Modular Biological Function Is Most Effectively Captured by Combining Molecular Interaction Data Types

PublishedLarge-scale molecular interaction data sets have the potential to provide a comprehensive, system-wide understanding of biological function. Although individual molecules can be promiscuous in terms of their contribution to function, molecular functions emerge from the specific interactions of molecules giving rise to modular organisation. As functions often derive from a range of mechanisms, we demonstrate that they are best studied using networks derived from different sources. Implementing a graph partitioning algorithm we identify subnetworks in yeast protein-protein interaction (PPI), genetic interaction and gene co-regulation networks. Among these subnetworks we identify cohesive subgraphs that we expect to represent functional modules in the different data types. We demonstrate significant overlap between the subgraphs generated from the different data types and show these overlaps can represent related functions as represented by the Gene Ontology (GO). Next, we investigate the correspondence between our subgraphs and the Gene Ontology. This revealed varying degrees of coverage of the biological process, molecular function and cellular component ontologies, dependent on the data type. For example, subgraphs from the PPI show enrichment for 84%, 58% and 93% of annotated GO terms, respectively. Integrating the interaction data into a combined network increases the coverage of GO. Furthermore, the different annotation types of GO are not predominantly associated with one of the interaction data types. Collectively our results demonstrate that successful capture of functional relationships by network data depends on both the specific biological function being characterised and the type of network data being used. We identify functions that require integrated information to be accurately represented, demonstrating the limitations of individual data types. Combining interaction subnetworks across data types is therefore essential for fully understanding the complex and emergent nature of biological function.JIM was funded by a Biotechnology and Biological Sciences Research Council (BBSRC) CASE studentship with industry partner Pfizer and RMA by a BBSRC studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

An optical fibre dynamic instrumented palpation sensor for the characterisation of biological tissue

AbstractThe diagnosis of prostate cancer using invasive techniques (such as biopsy and blood tests for prostate-specific antigen) and non-invasive techniques (such as digital rectal examination and trans-rectal ultrasonography) may be enhanced by using an additional dynamic instrumented palpation approach to prostate tissue classification. A dynamically actuated membrane sensor/actuator has been developed that incorporates an optical fibre Fabry–Pérot interferometer to record the displacement of the membrane when it is pressed on to different tissue samples. The membrane sensor was tested on a silicon elastomer prostate model with enlarged and stiffer material on one side to simulate early stage prostate cancer. The interferometer measurement was found to have high dynamic range and accuracy, with a minimum displacement resolution of ±0.4μm over a 721μm measurement range. The dynamic response of the membrane sensor when applied to different tissue types changed depending on the stiffness of the tissue being measured. This demonstrates the feasibility of an optically tracked dynamic palpation technique for classifying tissue type based on the dynamic response of the sensor/actuator

Parity-Violating Excitation of the \Delta(1232): Hadron Structure and New Physics

We consider prospects for studying the parity-violating (PV) electroweak excitation of the \Delta(1232) resonance with polarized electron scattering. Given present knowledge of Standard Model parameters, such PV experiments could allow a determination of the N -> \Delta electroweak helicity amplitudes. We discuss the experimental feasibility and theoretical interpretability of such a determination as well as the prospective implications for hadron structure theory. We also analyze the extent to which a PV N -> \Delta measurement could constrain various extensions of the Standard Model.Comment: 43 pages, RevTex, 8 PS figures, uses epsf.sty, rotate.sty, version to appear in Nucl. Phys. A, main points emphasized, some typos correcte

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

A Case of Propofol-Induced Oropharyngeal Angioedema and Bronchospasm

Propofol (2,6-diisopropylphenol) is an ultrashort-acting sedative agent with sedative and amnestic effects that is used not only for anesthesia but also for sedation during minor outpatient procedures and endoscopic examinations. Rare cases of anaphylaxis following propofol administration have been reported in the medical literature. Documentation of anaphylaxis is often lacking because the cause and effect relationship is often hard to prove. Only a minority of patients get referred for allergy testing to confirm the offending drug. Here we report a 74-year-old woman who had an anaphylactic reaction with severe oropharyngeal edema and bronchospasm for a few minutes after receiving propofol during endoscopic examination. An allergy skin test was positive for both propofol and soybean. Soybean in the intralipid is one component of propofol, and we concluded that this anaphylaxis was caused by soybean

Tectonic erosion and crustal relamination during the India-Asian continental collision: Insights from Eocene magmatism in the southeastern Gangdese belt

