Swimming Upstream: Identifying Proteomic Signals that Drive Transcriptional Changes using the Interactome and Multiple “-Omics” Datasets

available in PMC 2013 December 23Signaling and transcription are tightly integrated processes that underlie many cellular responses to the environment. A network of signaling events, often mediated by post-translational modification on proteins, can lead to long-term changes in cellular behavior by altering the activity of specific transcriptional regulators and consequently the expression level of their downstream targets. As many high-throughput, “-omics” methods are now available that can simultaneously measure changes in hundreds of proteins and thousands of transcripts, it should be possible to systematically reconstruct cellular responses to perturbations in order to discover previously unrecognized signaling pathways. This chapter describes a computational method for discovering such pathways that aims to compensate for the varying levels of noise present in these diverse data sources. Based on the concept of constraint optimization on networks, the method seeks to achieve two conflicting aims: (1) to link together many of the signaling proteins and differentially expressed transcripts identified in the experiments “constraints” using previously reported protein–protein and protein–DNA interactions, while (2) keeping the resulting network small and ensuring it is composed of the highest confidence interactions “optimization”. A further distinctive feature of this approach is the use of transcriptional data as evidence of upstream signaling events that drive changes in gene expression, rather than as proxies for downstream changes in the levels of the encoded proteins. We recently demonstrated that by applying this method to phosphoproteomic and transcriptional data from the pheromone response in yeast, we were able to recover functionally coherent pathways and to reveal many components of the cellular response that are not readily apparent in the original data. Here, we provide a more detailed description of the method, explore the robustness of the solution to the noise level of input data and discuss the effect of parameter values.National Cancer Institute (U.S.) ((NCI) Grant U54-CA112967)Natural Sciences and Engineering Research Council of Canada (Postgraduate scholarship)Massachusetts Institute of Technology (Eugene Bell Career Development Chair)National Cancer Institute (U.S.) (NCI integrative cancer biology program graduate fellowship

Fungal chitinases: diversity, mechanistic properties and biotechnological potential

Chitin derivatives, chitosan and substituted chito-oligosaccharides have a wide spectrum of applications ranging from medicine to cosmetics and dietary supplements. With advancing knowledge about the substrate-binding properties of chitinases, enzyme-based production of these biotechnologically relevant sugars from biological resources is becoming increasingly interesting. Fungi have high numbers of glycoside hydrolase family 18 chitinases with different substrate-binding site architectures. As presented in this review, the large diversity of fungal chitinases is an interesting starting point for protein engineering. In this review, recent data about the architecture of the substrate-binding clefts of fungal chitinases, in connection with their hydrolytic and transglycolytic abilities, and the development of chitinase inhibitors are summarized. Furthermore, the biological functions of chitinases, chitin and chitosan utilization by fungi, and the effects of these aspects on biotechnological applications, including protein overexpression and autolysis during industrial processes, are discussed in this review

The Influence of Disorder on Thermotropic Nematic Liquid Crystals Phase Behavior

We review the theoretical research on the influence of disorder on structure and phase behavior of condensed matter system exhibiting continuous symmetry breaking focusing on liquid crystal phase transitions. We discuss the main properties of liquid crystals as adequate systems in which several open questions with respect to the impact of disorder on universal phase and structural behavior could be explored. Main advantages of liquid crystalline materials and different experimental realizations of random field-type disorder imposed on liquid crystal phases are described

Functional Remineralization of Dentin Lesions Using Polymer-Induced Liquid-Precursor Process

