiles of electron density, lateral pressure, electric field, and dipole potential. While the bilayer structure is only marginally altered by lipid composition changes, dramatic effects are observed for the lateral pressure, electric field, and dipole potential profiles. Possible implications for membrane function are discussed.

Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy.

PubMed

Loquet, Antoine; Tolchard, James; Berbon, Melanie; Martinez, Denis; Habenstein, Birgit

2017-09-17

Supramolecular protein assemblies play fundamental roles in biological processes ranging from host-pathogen interaction, viral infection to the propagation of neurodegenerative disorders. Such assemblies consist in multiple protein subunits organized in a non-covalent way to form large macromolecular objects that can execute a variety of cellular functions or cause detrimental consequences. Atomic insights into the assembly mechanisms and the functioning of those macromolecular assemblies remain often scarce since their inherent insolubility and non-crystallinity often drastically reduces the quality of the data obtained from most techniques used in structural biology, such as X-ray crystallography and solution Nuclear Magnetic Resonance (NMR). We here present magic-angle spinning solid-state NMR spectroscopy (SSNMR) as a powerful method to investigate structures of macromolecular assemblies at atomic resolution. SSNMR can reveal atomic details on the assembled complex without size and solubility limitations. The protocol presented here describes the essential steps from the production of 13 C/ 15 N isotope-labeled macromolecular protein assemblies to the acquisition of standard SSNMR spectra and their analysis and interpretation. As an example, we show the pipeline of a SSNMR structural analysis of a filamentous protein assembly.

Site-specific identification of heparan and chondroitin sulfate glycosaminoglycans in hybrid proteoglycans.

PubMed

Noborn, Fredrik; Gomez Toledo, Alejandro; Green, Anders; Nasir, Waqas; Sihlbom, Carina; Nilsson, Jonas; Larson, Göran

2016-10-03

Heparan sulfate (HS) and chondroitin sulfate (CS) are complex polysaccharides that regulate important biological pathways in virtually all metazoan organisms. The polysaccharides often display opposite effects on cell functions with HS and CS structural motifs presenting unique binding sites for specific ligands. Still, the mechanisms by which glycan biosynthesis generates complex HS and CS polysaccharides required for the regulation of mammalian physiology remain elusive. Here we present a glycoproteomic approach that identifies and differentiates between HS and CS attachment sites and provides identity to the core proteins. Glycopeptides were prepared from perlecan, a complex proteoglycan known to be substituted with both HS and CS chains, further digested with heparinase or chondroitinase ABC to reduce the HS and CS chain lengths respectively, and thereafter analyzed by nLC-MS/MS. This protocol enabled the identification of three consensus HS sites and one hybrid site, carrying either a HS or a CS chain. Inspection of the amino acid sequence at the hybrid attachment locus indicates that certain peptide motifs may encode for the chain type selection process. This analytical approach will become useful when addressing fundamental questions in basic biology specifically in elucidating the functional roles of site-specific glycosylations of proteoglycans.

Climate change and species interactions: ways forward.

PubMed

Angert, Amy L; LaDeau, Shannon L; Ostfeld, Richard S

2013-09-01

With ongoing and rapid climate change, ecologists are being challenged to predict how individual species will change in abundance and distribution, how biotic communities will change in structure and function, and the consequences of these climate-induced changes for ecosystem functioning. It is now well documented that indirect effects of climate change on species abundances and distributions, via climatic effects on interspecific interactions, can outweigh and even reverse the direct effects of climate. However, a clear framework for incorporating species interactions into projections of biological change remains elusive. To move forward, we suggest three priorities for the research community: (1) utilize tractable study systems as case studies to illustrate possible outcomes, test processes highlighted by theory, and feed back into modeling efforts; (2) develop a robust analytical framework that allows for better cross-scale linkages; and (3) determine over what time scales and for which systems prediction of biological responses to climate change is a useful and feasible goal. We end with a list of research questions that can guide future research to help understand, and hopefully mitigate, the negative effects of climate change on biota and the ecosystem services they provide. © 2013 New York Academy of Sciences.

Tissue vascularization through 3D printing: Will technology bring us flow?

PubMed

Paulsen, S J; Miller, J S

2015-05-01

Though in vivo models provide the most physiologically relevant environment for studying tissue function, in vitro studies provide researchers with explicit control over experimental conditions and the potential to develop high throughput testing methods. In recent years, advancements in developmental biology research and imaging techniques have significantly improved our understanding of the processes involved in vascular development. However, the task of recreating the complex, multi-scale vasculature seen in in vivo systems remains elusive. 3D bioprinting offers a potential method to generate controlled vascular networks with hierarchical structure approaching that of in vivo networks. Bioprinting is an interdisciplinary field that relies on advances in 3D printing technology along with advances in imaging and computational modeling, which allow researchers to monitor cellular function and to better understand cellular environment within the printed tissue. As bioprinting technologies improve with regards to resolution, printing speed, available materials, and automation, 3D printing could be used to generate highly controlled vascularized tissues in a high throughput manner for use in regenerative medicine and the development of in vitro tissue models for research in developmental biology and vascular diseases. © 2015 Wiley Periodicals, Inc.

No wisdom in the crowd: genome annotation in the era of big data - current status and future prospects.

PubMed

Danchin, Antoine; Ouzounis, Christos; Tokuyasu, Taku; Zucker, Jean-Daniel

2018-07-01

Science and engineering rely on the accumulation and dissemination of knowledge to make discoveries and create new designs. Discovery-driven genome research rests on knowledge passed on via gene annotations. In response to the deluge of sequencing big data, standard annotation practice employs automated procedures that rely on majority rules. We argue this hinders progress through the generation and propagation of errors, leading investigators into blind alleys. More subtly, this inductive process discourages the discovery of novelty, which remains essential in biological research and reflects the nature of biology itself. Annotation systems, rather than being repositories of facts, should be tools that support multiple modes of inference. By combining deduction, induction and abduction, investigators can generate hypotheses when accurate knowledge is extracted from model databases. A key stance is to depart from 'the sequence tells the structure tells the function' fallacy, placing function first. We illustrate our approach with examples of critical or unexpected pathways, using MicroScope to demonstrate how tools can be implemented following the principles we advocate. We end with a challenge to the reader. © 2018 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

Organization of inorganic nanomaterials via programmable DNA self-assembly and peptide molecular recognition.

PubMed

Carter, Joshua D; LaBean, Thomas H

2011-03-22

An interesting alternative to top-down nanofabrication is to imitate biology, where nanoscale materials frequently integrate organic molecules for self-assembly and molecular recognition with ordered, inorganic minerals to achieve mechanical, sensory, or other advantageous functions. Using biological systems as inspiration, researchers have sought to mimic the nanoscale composite materials produced in nature. Here, we describe a combination of self-assembly, molecular recognition, and templating, relying on an oligonucleotide covalently conjugated to a high-affinity gold-binding peptide. After integration of the peptide-coupled DNA into a self-assembling superstructure, the templated peptides recognize and bind gold nanoparticles. In addition to providing new ways of building functional multinanoparticle systems, this work provides experimental proof that a single peptide molecule is sufficient for immobilization of a nanoparticle. This molecular construction strategy, combining DNA assembly and peptide recognition, can be thought of as programmable, granular, artificial biomineralization. We also describe the important observation that the addition of 1-2% Tween 20 surfactant to the solution during gold particle binding allows the gold nanoparticles to remain soluble within the magnesium-containing DNA assembly buffer under conditions that usually lead to the aggregation and precipitation of the nanoparticles.

Human milk oligosaccharides: The role in the fine-tuning of innate immune responses.

PubMed

Kulinich, Anna; Liu, Li

2016-09-02

In order to secure the health of newborns over the period of immune immaturity during the first months of life, a mother provides her offspring with passive protection: bioactive molecules transferred through the placenta and breast milk. It is well known that human milk contains immunoglobulins (Ig), immune cells and diverse cytokines, which affect newborn directly or indirectly and contribute to the maturation of the immune system. However, in addition to the above-stated molecules, human milk oligosaccharides (HMOs), a complex mixture of free indigestible carbohydrates with multiple functions, play exceptional roles in the functioning of the infants' immune system. These biological molecules have been studied over decades, however, interest in HMOs does not seem to have abated. Although biological activities of oligosaccharides from human milk have been explicitly reviewed, information regarding the role of HMOs in inflammation remains rather fragmented. The purpose of this review is to compile existing knowledge about the role of certain species of HMOs, including fucosylated, galactosylated and sialylated oligosaccharides, and their signaling pathways in immunity and inflammation. The advances in applying this information to the treatment of diseases in infants as well as adults were also reviewed here. Copyright © 2016 Elsevier Ltd. All rights reserved.

Network motif frequency vectors reveal evolving metabolic network organisation.

PubMed

Pearcy, Nicole; Crofts, Jonathan J; Chuzhanova, Nadia

2015-01-01

At the systems level many organisms of interest may be described by their patterns of interaction, and as such, are perhaps best characterised via network or graph models. Metabolic networks, in particular, are fundamental to the proper functioning of many important biological processes, and thus, have been widely studied over the past decade or so. Such investigations have revealed a number of shared topological features, such as a short characteristic path-length, large clustering coefficient and hierarchical modular structure. However, the extent to which evolutionary and functional properties of metabolism manifest via this underlying network architecture remains unclear. In this paper, we employ a novel graph embedding technique, based upon low-order network motifs, to compare metabolic network structure for 383 bacterial species categorised according to a number of biological features. In particular, we introduce a new global significance score which enables us to quantify important evolutionary relationships that exist between organisms and their physical environments. Using this new approach, we demonstrate a number of significant correlations between environmental factors, such as growth conditions and habitat variability, and network motif structure, providing evidence that organism adaptability leads to increased complexities in the resultant metabolic networks.

GPR107, a G-protein-coupled receptor essential for intoxication by Pseudomonas aeruginosa exotoxin A, localizes to the Golgi and is cleaved by furin.

PubMed

Tafesse, Fikadu G; Guimaraes, Carla P; Maruyama, Takeshi; Carette, Jan E; Lory, Stephen; Brummelkamp, Thijn R; Ploegh, Hidde L

2014-08-29

A number of toxins, including exotoxin A (PE) of Pseudomonas aeruginosa, kill cells by inhibiting protein synthesis. PE kills by ADP-ribosylation of the translation elongation factor 2, but many of the host factors required for entry, membrane translocation, and intracellular transport remain to be elucidated. A genome-wide genetic screen in human KBM7 cells was performed to uncover host factors used by PE, several of which were confirmed by CRISPR/Cas9-gene editing in a different cell type. Several proteins not previously implicated in the PE intoxication pathway were identified, including GPR107, an orphan G-protein-coupled receptor. GPR107 localizes to the trans-Golgi network and is essential for retrograde transport. It is cleaved by the endoprotease furin, and a disulfide bond connects the two cleaved fragments. Compromising this association affects the function of GPR107. The N-terminal region of GPR107 is critical for its biological function. GPR107 might be one of the long-sought receptors that associates with G-proteins to regulate intracellular vesicular transport. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Discovery of new candidate genes related to brain development using protein interaction information.

PubMed

Chen, Lei; Chu, Chen; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

2015-01-01

Human brain development is a dramatic process composed of a series of complex and fine-tuned spatiotemporal gene expressions. A good comprehension of this process can assist us in developing the potential of our brain. However, we have only limited knowledge about the genes and gene functions that are involved in this biological process. Therefore, a substantial demand remains to discover new brain development-related genes and identify their biological functions. In this study, we aimed to discover new brain-development related genes by building a computational method. We referred to a series of computational methods used to discover new disease-related genes and developed a similar method. In this method, the shortest path algorithm was executed on a weighted graph that was constructed using protein-protein interactions. New candidate genes fell on at least one of the shortest paths connecting two known genes that are related to brain development. A randomization test was then adopted to filter positive discoveries. Of the final identified genes, several have been reported to be associated with brain development, indicating the effectiveness of the method, whereas several of the others may have potential roles in brain development.

Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics.

PubMed

Chen, Caressa; Termglinchan, Vittavat; Karakikes, Ioannis

2017-05-01

Heart failure (HF), a common sequela of cardiovascular diseases, remains a staggering clinical problem, associated with high rates of morbidity and mortality worldwide. Advances in pharmacological, interventional, and operative management have improved patient care, but these interventions are insufficient to halt the progression of HF, particularly the end-stage irreversible loss of functional cardiomyocytes. Innovative therapies that could prevent HF progression and improve the function of the failing heart are urgently needed. Following successful preclinical studies, two main strategies have emerged as potential solutions: cardiac gene therapy and cardiac regeneration through stem and precursor cell transplantation. Many potential gene- and cell-based therapies have entered into clinical studies, intending to ameliorate cardiac dysfunction in patients with advanced HF. In this review, we focus on the recent advances in cell- and gene-based therapies in the context of cardiovascular disease, emphasizing the most advanced therapies. The principles and mechanisms of action of gene and cell therapies for HF are discussed along with the limitations of current approaches. Finally, we highlight the emerging technologies that hold promise to revolutionize the biological therapies for cardiovascular diseases. Stem Cells 2017;35:1131-1140. © 2017 AlphaMed Press.

Secapin, a bee venom peptide, exhibits anti-fibrinolytic, anti-elastolytic, and anti-microbial activities.

PubMed

Lee, Kwang Sik; Kim, Bo Yeon; Yoon, Hyung Joo; Choi, Yong Soo; Jin, Byung Rae

2016-10-01

Bee venom contains a variety of peptide constituents that have various biological, toxicological, and pharmacological actions. However, the biological actions of secapin, a venom peptide in bee venom, remain largely unknown. Here, we provide the evidence that Asiatic honeybee (Apis cerana) secapin (AcSecapin-1) exhibits anti-fibrinolytic, anti-elastolytic, and anti-microbial activities. The recombinant mature AcSecapin-1 peptide was expressed in baculovirus-infected insect cells. AcSecapin-1 functions as a serine protease inhibitor-like peptide that has inhibitory effects against plasmin, elastases, microbial serine proteases, trypsin, and chymotrypsin. Consistent with these functions, AcSecapin-1 inhibited the plasmin-mediated degradation of fibrin to fibrin degradation products, thus indicating the role of AcSecapin-1 as an anti-fibrinolytic agent. AcSecapin-1 also inhibited both human neutrophil and porcine pancreatic elastases. Furthermore, AcSecapin-1 bound to bacterial and fungal surfaces and exhibited anti-microbial activity against fungi and gram-positive and gram-negative bacteria. Taken together, our data demonstrated that the bee venom peptide secapin has multifunctional roles as an anti-fibrinolytic agent during fibrinolysis and an anti-microbial agent in the innate immune response. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

PubMed Central

Ten, Vadim S.

2017-01-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units—alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise. PMID:27901512

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants.

PubMed

Ten, Vadim S

2017-02-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

A new method to improve network topological similarity search: applied to fold recognition

PubMed Central

Lhota, John; Hauptman, Ruth; Hart, Thomas; Ng, Clara; Xie, Lei

2015-01-01

Motivation: Similarity search is the foundation of bioinformatics. It plays a key role in establishing structural, functional and evolutionary relationships between biological sequences. Although the power of the similarity search has increased steadily in recent years, a high percentage of sequences remain uncharacterized in the protein universe. Thus, new similarity search strategies are needed to efficiently and reliably infer the structure and function of new sequences. The existing paradigm for studying protein sequence, structure, function and evolution has been established based on the assumption that the protein universe is discrete and hierarchical. Cumulative evidence suggests that the protein universe is continuous. As a result, conventional sequence homology search methods may be not able to detect novel structural, functional and evolutionary relationships between proteins from weak and noisy sequence signals. To overcome the limitations in existing similarity search methods, we propose a new algorithmic framework—Enrichment of Network Topological Similarity (ENTS)—to improve the performance of large scale similarity searches in bioinformatics. Results: We apply ENTS to a challenging unsolved problem: protein fold recognition. Our rigorous benchmark studies demonstrate that ENTS considerably outperforms state-of-the-art methods. As the concept of ENTS can be applied to any similarity metric, it may provide a general framework for similarity search on any set of biological entities, given their representation as a network. Availability and implementation: Source code freely available upon request Contact: lxie@iscb.org PMID:25717198

CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells.

PubMed

Lupia, Michela; Angiolini, Francesca; Bertalot, Giovanni; Freddi, Stefano; Sachsenmeier, Kris F; Chisci, Elisa; Kutryb-Zajac, Barbara; Confalonieri, Stefano; Smolenski, Ryszard T; Giovannoni, Roberto; Colombo, Nicoletta; Bianchi, Fabrizio; Cavallaro, Ugo

2018-04-10

Cancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role of ovarian CICs (OCICs) remain elusive. Here, we have capitalized on primary cells either from OC or from its tissues of origin to obtain the transcriptomic profile associated with OCICs. Among the genes differentially expressed in OCICs, we focused on CD73, which encodes the membrane-associated 5'-ectonucleotidase. The genetic inactivation of CD73 in OC cells revealed that this molecule is causally involved in sphere formation and tumor initiation, thus emerging as a driver of OCIC function. Furthermore, functional inhibition of CD73 via either a chemical compound or a neutralizing antibody reduced sphere formation and tumorigenesis, highlighting the druggability of CD73 in the context of OCIC-directed therapies. The biological function of CD73 in OCICs required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCIC function at the transcriptional level. CD73, therefore, is involved in OCIC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Development of soil chemical and biological properties in the initial stages of post-mining deposition sites.

PubMed

Monokrousos, Nikolaos; Boutsis, George; Diamantopoulos, John D

2014-12-01

The aim of this study was to assess the seasonal development of the physicochemical (pH, organic C, organic N, extractable P, Ca(2+), Mg(2+)) and biological soil properties (microbial biomass, activities of urease, dehydrogenase and alkaline phosphatase) of the topsoil of mine deposition sites that differed based on the material used exclusively for their creation: (a) marlstones, (b) red-grey formations (RGF), and (c) fly ash (FA), during the first year after their creation. Our hypothesis was that all deposition sites, regardless the material they consist of, present equal opportunities for the establishment of spontaneous vegetation. All macronutrients concentrations (P, Ca(2+), and Mg(2+)) remained constant with time and were found to be higher in the FA sites. Organic C, organic N, all enzyme activities, and microbial biomass were higher in the RGF and marl depositions, with marl sites presenting the highest values. All values of biological variables, with the exception of alkaline phosphatase, increased with time. The alkaline environment along with the slow improvement in soil biological properties of the FA sites seemed to present the most unfavorable conditions for spontaneous vegetation growth. On the contrary, the other two spoil materials presented significant improvement in the initial stages of soil formation in terms of soil functionality.

Genomics, systems biology and drug development for infectious diseases.

PubMed

Sakata, Tomoyo; Winzeler, Elizabeth A

2007-12-01

Although a variety of drugs are available for many infectious diseases that predominantly affect the developing world reasons remain for continuing to search for new chemotherapeutics. First, the development of microbial resistance has made some of the most effective and inexpensive drug regimes unreliable and dangerous to use on severely ill patients. Second, many existing antimicrobial drugs show toxicity or are too expensive for countries where the per capita income is in the order of hundreds of dollars per year. In recognition of this, new publicly and privately financed drug discovery efforts have been established to identify and develop new therapies for diseases such as tuberculosis, malaria and AIDS. This in turn, has intensified the need for tools to facilitate drug identification for those microbes whose molecular biology is poorly understood, or which are difficult to grow in the laboratory. While much has been written about how functional genomics can be used to find novel protein targets for chemotherapeutics this review will concentrate on how genome-wide, systems biology approaches may be used following whole organism, cell-based screening to understand the mechanism of drug action or to identify biological targets of small molecules. Here we focus on protozoan parasites, however, many of the approaches can be applied to pathogenic bacteria or parasitic helminths, insects or disease-causing fungi.

Lysine-functionalized nanodiamonds as gene carriers: development of stable colloidal dispersion for in vitro cellular uptake studies and siRNA delivery application

PubMed Central

Alwani, Saniya; Kaur, Randeep; Michel, Deborah; Chitanda, Jackson M; Verrall, Ronald E; Karunakaran, Chithra; Badea, Ildiko

2016-01-01

Purpose Nanodiamonds (NDs) are emerging as an attractive tool for gene therapeutics. To reach their full potential for biological application, NDs should maintain their colloidal stability in biological milieu. This study describes the behavior of lysine-functionalized ND (lys-ND) in various dispersion media, with an aim to limit aggregation and improve the colloidal stability of ND-gene complexes called diamoplexes. Furthermore, cellular and macromolecular interactions of lys-NDs are also analyzed in vitro to establish the understanding of ND-mediated gene transfer in cells. Methods lys-NDs were synthesized earlier through covalent conjugation of lysine amino acid to carboxylated NDs surface generated through re-oxidation in strong oxidizing acids. In this study, dispersions of lys-NDs were prepared in various media, and the degree of sedimentation was monitored for 72 hours. Particle size distributions and zeta potential measurements were performed for a period of 25 days to characterize the physicochemical stability of lys-NDs in the medium. The interaction profile of lys-NDs with fetal bovine serum showed formation of a protein corona, which was evaluated by size and charge distribution measurements. Uptake of lys-NDs in cervical cancer cells was analyzed by scanning transmission X-ray microscopy, flow cytometry, and confocal microscopy. Cellular uptake of diamoplexes (complex of lys-NDs with small interfering RNA) was also analyzed using flow cytometry. Results Aqueous dispersion of lys-NDs showed minimum sedimentation and remained stable over a period of 25 days. Size distributions showed good stability, remaining under 100 nm throughout the testing period. A positive zeta potential of >+20 mV indicated a preservation of surface charges. Size distribution and zeta potential changed for lys-NDs after incubation with blood serum, suggesting an interaction with biomolecules, mainly proteins, and a possible formation of a protein corona. Cellular internalization of lys-NDs was confirmed by various techniques such as confocal microscopy, soft X-ray spectroscopy, and flow cytometry. Conclusion This study establishes that dispersion of lys-NDs in aqueous medium maintains long-term stability and also provides evidence that lysine functionalization enables NDs to interact effectively with the biological system to be used for RNAi therapeutics. PMID:26929623