Understanding the processes of tectonic erosion and crustal relamination during continental collision has important implications for the growth and differentiation of the continental crust. The discrepancy in isotopic compositions between the pre- and syn-collision magmatic rocks from the Gangdese belt in south Tibet provides an opportunity for studying these processes during the India-Asian collision. The Nyingchi granites and Confluence hornblende gabbros from the eastern Gangdese belt have zircon U-Pb ages of ca. 50 Ma. The Nyingchi granites have high Sr/Y and (Dy/Yb)N ratios, indicating that the magma was generated under eclogite-facies conditions. Their Sr-Nd-Pb-Hf isotopic compositions require significant incorporation of ancient supracrustal materials from the Gangdese belt and the Indian continent. The Confluence hornblende gabbros display arc-like trace element patterns but have enriched Sr-Nd-Pb-Hf isotopic compositions compared with those from the Jurassic-Cretaceous arc magmatic rocks, indicating significant input of ancient components into their mantle sources. The occurrence of the Cenozoic felsic metamorphic rocks in the lower crust of the Gangdese belt allows us to propose that the Nyingchi high Sr/Y granites were derived from partial melting of relaminated crustal materials which were removed from the Gangdese belt by tectonic erosion and the subducted Indian continent. The Confluence gabbros were sourced from lithospheric mantle which was metasomatized by inputs from relaminated crustal materials derived from the Gangdese belt and the subducted Indian continent. The estimated tectonic erosion rate is 150–188 km3/km/my, indicating significant crustal loss occurred during continental collision. Our study demonstrates that tectonic erosion and crustal relamination play an important role in the refinement of the composition of continental crust during continental collision

mTORC1 underlies ageâ related muscle fiber damage and loss by inducing oxidative stress and catabolism

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these ageâ related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1’s activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3’s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to ageâ related muscle atrophy, and GDF signaling is a proposed mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/1/acel12943-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/2/acel12943.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/3/acel12943-sup-0001-FigS1-S14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/4/acel12943_am.pd

Performance-limiting nanoscale trap clusters at grain junctions in halide perovskites.

Halide perovskite materials have promising performance characteristics for low-cost optoelectronic applications. Photovoltaic devices fabricated from perovskite absorbers have reached power conversion efficiencies above 25 per cent in single-junction devices and 28 per cent in tandem devices1,2. This strong performance (albeit below the practical limits of about 30 per cent and 35 per cent, respectively3) is surprising in thin films processed from solution at low-temperature, a method that generally produces abundant crystalline defects4. Although point defects often induce only shallow electronic states in the perovskite bandgap that do not affect performance5, perovskite devices still have many states deep within the bandgap that trap charge carriers and cause them to recombine non-radiatively. These deep trap states thus induce local variations in photoluminescence and limit the device performance6. The origin and distribution of these trap states are unknown, but they have been associated with light-induced halide segregation in mixed-halide perovskite compositions7 and with local strain8, both of which make devices less stable9. Here we use photoemission electron microscopy to image the trap distribution in state-of-the-art halide perovskite films. Instead of a relatively uniform distribution within regions of poor photoluminescence efficiency, we observe discrete, nanoscale trap clusters. By correlating microscopy measurements with scanning electron analytical techniques, we find that these trap clusters appear at the interfaces between crystallographically and compositionally distinct entities. Finally, by generating time-resolved photoemission sequences of the photo-excited carrier trapping process10,11, we reveal a hole-trapping character with the kinetics limited by diffusion of holes to the local trap clusters. Our approach shows that managing structure and composition on the nanoscale will be essential for optimal performance of halide perovskite devices

Characterization of the SNAG and SLUG Domains of Snail2 in the Repression of E-Cadherin and EMT Induction: Modulation by Serine 4 Phosphorylation

Snail1 and Snail2, two highly related members of the Snail superfamily, are direct transcriptional repressors of E-cadherin and EMT inducers. Previous comparative gene profiling analyses have revealed important differences in the gene expression pattern regulated by Snail1 and Snail2, indicating functional differences between both factors. The molecular mechanism of Snail1-mediated repression has been elucidated to some extent, but very little is presently known on the repression mediated by Snail2. In the present work, we report on the characterization of Snail2 repression of E-cadherin and its regulation by phosphorylation. Both the N-terminal SNAG and the central SLUG domains of Snail2 are required for efficient repression of the E-cadherin promoter. The co-repressor NCoR interacts with Snail2 through the SNAG domain, while CtBP1 is recruited through the SLUG domain. Interestingly, the SNAG domain is absolutely required for EMT induction while the SLUG domain plays a negative modulation of Snail2 mediated EMT. Additionally, we identify here novel in vivo phosphorylation sites at serine 4 and serine 88 of Snail2 and demonstrate the functional implication of serine 4 in the regulation of Snail2-mediated repressor activity of E-cadherin and in Snail2 induction of EMT