It was hypothesized that applying the polymer-induced liquid-precursor (PILP) system to artificial lesions would result in time-dependent functional remineralization of carious dentin lesions that restores the mechanical properties of demineralized dentin matrix. 140 µm deep artificial caries lesions were remineralized via the PILP process for 7–28 days at 37°C to determine temporal remineralization characteristics. Poly-L-aspartic acid (27 KDa) was used as the polymeric process-directing agent and was added to the remineralization solution at a calcium-to-phosphate ratio of 2.14 (mol/mol). Nanomechanical properties of hydrated artificial lesions had a low reduced elastic modulus (ER = 0.2 GPa) region extending about 70 μm into the lesion, with a sloped region to about 140 μm where values reached normal dentin (18–20 GPa). After 7 days specimens recovered mechanical properties in the sloped region by 51% compared to the artificial lesion. Between 7–14 days, recovery of the outer portion of the lesion continued to a level of about 10 GPa with 74% improvement. 28 days of PILP mineralization resulted in 91% improvement of ER compared to the artificial lesion. These differences were statistically significant as determined from change-point diagrams. Mineral profiles determined by micro x-ray computed tomography were shallower than those determined by nanoindentation, and showed similar changes over time, but full mineral recovery occurred after 14 days in both the outer and sloped portions of the lesion. Scanning electron microscopy and energy dispersive x-ray analysis showed similar morphologies that were distinct from normal dentin with a clear line of demarcation between the outer and sloped portions of the lesion. Transmission electron microscopy and selected area electron diffraction showed that the starting lesions contained some residual mineral in the outer portions, which exhibited poor crystallinity. During remineralization, intrafibrillar mineral increased and crystallinity improved with intrafibrillar mineral exhibiting the orientation found in normal dentin or bone

De las catacumbas a los últimos confines: violencia, sentido y representación en los periplos del martirio

En este trabajo propongo un análisis transversal de las figuras del mártir y del martirio. Recurriendo a la noción de mediación, en la primera parte analizo el rol protagónico de las representaciones del martirio en las prácticas de la memoria durante la segunda mitad del siglo XVI. Analizo algunas de las condiciones que contribuyeron a la emergencia de una "cultura del martirio" y el rol de las mediaciones en tal surgimiento. En la segunda parte, estudio la forma en que el (re)descubrimiento de las catacumbas romanas, abrió un campo de producción de sentido en torno a la figura del martirio. En la tercera parte, centrándome en la Compañía de Jesús, analizo algunas mediaciones a través de las cuáles las figuras del martirio transgredieron las fronteras de iglesias y conventos para proyectarse a los últimos confines en un mundo en plena expansión.Neste artigo proponho uma análise transversal das figuras do mártir e do martírio. Usando a noção de mediação, na primeira parte eu tento analisar o papel de liderança de representações de martírio em práticas de memória durante a segunda metade do século XVI. Eu analiso algumas das condições que contribuíram para o surgimento de uma "cultura do martírio" e o papel da mediação nesta emergência. Na segunda parte, eu estudo como a (re) descoberta das catacumbas romanas abriu um campo de produção de significados em torno da figura do martírio. Na terceira parte, com foco na Companhia de Jesus, analiso algumas mediações pelas quais as representações do martírio transgrediram as fronteiras de igrejas e conventos para se projetar nas fronteiras de um mundo em plena expansão mundial.This paper proposes a cross-sectional analysis of martyr and martyrdom. Through the notion of mediation, in the first part I analyze the leading role of representations of martyrdom in memory practices during the second half of the sixteenth century. I analyze some of the conditions that contributed to the emergence of a "martyrdom's culture" and the role of mediation in such emergence. The second part studies how the (re)discovery of the Roman catacombs encouraged the production of meanings around the figure of martyrdom. In the third part, focusing on the Society of Jesus, I analyze a few instances of mediation through which the figures of martyrdom transgressed the boundaries of churches and convents to project themselves to the last frontiers of a world in full expansion.Fil: Salamanca Villamizar, Carlos Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Comparative Genomics of Gardnerella vaginalis Strains Reveals Substantial Differences in Metabolic and Virulence Potential

