Journal of Molecular Biology

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  • Corrigendum to “Statistical Mechanics of Monod–Wyman–Changeux” [J Mol Biol 425 (9) (May 13 2013) 1433-1460]
    [Dec 2014]

    Publication date: 12 December 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 24

    Author(s): Sarah Marzen , Hernan G. Garcia , Rob Phillips







    Categories: Journal Articles
  • Experimental validation of plant peroxisomal targeting prediction algorithms by systematic comparison of in vivo import efficiency and in vitro PTS1 binding affinity
    [Dec 2014]

    Publication date: Available online 10 December 2014
    Source:Journal of Molecular Biology

    Author(s): Nicola S. Skoulding , Gopal Chowdhary , Mara J. Deus , Alison Baker , Sigrun Reumann , Stuart L. Warriner

    Most peroxisomal matrix proteins possess a C-terminal targeting signal type 1 (PTS1). Accurate prediction of functional PTS1 sequences and their relative strength by computational methods is essential for determination of peroxisomal proteomes in silico, but has proved challenging, due to high sequence variability of non-canonical targeting signals, particularly in higher plants, and low availability of experimentally validated non-canonical examples. In this study in silico predictions were compared with in vivo targeting analyses and in vitro thermodynamic binding of mutated variants within the context of one model targeting sequence. There was broad agreement between the methods for entire PTS1 domains and position-specific single amino acid (aa) residues, including residues upstream of the PTS1 tripeptide. The hierarchy Leu>Met>Ile>Val at the C-terminal position was determined for all methods but both experimental approaches suggest Tyr is under weighted in the prediction algorithm due to the absence of this residue in the positive training dataset. A combination of methods better defines the score range that discriminates a functional PTS1. In vitro binding to the PEX5 receptor could discriminate amongst strong targeting signals whilst in vivo targeting assays were more sensitive, allowing detection of weak functional import signals that were below the limit of detection in the binding assay. Together the data provide a comprehensive assessment of the factors driving PTS1 efficacy and provide a framework for the more quantitative assessment of the protein import pathway in higher plants.
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    Categories: Journal Articles
  • Human Apurinic/Apyrimidinic Endonuclease 1 (APE1) has 3’ RNA Phosphatase and 3’ Exoribonuclease Activities
    [Dec 2014]

    Publication date: Available online 10 December 2014
    Source:Journal of Molecular Biology

    Author(s): Manbir Chohan , Sebastian Mackedenski , Wai-Ming Li , Chow H. Lee

    Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant mammalian enzyme in DNA base excision repair pathway that cleaves the DNA backbone immediately 5’ to abasic sites. In addition to its abasic endonuclease activity, APE1 has 3’ phosphatase and 3’-5’ exonuclease activities against DNA. We recently identified APE1 as an endoribonuclease that preferentially cleaves at UA, UG, and CA sites in single-stranded regions of RNAs, and can regulate c-myc mRNA level and half-life in cells. APE1 can also endonucleolytically cleave abasic single-stranded RNA. Here, we show for the first time that the human APE1 has 3’ RNA phosphatase and 3’ exoribonuclease activity. Using three distinct RNA substrates, we show that APE1, but not RNase A, can remove the phosphoryl group from the 3’ end of RNA decay products. Studies using various site-directed APE1 mutant proteins (H309N, H309S, D283N, N68A, D210N, Y171F, D308A, F266A, and D70A) suggest that the 3’ RNA phosphatase activity shares the same active centre as its other known nuclease activities. A number of APE1 variants previously identified in the human population, including the most common D148E variant, have greater than 80% reduction in the 3’ RNA phosphatase activity. APE1 can remove a ribonucleotide from the 3’ overhang of RNA decay product, but its 3’-5’ exoribonuclease activity against unstructured poly(A), poly(C), and poly(U) RNAs is relatively weak. This study further underscores the significance of understanding the role of APE1 in RNA metabolism in vivo.
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    Categories: Journal Articles
  • Computational de novo design of a self-assembling peptide with predefined structure
    [Dec 2014]

    Publication date: Available online 10 December 2014
    Source:Journal of Molecular Biology

    Author(s): Sabine Kaltofen , Chenge Li , Po-Ssu Huang , Louise C. Serpell , Andreas Barth , Ingemar André

    Protein and peptide self-assembly is a powerful design principle for engineering of new biomolecules. More sophisticated biomaterials could be built if both the structure of the overall assembly as well as that of the self-assembling building block could be controlled. To approach this problem we developed a computational design protocol to enable de novo design of self-assembling peptides with predefined structure. The protocol was used to design a peptide building block with a βαβ fold that self-assembles into fibrilar structures. The peptide associates into a double β-sheet structure with tightly packed α-helices decorating the exterior of the fibrils. Using circular dichroism, Fourier transform infrared spectroscopy, electron microscopy and X-ray fiber diffraction we demonstrate that the peptide adopts the designed conformation. The results demonstrate that computational protein design can be used to engineer protein and peptide assemblies with predefined three-dimensional structures, which can serve as scaffolds for the development of functional biomaterials. Rationally designed proteins and peptides could also be used to investigate the subtle energetic and entropic tradeoffs in natural self-assembly processes and the relation between assembly structure and assembly mechanism. We demonstrate that the de novo designed peptide self-assembles with a mechanism that is more complicated than expected, in a process where small changes in solution conditions can lead to significant differences in assembly properties and conformation. These results highlight that formation of structured protein/peptide assemblies is often dependent on the formation of weak but highly precise intermolecular interactions.
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    Categories: Journal Articles
  • The Crystal Structure of the Human Titin:Obscurin Complex Reveals a Conserved Yet Specific Muscle M-band Zipper Module
    [Dec 2014]

    Publication date: Available online 6 December 2014
    Source:Journal of Molecular Biology

    Author(s): Stefano Pernigo , Atsushi Fukuzawa , Alessandro Pandini , Mark Holt , Jens Kleinjung , Mathias Gautel , Roberto A. Steiner

    M10 is the most C-terminal immunoglobulin (Ig) domain of the giant protein titin and a frequent target of disease-linked mutations. Currently, it is the only known muscle Ig-domain able to interact with two alternative ligands – obscurin and obscurin-like-1 (Obsl1) – in different sarcomeric subregions. Obscurin and Obsl1 use their homologous N-terminal Ig domain (O1 in obscurin and OL1 in Obsl1) to bind M10 in a mutually exclusive manner. We present here the X-ray structure of the human titin:obscurin M10:O1 complex extending our previous work on the M10:OL1 interaction. Similar to M10:OL1, the M10:O1 complex displays a chevron-shaped antiparallel Ig-Ig architecture held together by a conserved molecular interface, which we validated by isothermal titration calorimetry and sorting experiments in neonatal rat cardiomyocytes (NRCs). O1 although structurally related to OL1 and M10, both members of the I-set Ig family, presents an intriguing switch of its βA’ strand. This leads to structural differences between the complexes, particularly, for the ‘open-side’ of the chevron-shaped assembly. A bioinformatics analysis reveals that the βA’-switch observed for O1 is rare and that it is involved in mediating protein-protein interactions. Molecular Dynamics simulations also suggest that this topological alteration substantially increases local flexibility compared to the conventional I-set Ig domains. The O1/OL1 Ig domains are candidate discriminatory structural modules potentially directing the binding of specific additional partners at the M-band. Cellular sorting experiments in NRCs are consistent with the view that the titin:obscurin/Obsl1 complexes might be a platform for higher order interactions.
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    Categories: Journal Articles
  • Structure of an APC3-APC16 complex: Insights into assembly of the Anaphase Promoting Complex/Cyclosome
    [Dec 2014]

    Publication date: Available online 6 December 2014
    Source:Journal of Molecular Biology

    Author(s): Masaya Yamaguchi , Shanshan Yu , Renping Qiao , Florian Weissmann , Darcie J. Miller , Ryan VanderLinden , Nicholas G. Brown , Jeremiah J. Frye , Jan-Michael Peters , Brenda A. Schulman