Gene Function Hypotheses for the Campylobacter jejuni Glycome Generated by a Logic-Based Approach

PubMed Central

Sternberg, Michael J.E.; Tamaddoni-Nezhad, Alireza; Lesk, Victor I.; Kay, Emily; Hitchen, Paul G.; Cootes, Adrian; van Alphen, Lieke B.; Lamoureux, Marc P.; Jarrell, Harold C.; Rawlings, Christopher J.; Soo, Evelyn C.; Szymanski, Christine M.; Dell, Anne; Wren, Brendan W.; Muggleton, Stephen H.

2013-01-01

Increasingly, experimental data on biological systems are obtained from several sources and computational approaches are required to integrate this information and derive models for the function of the system. Here, we demonstrate the power of a logic-based machine learning approach to propose hypotheses for gene function integrating information from two diverse experimental approaches. Specifically, we use inductive logic programming that automatically proposes hypotheses explaining the empirical data with respect to logically encoded background knowledge. We study the capsular polysaccharide biosynthetic pathway of the major human gastrointestinal pathogen Campylobacter jejuni. We consider several key steps in the formation of capsular polysaccharide consisting of 15 genes of which 8 have assigned function, and we explore the extent to which functions can be hypothesised for the remaining 7. Two sources of experimental data provide the information for learning—the results of knockout experiments on the genes involved in capsule formation and the absence/presence of capsule genes in a multitude of strains of different serotypes. The machine learning uses the pathway structure as background knowledge. We propose assignments of specific genes to five previously unassigned reaction steps. For four of these steps, there was an unambiguous optimal assignment of gene to reaction, and to the fifth, there were three candidate genes. Several of these assignments were consistent with additional experimental results. We therefore show that the logic-based methodology provides a robust strategy to integrate results from different experimental approaches and propose hypotheses for the behaviour of a biological system. PMID:23103756

Gene function hypotheses for the Campylobacter jejuni glycome generated by a logic-based approach.

PubMed

Sternberg, Michael J E; Tamaddoni-Nezhad, Alireza; Lesk, Victor I; Kay, Emily; Hitchen, Paul G; Cootes, Adrian; van Alphen, Lieke B; Lamoureux, Marc P; Jarrell, Harold C; Rawlings, Christopher J; Soo, Evelyn C; Szymanski, Christine M; Dell, Anne; Wren, Brendan W; Muggleton, Stephen H

2013-01-09

Increasingly, experimental data on biological systems are obtained from several sources and computational approaches are required to integrate this information and derive models for the function of the system. Here, we demonstrate the power of a logic-based machine learning approach to propose hypotheses for gene function integrating information from two diverse experimental approaches. Specifically, we use inductive logic programming that automatically proposes hypotheses explaining the empirical data with respect to logically encoded background knowledge. We study the capsular polysaccharide biosynthetic pathway of the major human gastrointestinal pathogen Campylobacter jejuni. We consider several key steps in the formation of capsular polysaccharide consisting of 15 genes of which 8 have assigned function, and we explore the extent to which functions can be hypothesised for the remaining 7. Two sources of experimental data provide the information for learning-the results of knockout experiments on the genes involved in capsule formation and the absence/presence of capsule genes in a multitude of strains of different serotypes. The machine learning uses the pathway structure as background knowledge. We propose assignments of specific genes to five previously unassigned reaction steps. For four of these steps, there was an unambiguous optimal assignment of gene to reaction, and to the fifth, there were three candidate genes. Several of these assignments were consistent with additional experimental results. We therefore show that the logic-based methodology provides a robust strategy to integrate results from different experimental approaches and propose hypotheses for the behaviour of a biological system. Copyright © 2012 Elsevier Ltd. All rights reserved.

First report of the pituitary adenylate cyclase activating polypeptide (PACAP) in crustaceans: conservation of its functions as growth promoting factor and immunomodulator in the white shrimp Litopenaeus vannamei.