Gardnerella vaginalis is described as a common vaginal bacterial species whose presence correlates strongly with bacterial vaginosis (BV). Here we report the genome sequencing and comparative analyses of three strains of G. vaginalis. Strains 317 (ATCC 14019) and 594 (ATCC 14018) were isolated from the vaginal tracts of women with symptomatic BV, while Strain 409-05 was isolated from a healthy, asymptomatic individual with a Nugent score of 9.Substantial genomic rearrangement and heterogeneity were observed that appeared to have resulted from both mobile elements and substantial lateral gene transfer. These genomic differences translated to differences in metabolic potential. All strains are equipped with significant virulence potential, including genes encoding the previously described vaginolysin, pili for cytoadhesion, EPS biosynthetic genes for biofilm formation, and antimicrobial resistance systems, We also observed systems promoting multi-drug and lantibiotic extrusion. All G. vaginalis strains possess a large number of genes that may enhance their ability to compete with and exclude other vaginal colonists. These include up to six toxin-antitoxin systems and up to nine additional antitoxins lacking cognate toxins, several of which are clustered within each genome. All strains encode bacteriocidal toxins, including two lysozyme-like toxins produced uniquely by strain 409-05. Interestingly, the BV isolates encode numerous proteins not found in strain 409-05 that likely increase their pathogenic potential. These include enzymes enabling mucin degradation, a trait previously described to strongly correlate with BV, although commonly attributed to non-G. vaginalis species.Collectively, our results indicate that all three strains are able to thrive in vaginal environments, and therein the BV isolates are capable of occupying a niche that is unique from 409-05. Each strain has significant virulence potential, although genomic and metabolic differences, such as the ability to degrade mucin, indicate that the detection of G. vaginalis in the vaginal tract provides only partial information on the physiological potential of the organism

Effectiveness of manual therapies: the UK evidence report

<p>Abstract</p> <p>Background</p> <p>The purpose of this report is to provide a succinct but comprehensive summary of the scientific evidence regarding the effectiveness of manual treatment for the management of a variety of musculoskeletal and non-musculoskeletal conditions.</p> <p>Methods</p> <p>The conclusions are based on the results of systematic reviews of randomized clinical trials (RCTs), widely accepted and primarily UK and United States evidence-based clinical guidelines, plus the results of all RCTs not yet included in the first three categories. The strength/quality of the evidence regarding effectiveness was based on an adapted version of the grading system developed by the US Preventive Services Task Force and a study risk of bias assessment tool for the recent RCTs.</p> <p>Results</p> <p>By September 2009, 26 categories of conditions were located containing RCT evidence for the use of manual therapy: 13 musculoskeletal conditions, four types of chronic headache and nine non-musculoskeletal conditions. We identified 49 recent relevant systematic reviews and 16 evidence-based clinical guidelines plus an additional 46 RCTs not yet included in systematic reviews and guidelines.</p> <p>Additionally, brief references are made to other effective non-pharmacological, non-invasive physical treatments.</p> <p>Conclusions</p> <p>Spinal manipulation/mobilization is effective in adults for: acute, subacute, and chronic low back pain; migraine and cervicogenic headache; cervicogenic dizziness; manipulation/mobilization is effective for several extremity joint conditions; and thoracic manipulation/mobilization is effective for acute/subacute neck pain. The evidence is inconclusive for cervical manipulation/mobilization alone for neck pain of any duration, and for manipulation/mobilization for mid back pain, sciatica, tension-type headache, coccydynia, temporomandibular joint disorders, fibromyalgia, premenstrual syndrome, and pneumonia in older adults. Spinal manipulation is not effective for asthma and dysmenorrhea when compared to sham manipulation, or for Stage 1 hypertension when added to an antihypertensive diet. In children, the evidence is inconclusive regarding the effectiveness for otitis media and enuresis, and it is not effective for infantile colic and asthma when compared to sham manipulation.</p> <p>Massage is effective in adults for chronic low back pain and chronic neck pain. The evidence is inconclusive for knee osteoarthritis, fibromyalgia, myofascial pain syndrome, migraine headache, and premenstrual syndrome. In children, the evidence is inconclusive for asthma and infantile colic.</p

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes