A pharmaceutical model for the molecular evolution of microbial natural products

Abstract Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two-step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre-existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.Peer reviewe

Temporomandibular joint prosthesis in cancer reconstruction preceding radiation therapy

Total joint prostheses are a viable treatment option after removal of malignancies invading the temporomandibular joint, even when adjuvant radiation therapy is required.publishedVersio

Potentialities of LL37 for Wound Healing Applications: Study of Its Activity in Synergy with Biodegradable Composites Made of PVA and CA

Wound healing is a dynamic and complex process that results from the interaction between cytokines, growth factors, blood components and the extracellular matrix. Conventional dressings made of natural or synthetic materials have only the ability to manage the wound and protect it from repeated trauma. With the advancement of technology, wound dressings have evolved and are now capable of intervening in the healing process by targeting specific features of the wound, aside from protecting the wounded site. In this work, bioactive dressings capable of promoting healing and fighting infection in chronic wounds were explored. Various antimicrobial biomolecules were examined in light of their pathogen fighting skills and immunoregulatory potentialities. Dressing production processes were also investigated. Biodegradable composite dressings made of poly(vinyl alcohol), polycaprolactone, chitosan and cellulose blends were our main focus. The goal was to evaluate the synergistic effect of biomolecules and biodegradable polymeric dressings, considering the local and systemic treatment demands of chronic wounds.Portuguese Foundation for Science and Technology (FCT), FEDER funds by means of Competitive Factors Operational Program (POCI) for funding the projects POCI-01-0145-FEDER-028074 and UID/CTM/00264/201

Could Public Restrooms Be an Environment for Bacterial Resistomes?

PMCID: PMC3547874This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Minimization of phonon-tunneling dissipation in mechanical resonators

Micro- and nanoscale mechanical resonators have recently emerged as ubiquitous devices for use in advanced technological applications, for example in mobile communications and inertial sensors, and as novel tools for fundamental scientific endeavors. Their performance is in many cases limited by the deleterious effects of mechanical damping. Here, we report a significant advancement towards understanding and controlling support-induced losses in generic mechanical resonators. We begin by introducing an efficient numerical solver, based on the "phonon-tunneling" approach, capable of predicting the design-limited damping of high-quality mechanical resonators. Further, through careful device engineering, we isolate support-induced losses and perform the first rigorous experimental test of the strong geometric dependence of this loss mechanism. Our results are in excellent agreement with theory, demonstrating the predictive power of our approach. In combination with recent progress on complementary dissipation mechanisms, our phonon-tunneling solver represents a major step towards accurate prediction of the mechanical quality factor.Comment: 12 pages, 4 figure

Impetigo herpetiformis during the puerperium triggered by secondary hypoparathyroidism: a case report

A 38-year-old multiparous woman with post thyroidectomy hypoparathyroidism developed pruritic erythematous patches with multiple pustules on its margins on her thighs and groin accompanied by fever few days after delivery by caesarean section. Impetigo herpetiformis was diagnosed based on the typical clinicopathological findings. The patient was treated with intravenous fluids, calcium, Calcitrol and corticosteroids. The correction of hypocalcaemia was accompanied with rapid improvement of her skin disease and general condition. Our case is the fourth case of impetigo herpetiformis initially presented during puerperium and the first case of puerperal impetigo herpetiformis that is precipitated by secondary hypoparathyroidism. The awareness of the possible occurrence of impetigo herpetiformis during the puerperium allows early diagnosis, treatment and prevention of maternal complications

Mid-infrared plasmons in scaled graphene nanostructures

Plasmonics takes advantage of the collective response of electrons to electromagnetic waves, enabling dramatic scaling of optical devices beyond the diffraction limit. Here, we demonstrate the mid-infrared (4 to 15 microns) plasmons in deeply scaled graphene nanostructures down to 50 nm, more than 100 times smaller than the on-resonance light wavelength in free space. We reveal, for the first time, the crucial damping channels of graphene plasmons via its intrinsic optical phonons and scattering from the edges. A plasmon lifetime of 20 femto-seconds and smaller is observed, when damping through the emission of an optical phonon is allowed. Furthermore, the surface polar phonons in SiO2 substrate underneath the graphene nanostructures lead to a significantly modified plasmon dispersion and damping, in contrast to a non-polar diamond-like-carbon (DLC) substrate. Much reduced damping is realized when the plasmon resonance frequencies are close to the polar phonon frequencies. Our study paves the way for applications of graphene in plasmonic waveguides, modulators and detectors in an unprecedentedly broad wavelength range from sub-terahertz to mid-infrared.Comment: submitte

Aidnogenesis via Leptogenesis and Dark Sphalerons

We discuss aidnogenesis, the generation of a dark matter asymmetry via new sphaleron processes associated to an extra non-abelian gauge symmetry common to both the visible and the dark sectors. Such a theory can naturally produce an abundance of asymmetric dark matter which is of the same size as the lepton and baryon asymmetries, as suggested by the similar sizes of the observed baryonic and dark matter energy content, and provide a definite prediction for the mass of the dark matter particle. We discuss in detail a minimal realization in which the Standard Model is only extended by dark matter fermions which form "dark baryons" through an SU(3) interaction, and a (broken) horizontal symmetry that induces the new sphalerons. The dark matter mass is predicted to be approximately 6 GeV, close to the region favored by DAMA and CoGeNT. Furthermore, a remnant of the horizontal symmetry should be broken at a lower scale and can also explain the Tevatron dimuon anomaly.Comment: Minor changes, discussion of present constraints expanded. 16 pages, 2 eps figures, REVTeX

Impaired decisional impulsivity in pathological videogamers

Abstract Background Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort. Methods Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment. Results In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time. Conclusions We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management

An ontology-based search engine for protein-protein interactions

<p>Abstract</p> <p>Background</p> <p>Keyword matching or ID matching is the most common searching method in a large database of protein-protein interactions. They are purely syntactic methods, and retrieve the records in the database that contain a keyword or ID specified in a query. Such syntactic search methods often retrieve too few search results or no results despite many potential matches present in the database.</p> <p>Results</p> <p>We have developed a new method for representing protein-protein interactions and the Gene Ontology (GO) using modified Gödel numbers. This representation is hidden from users but enables a search engine using the representation to efficiently search protein-protein interactions in a biologically meaningful way. Given a query protein with optional search conditions expressed in one or more GO terms, the search engine finds all the interaction partners of the query protein by unique prime factorization of the modified Gödel numbers representing the query protein and the search conditions.</p> <p>Conclusion</p> <p>Representing the biological relations of proteins and their GO annotations by modified Gödel numbers makes a search engine efficiently find all protein-protein interactions by prime factorization of the numbers. Keyword matching or ID matching search methods often miss the interactions involving a protein that has no explicit annotations matching the search condition, but our search engine retrieves such interactions as well if they satisfy the search condition with a more specific term in the ontology.</p