PubMed

Lugo, Juana María; Carpio, Yamila; Morales, Reynold; Rodríguez-Ramos, Tania; Ramos, Laida; Estrada, Mario Pablo

2013-12-01

The high conservation of the pituitary adenylate cyclase activating polypeptide (PACAP) sequence indicates that this peptide fulfills important biological functions in a broad spectrum of organisms. However, in invertebrates, little is known about its presence and its functions remain unclear. Up to now, in non-mammalian vertebrates, the majority of studies on PACAP have focused mainly on the localization, cloning and structural evolution of this peptide. As yet, little is known about its biological functions as growth factor and immunomodulator in lower vertebrates. Recently, we have shown that PACAP, apart from its neuroendocrine role, influences immune functions in larval and juvenile fish. In this work, we isolated for the first time the cDNA encoding the mature PACAP from a crustacean species, the white shrimp Litopenaeus vannamei, corroborating its high degree of sequence conservation, when compared to sequences reported from tunicates to mammalian vertebrates. Based on this, we have evaluated the effects of purified recombinant Clarias gariepinus PACAP administrated by immersion baths on white shrimp growth and immunity. We demonstrated that PACAP improves hemocyte count, superoxide dismutase, lectins and nitric oxide synthase derived metabolites in treated shrimp related with an increase in total protein concentration and growth performance. From our results, PACAP acts as a regulator of shrimp growth and immunity, suggesting that in crustaceans, as in vertebrate organisms, PACAP is an important molecule shared by both the endocrine and the immune systems. Copyright © 2013 Elsevier Ltd. All rights reserved.

Rapid evolution of larval life history, adult immune function and flight muscles in a poleward-moving damselfly.

PubMed

Therry, L; Nilsson-Örtman, V; Bonte, D; Stoks, R

2014-01-01

Although a growing number of studies have documented the evolution of adult dispersal-related traits at the range edge of poleward-expanding species, we know little about evolutionary changes in immune function or traits expressed by nondispersing larvae. We investigated differentiation in larval (growth and development) and adult traits (immune function and flight-related traits) between replicated core and edge populations of the poleward-moving damselfly Coenagrion scitulum. These traits were measured on individuals reared in a common garden experiment at two different food levels, as allocation trade-offs may be easier to detect under energy shortage. Edge individuals had a faster larval life history (growth and development rates), a higher adult immune function and a nearly significant higher relative flight muscle mass. Most of the differentiation between core and edge populations remained and edge populations had a higher relative flight muscle mass when corrected for latitude-specific thermal regimes, and hence could likely be attributed to the range expansion process per se. We here for the first time document a higher immune function in individuals at the expansion front of a poleward-expanding species and documented the rarely investigated evolution of faster life histories during range expansion. The rapid multivariate evolution in these ecological relevant traits between edge and core populations is expected to translate into changed ecological interactions and therefore has the potential to generate novel eco-evolutionary dynamics at the expansion front. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

Isolation, Separation, and Preconcentration of Biologically Active Compounds from Plant Matrices by Extraction Techniques.

PubMed

Raks, Victoria; Al-Suod, Hossam; Buszewski, Bogusław

2018-01-01

Development of efficient methods for isolation and separation of biologically active compounds remains an important challenge for researchers. Designing systems such as organomineral composite materials that allow extraction of a wide range of biologically active compounds, acting as broad-utility solid-phase extraction agents, remains an important and necessary task. Selective sorbents can be easily used for highly selective and reliable extraction of specific components present in complex matrices. Herein, state-of-the-art approaches for selective isolation, preconcentration, and separation of biologically active compounds from a range of matrices are discussed. Primary focus is given to novel extraction methods for some biologically active compounds including cyclic polyols, flavonoids, and oligosaccharides from plants. In addition, application of silica-, carbon-, and polymer-based solid-phase extraction adsorbents and membrane extraction for selective separation of these compounds is discussed. Potential separation process interactions are recommended; their understanding is of utmost importance for the creation of optimal conditions to extract biologically active compounds including those with estrogenic properties.