    The Anaphase Promoting Complex/Cyclosome (APC/C) is a massive E3 ligase that controls mitosis by catalyzing ubiquitination of key cell cycle regulatory proteins. The APC/C assembly contains two subcomplexes: the “Platform” centers around a cullin-RING-like E3 ligase catalytic core; the “Arc Lamp” is a hub that mediates transient association with regulators and ubiquitination substrates. The Arc Lamp contains the small subunits APC16, CDC26, and APC13, and tetratricopeptide repeat (TPR) proteins (APC7, APC3, APC6, and APC8) that homodimerize and stack with quasi-twofold symmetry. Within the APC/C complex, APC3 serves as center for regulation. APC3’s TPR motifs recruit substrate-binding coactivators, CDC20 and CDH1, via their C-terminal conserved Ile-Arg (IR) tail sequences. Human APC3 also binds APC16 and APC7, and contains a >200-residue loop that is heavily phosphorylated during mitosis, although the basis for APC3 interactions and whether loop phosphorylation is required for ubiquitination are unclear. Here, we map the basis for human APC3 assembly with APC16 and APC7, report crystal structures of APC3Δloop alone and in complex with the C-terminal domain of APC16, and test roles of APC3’s loop and IR-tail binding surfaces in APC/C-catalyzed ubiquitination. The structures show how one APC16 binds asymmetrically to the symmetric APC3 dimer, and together with biochemistry and prior data explain how APC16 recruits APC7 to APC3, show how APC3’s C-terminal domain is rearranged in the full APC/C assembly, and visualize residues in the IR-tail binding cleft important for coactivator-dependent ubiquitination. Overall, the results provide insights into assembly, regulation, and interactions of TPR proteins and the APC/C.
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    Categories: Journal Articles
  • Mapping the gating and permeation pathways in the voltage-gated proton channel Hv1
    [Dec 2014]

    Publication date: Available online 4 December 2014
    Source:Journal of Molecular Biology

    Author(s): Adam Chamberlin , Feng Qiu , Yibo Wang , Sergei Y. Noskov , H. Peter Larsson

    Voltage-gated proton channels (Hv1) are ubiquitous throughout nature and are implicated in numerous physiological processes. The gene encoding for Hv1 however was only identified in 2006. The lack of sufficient structural information of this channel has hampered the understanding of the molecular mechanism of channel activation and proton permeation. This study uses both simulation and experimental approaches to further develop existing models of the Hv1 channel. Our study provides insights into features of channel gating and proton permeation pathway. We compare open- and closed-state structures developed previously with a recent crystal structure that traps the channel in a presumably closed state. Insights into gating pathways were provided using a combination of all-atom MD simulations with a swarm-of-trajectories with the string method for extensive transition path sampling and evolution. A detailed residue-residue interaction profile and a hydration profile were studied to map the gating pathway in this channel. In particular it allows us to identify potential intermediate states and compare them to the experimentally observed crystal structure of Takeshita et al [1]. The mechanisms governing ion transport in the WT and mutant Hv1 channels were studied by a combination of electrophysiological recordings and free energy simulations. With these results we were able to further refine ideas about the location and function of the selectivity filter. The refined structural models will be essential for future investigations of this channel and the development of new drugs targeting cellular proton transport.
    Graphical abstract Highlights Our study reports on basic biophysical principles governing selective ion permeation in voltage-gated proton channels, which are membrane proteins with important roles in immune response and fertility. To further confirm and develop our model we compared it to recently reported crystal structures. To gain further insight into the mechanisms of ion selectivity in these channels were performed in-vivo and in-silico mutations on the channels and investigated their functioning. We found that targeted modifications around the constriction zone formed in an open state of the channel dramatically affects ion selectivity of the channel enabling transport of Na+. We also further investigate the gating behavior of the wild-type structures. Our in-silico predictions were confirmed experimentally both with regard to the mutant and the wild-type structures, further establishing the validity of the channel model for future applications in drug development targeting proton channels.




    Categories: Journal Articles
  • An Improved Single-chain Fab Platform for Efficient Display and Recombinant Expression
    [Dec 2014]

    Publication date: Available online 3 December 2014
    Source:Journal of Molecular Biology

    Author(s): James T. Koerber , Michael J. Hornsby , James A. Wells

    Antibody phage display libraries combined with high-throughput selections have recently demonstrated tremendous promise to create the next generation of renewable, recombinant antibodies to study proteins and their many post-translational modification states; however many challenges still remain, such as optimized antibody scaffolds. Recently, a single-chain Fab (scFab) format, in which the carboxy-terminus of the light chain is linked to the amino-terminus of the heavy chain, was described to potentially combine the high display levels of a single-chain Fv with the high stability of purified Fabs. However, this format required removal of the interchain disulfide bond to achieve modest display levels and subsequent bacterial expression resulted in high levels of aggregated scFab, hindering further use of scFabs. Here, we developed an improved scFab format that retains the interchain disulfide bond by increasing the linker length between the light and heavy chains to improve display and bacterial expression levels to 1-3mg per liter. Furthermore, rerouting of the scFab to the co-translational signal recognition particle (SRP) pathway combined with reengineering of the signal peptide sequence results in display levels 24-fold above the original scFab format and 3-fold above parent Fab levels. This optimized scFab scaffold can be easily reformatted in a single step for expression in a bacterial or mammalian host to produce stable (81°C Tm), predominantly monomeric (>90%) antibodies at a high yield. Ultimately, this new scFab format will advance high-throughput antibody generation platforms to discover the next generation of research and therapeutic antibodies.
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    Categories: Journal Articles
  • Specificity Determinants in Small Multidrug Transporters
    [Dec 2014]

    Publication date: Available online 3 December 2014
    Source:Journal of Molecular Biology

    Author(s): Shlomo Brill , Ofir Sade-Falk , Yael Elbaz-Alon , Shimon Schuldiner

    Multiple-antibiotic resistance has become a major global public health concern, and to overcome this problem, it is necessary to understand the resistance mechanisms that allow survival of the microorganisms at the molecular level. One mechanism responsible for such resistance involves active removal of the antibiotic from the pathogen cell by MDTs (multidrug transporters). A prominent MDT feature is their high polyspecificity allowing for a single transporter to confer resistance against a range of drugs. Here we present the molecular mechanism underlying substrate recognition in EmrE, a small MDT from Escherichia coli. EmrE is known to have a substrate preference for aromatic, cationic compounds, such as methyl viologen (MV2+). In this work, we use a combined bioinformatic and biochemical approach to identify one of the major molecular determinants involved in MV2+ transport and resistance. Replacement of an Ala residue with Ser in weakly resistant SMRs from Bacillus pertussis and Mycobacterium tuberculosis enables them to provide robust resistance to MV2+ and to transport MV2+ and has negligible effects on the interaction with other substrates. This shows that the residue identified herein is uniquely positioned in the binding site so as to be exclusively involved in the mediating of MV2+ transport and resistance, both in EmrE and in other homologues. This work provides clues toward uncovering how specificity is achieved within the binding pocket of a polyspecific transporter that may open new possibilities as to how these transporters can be manipulated to bind a designed set of drugs.
    Graphical abstract




    Categories: Journal Articles
  • Permeation and Dynamics of an Open-Activated TRPV1 Channel
    [Dec 2014]

    Publication date: Available online 3 December 2014
    Source:Journal of Molecular Biology

    Author(s): Leonardo Darré , Simone Furini , Carmen Domene

    Transient receptor potential (TRP) ion channels constitute a large and diverse protein family, found in yeast and widespread in the animal kingdom. TRP channels work as sensors for a wide range of cellular and environmental signals. Understanding how these channels respond to physical and chemical stimuli has been hindered by the limited structural information available until now. The three-dimensional structure of the vanilloid receptor 1 (TRPV1) was recently determined by single particle electron cryo-microscopy, offering for the first time the opportunity to explore ionic conduction in TRP channels at atomic detail. In this study, we present molecular dynamics simulations of the open-activated pore domain of TRPV1 in the presence of three cationic species: Na+, Ca2+ and K+. The dynamics of these ions while interacting with the channel pore allowed us to rationalize their permeation mechanism in terms of a pathway involving three binding sites at the intracellular cavity, as well as the extracellular and intracellular entrance of the selectivity filter. Furthermore, conformational analysis of the pore in the presence of these ions reveals specific ion-mediated structural changes in the selectivity filter, which influences the permeability properties of the TRPV1 channel.
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    Categories: Journal Articles
  • A Novel Open-Barrel Structure of Octameric Translin Reveals a Potential RNA Entryway
    [Dec 2014]

    Publication date: Available online 26 November 2014
    Source:Journal of Molecular Biology

    Author(s): Elad Eliahoo , Ailie Marx , Haim Manor , Akram Alian

    The single-stranded DNA (ssDNA)/RNA binding protein translin was suggested to be involved in chromosomal translocations, telomere metabolism, and mRNA transport and translation. Oligonucleotide binding surfaces map within a closed cavity of translin octameric barrels, raising the question as to how DNA/RNA gain access to this inner cavity, particularly given that, to date, none of the barrel structures reported hint to an entryway. Here, we argue against a mechanism by which translin octamers may “dissociate and reassemble” upon RNA binding and report a novel “open”-barrel structure of human translin revealing a feasible DNA/RNA entryway into the cavity. Additionally, we report that translin not only is confined to binding of ssDNA oligonucleotides, or single-stranded extensions of double-stranded DNA (dsDNA), but also can bind single-stranded sequences internally embedded in dsDNA molecules.
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    Categories: Journal Articles
  • Editorial Board
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23









    Categories: Journal Articles
  • Contents List
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23









    Categories: Journal Articles
  • Editorial Overview: Insights into Molecular Mechanisms of Microbiota
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Eric C. Martens , Justin L. Sonnenburg , David A. Relman







    Categories: Journal Articles
  • The Molecular Basis of Bacterial–Insect Symbiosis
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Angela E. Douglas

    Insects provide experimentally tractable and cost-effective model systems to investigate the molecular basis of animal–bacterial interactions. Recent research is revealing the central role of the insect innate immune system, especially anti-microbial peptides and reactive oxygen species, in regulating the abundance and composition of the microbiota in various insects, including Drosophila and the mosquitoes Aedes and Anopheles. Interactions between the immune system and microbiota are, however, bidirectional with evidence that members of the resident microbiota can promote immune function, conferring resistance to pathogens and parasites by both activation of immune effectors and production of toxins. Antagonistic and mutualistic interactions among bacteria have also been implicated as determinants of the microbiota composition, including exclusion of pathogens, but the molecular mechanisms are largely unknown. Some bacteria are crucial for insect nutrition, through provisioning of specific nutrients (e.g., B vitamins, essential amino acids) and modulation of the insect nutritional sensing and signaling pathways (e.g., insulin signaling) that regulate nutrient allocation, especially to lipid and other energy reserves. A key challenge for future research is to identify the molecular interaction between specific bacterial effectors and animal receptors, as well as to determine how these interactions translate into microbiota-dependent signaling, metabolism, and immune function in the host.
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    Categories: Journal Articles
  • A Perspective on the Complexity of Dietary Fiber Structures and Their Potential Effect on the Gut Microbiota
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Bruce R. Hamaker , Yunus E. Tuncil

    Even though there are many factors that determine the human colon microbiota composition, diet is an important one because most microorganisms in the colon obtain energy for their growth by degrading complex dietary compounds, particularly dietary fibers. While fiber carbohydrates that escape digestion in the upper gastrointestinal tract are recognized to have a range of structures, the vastness in number of chemical structures from the perspective of the bacteria is not well appreciated. In this article, we introduce the concept of “discrete structure” that is defined as a unique chemical structure, often within a fiber molecule, which aligns with encoded gene clusters in bacterial genomes. The multitude of discrete structures originates from the array of different fiber types coupled with structural variations within types due to genotype and growing environment, anatomical parts of the grain or plant, discrete regions within polymers, and size of oligosaccharides and small polysaccharides. These thousands of discrete structures conceivably could be used to favor bacteria in the competitive colon environment. A global framework needs to be developed to better understand how dietary fibers can be used to obtain predicted changes in microbiota composition for improved health. This will require a multi-disciplinary effort that includes biological scientists, clinicians, and carbohydrate specialists.
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    Categories: Journal Articles
  • The Devil Lies in the Details: How Variations in Polysaccharide Fine-Structure Impact the Physiology and Evolution of Gut Microbes
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Eric C. Martens , Amelia G. Kelly , Alexandra S. Tauzin , Harry Brumer

    The critical importance of gastrointestinal microbes to digestion of dietary fiber in humans and other mammals has been appreciated for decades. Symbiotic microorganisms expand mammalian digestive physiology by providing an armament of diverse polysaccharide-degrading enzymes, which are largely absent in mammalian genomes. By out-sourcing this aspect of digestive physiology to our gut microbes, we maximize our ability to adapt to different carbohydrate nutrients on timescales as short as several hours due to the ability of the gut microbial community to rapidly alter its physiology from meal to meal. Because of their ability to pick up new traits by lateral gene transfer, our gut microbes also enable adaption over time periods as long as centuries and millennia by adjusting their gene content to reflect cultural dietary trends. Despite a vast amount of sequence-based insight into the metabolic potential of gut microbes, the specific mechanisms by which symbiotic gut microorganisms recognize and attack complex carbohydrates remain largely undefined. Here, we review the recent literature on this topic and posit that numerous, subtle variations in polysaccharides diversify the spectrum of available nutrient niches, each of which may be best filled by a subset of microorganisms that possess the corresponding proteins to recognize and degrade different carbohydrates. Understanding these relationships at precise mechanistic levels will be essential to obtain a complete understanding of the forces shaping gut microbial ecology and genomic evolution, as well as devising strategies to intentionally manipulate the composition and physiology of the gut microbial community to improve health.
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    Categories: Journal Articles
  • The Yin and Yang of Bacterial Resilience in the Human Gut Microbiota
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Molly K. Gibson , Mitchell W. Pesesky , Gautam Dantas

    The human gut is home to trillions of microbes that form a symbiotic relationship with the human host. During health, the intestinal microbiota provides many benefits to the host and is generally resistant to colonization by new species; however, disruption of this complex community can lead to pathogen invasion, inflammation, and disease. Restoration and maintenance of a healthy gut microbiota composition requires effective therapies to reduce and prevent colonization of harmful bacteria (pathogens) while simultaneously promoting growth of beneficial bacteria (probiotics). Here we review the mechanisms by which the host modulates the gut community composition during health and disease, and we discuss prospects for antibiotic and probiotic therapy for restoration of a healthy intestinal community following disruption.
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    Categories: Journal Articles
  • The Microbiota, Chemical Symbiosis, and Human Disease
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Matthew R. Redinbo

    Our understanding of mammalian–microbial mutualism has expanded by combing microbial sequencing with evolving molecular and cellular methods, as well as unique model systems. Here, the recent literature linking the microbiota to diseases of three of the key mammalian mucosal epithelial compartments—nasal, lung, and gastrointestinal tract—is reviewed with a focus on new knowledge about the taxa, species, proteins, and chemistry that promote health and impact progression toward disease. The information presented is further organized by specific diseases now associated with the microbiota: Staphylococcus aureus infection and rhinosinusitis in the nasal-sinus mucosa, as well as cystic fibrosis, chronic obstructive pulmonary disorder, and asthma in the pulmonary tissues. For the vast and microbially dynamic gastrointestinal compartment, several disorders are considered, including obesity, atherosclerosis, Crohn's disease, ulcerative colitis, drug toxicity, and even autism. Our appreciation of the chemical symbiosis ongoing between human systems and the microbiota continues to grow and suggests new opportunities for modulating this symbiosis using designed interventions.
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    Categories: Journal Articles
  • Molecular Bases and Role of Viruses in the Human Microbiome
    [Dec 2014]

    Publication date: 25 November 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 23

    Author(s): Shira R. Abeles , David T. Pride

    Viruses are dependent biological entities that interact with the genetic material of most cells on the planet, including the trillions within the human microbiome. Their tremendous diversity renders analysis of human viral communities (“viromes”) to be highly complex. Because many of the viruses in humans are bacteriophage, their dynamic interactions with their cellular hosts add greatly to the complexities observed in examining human microbial ecosystems. We are only beginning to be able to study human viral communities on a large scale, mostly as a result of recent and continued advancements in sequencing and bioinformatic technologies. Bacteriophage community diversity in humans not only is inexorably linked to the diversity of their cellular hosts but also is due to their rapid evolution, horizontal gene transfers, and intimate interactions with host nucleic acids. There are vast numbers of observed viral genotypes on many body surfaces studied, including the oral, gastrointestinal, and respiratory tracts, and even in the human bloodstream, which previously was considered a purely sterile environment. The presence of viruses in blood suggests that virome members can traverse mucosal barriers, as indeed these communities are substantially altered when mucosal defenses are weakened. Perhaps the most interesting aspect of human viral communities is the extent to which they can carry gene functions involved in the pathogenesis of their hosts, particularly antibiotic resistance. Persons in close contact with each other have been shown to share a fraction of oral virobiota, which could potentially have important implications for the spread of antibiotic resistance to healthy individuals. Because viruses can have a large impact on ecosystem dynamics through mechanisms such as the transfers of beneficial gene functions or the lysis of certain populations of cellular hosts, they may have both beneficial and detrimental roles that affect human health, including improvements in microbial resilience to disturbances, immune evasion, maintenance of physiologic processes, and altering the microbial community in ways that promote or prevent pathogen colonization.
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    Categories: Journal Articles