Copper and Iron Homeostasis in Plants: The Challenges of Oxidative Stress

PubMed Central

Pilon, Marinus

2013-01-01

Abstract Significance: Photosynthesis, the process that drives life on earth, relies on transition metal (e.g., Fe and Cu) containing proteins that participate in electron transfer in the chloroplast. However, the light reactions also generate high levels of reactive oxygen species (ROS), which makes metal use in plants a challenge. Recent Advances: Sophisticated regulatory networks govern Fe and Cu homeostasis in response to metal ion availability according to cellular needs and priorities. Molecular remodeling in response to Fe or Cu limitation leads to its economy to benefit photosynthesis. Fe toxicity is prevented by ferritin, a chloroplastic Fe-storage protein in plants. Recent studies on ferritin function and regulation revealed the interplay between iron homeostasis and the redox balance in the chloroplast. Critical Issues: Although the connections between metal excess and ROS in the chloroplast are established at the molecular level, the mechanistic details and physiological significance remain to be defined. The causality/effect relationship between transition metals, redox signals, and responses is difficult to establish. Future Directions: Integrated approaches have led to a comprehensive understanding of Cu homeostasis in plants. However, the biological functions of several major families of Cu proteins remain unclear. The cellular priorities for Fe use under deficiency remain largely to be determined. A number of transcription factors that function to regulate Cu and Fe homeostasis under deficiency have been characterized, but we have not identified regulators that mediate responses to excess. Importantly, details of metal sensing mechanisms and cross talk to ROS-sensing mechanisms are so far poorly documented in plants. Antioxid. Redox Signal. 19, 919–932. PMID:23199018

Tribbles pseudokinases: novel targets for chemical biology and drug discovery?

PubMed

Foulkes, Daniel M; Byrne, Dominic P; Bailey, Fiona P; Eyers, Patrick A

2015-10-01

Tribbles (TRIB) proteins are pseudokinase mediators of eukaryotic signalling that have evolved important roles in lipoprotein metabolism, immune function and cellular differentiation and proliferation. In addition, an evolutionary-conserved modulation of PI3K/AKT signalling pathways highlights them as novel and rather unusual pharmaceutical targets. The three human TRIB family members are uniquely defined by an acidic pseudokinase domain containing a 'broken' α C-helix and a MEK (MAPK/ERK)-binding site at the end of the putative C-lobe and a distinct C-terminal peptide motif that interacts directly with a small subset of cellular E3 ubiquitin ligases. This latter interaction drives proteasomal-dependent degradation of networks of transcription factors, whose rate of turnover determines the biological attributes of individual TRIB family members. Defining the function of individual Tribs has been made possible through evaluation of individual TRIB knockout mice, siRNA/overexpression approaches and genetic screening in flies, where the single TRIB gene was originally described 15 years ago. The rapidly maturing TRIB field is primed to exploit chemical biology approaches to evaluate endogenous TRIB signalling events in intact cells. This will help define how TRIB-driven protein-protein interactions and the atypical TRIB ATP-binding site, fit into cellular signalling modules in experimental scenarios where TRIB-signalling complexes remain unperturbed. In this mini-review, we discuss how small molecules can reveal rate-limiting signalling outputs and functions of Tribs in cells and intact organisms, perhaps serving as guides for the development of new drugs. We predict that appropriate small molecule TRIB ligands will further accelerate the transition of TRIB pseudokinase analysis into the mainstream of cell signalling. © 2015 Authors; published by Portland Press Limited.

Enhancement of DFT-calculations at petascale: Nuclear Magnetic Resonance, Hybrid Density Functional Theory and Car-Parrinello calculations

NASA Astrophysics Data System (ADS)

Varini, Nicola; Ceresoli, Davide; Martin-Samos, Layla; Girotto, Ivan; Cavazzoni, Carlo

2013-08-01

One of the most promising techniques used for studying the electronic properties of materials is based on Density Functional Theory (DFT) approach and its extensions. DFT has been widely applied in traditional solid state physics problems where periodicity and symmetry play a crucial role in reducing the computational workload. With growing compute power capability and the development of improved DFT methods, the range of potential applications is now including other scientific areas such as Chemistry and Biology. However, cross disciplinary combinations of traditional Solid-State Physics, Chemistry and Biology drastically improve the system complexity while reducing the degree of periodicity and symmetry. Large simulation cells containing of hundreds or even thousands of atoms are needed to model these kind of physical systems. The treatment of those systems still remains a computational challenge even with modern supercomputers. In this paper we describe our work to improve the scalability of Quantum ESPRESSO (Giannozzi et al., 2009 [3]) for treating very large cells and huge numbers of electrons. To this end we have introduced an extra level of parallelism, over electronic bands, in three kernels for solving computationally expensive problems: the Sternheimer equation solver (Nuclear Magnetic Resonance, package QE-GIPAW), the Fock operator builder (electronic ground-state, package PWscf) and most of the Car-Parrinello routines (Car-Parrinello dynamics, package CP). Final benchmarks show our success in computing the Nuclear Magnetic Response (NMR) chemical shift of a large biological assembly, the electronic structure of defected amorphous silica with hybrid exchange-correlation functionals and the equilibrium atomic structure of height Porphyrins anchored to a Carbon Nanotube, on many thousands of CPU cores.