Opioids depress cortical centers responsible for the volitional control of respiration

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem

Stable isotope values in modern bryozoan carbonate from New Zealand and implications for paleoenvironmental interpretation

Bryozoan carbonate contains useful geochemical evidence of temperate shelf paleoenvironments. Stable isotope values were determined for 103 modern marine bryozoan skeletons representing 30 species from New Zealand. δ18O values range from -1.4 to 2.8 VPDB, while δ13C range from -4.5 to 2.8 VPDB (values uncorrected for mineralogical variation). These values are distinct from those of both tropical marine skeletons and New Zealand Tertiary fossils. Most bryozoans secrete carbonate in or near isotopic equilibrium with sea water, except for Celleporina and Steginoporella. The complex and variable mineralogies of the bryozoans reported here make correction for mineralogical effects problematic. Nevertheless, mainly aragonitic forms display higher isotope values, as anticipated. Both temperature and salinity constrain δ18O and δ13C values, and vary with latitude and water depth. Ten samples from a single branch of Cinctipora elegans from the Otago shelf cover a narrow range, although the striking difference in carbon isotope values between the endozone and exozone probably reflects different mineralisation histories. Our stable isotope results from three different laboratories on a single population from a single location are encouragingly consistent. Monomineralic bryozoans, when carefully chosen to avoid species suspected of vital fractionation, have considerable potential as geochemical paleoenvironmental indicators, particularly in temperate marine environments where bryozoans are dominant sediment producers

Higher Structures in M-Theory

The key open problem of string theory remains its non-perturbative completion to M-theory. A decisive hint to its inner workings comes from numerous appearances of higher structures in the limits of M-theory that are already understood, such as higher degree flux fields and their dualities, or the higher algebraic structures governing closed string field theory. These are all controlled by the higher homotopy theory of derived categories, generalised cohomology theories, and $L_\infty$-algebras. This is the introductory chapter to the proceedings of the LMS/EPSRC Durham Symposium on Higher Structures in M-Theory. We first review higher structures as well as their motivation in string theory and beyond. Then we list the contributions in this volume, putting them into context.Comment: 22 pages, Introductory Article to Proceedings of LMS/EPSRC Durham Symposium Higher Structures in M-Theory, August 2018, references update

A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED

RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes. METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement. RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity

The Anatomy of the bill Tip of Kiwi and Associated Somatosensory Regions of the Brain: Comparisons with Shorebirds

Three families of probe-foraging birds, Scolopacidae (sandpipers and snipes), Apterygidae (kiwi), and Threskiornithidae (ibises, including spoonbills) have independently evolved long, narrow bills containing clusters of vibration-sensitive mechanoreceptors (Herbst corpuscles) within pits in the bill-tip. These ‘bill-tip organs’ allow birds to detect buried or submerged prey via substrate-borne vibrations and/or interstitial pressure gradients. Shorebirds, kiwi and ibises are only distantly related, with the phylogenetic divide between kiwi and the other two taxa being particularly deep. We compared the bill-tip structure and associated somatosensory regions in the brains of kiwi and shorebirds to understand the degree of convergence of these systems between the two taxa. For comparison, we also included data from other taxa including waterfowl (Anatidae) and parrots (Psittaculidae and Cacatuidae), non-apterygid ratites, and other probe-foraging and non probe-foraging birds including non-scolopacid shorebirds (Charadriidae, Haematopodidae, Recurvirostridae and Sternidae). We show that the bill-tip organ structure was broadly similar between the Apterygidae and Scolopacidae, however some inter-specific variation was found in the number, shape and orientation of sensory pits between the two groups. Kiwi, scolopacid shorebirds, waterfowl and parrots all shared hypertrophy or near-hypertrophy of the principal sensory trigeminal nucleus. Hypertrophy of the nucleus basorostralis, however, occurred only in waterfowl, kiwi, three of the scolopacid species examined and a species of oystercatcher (Charadriiformes: Haematopodidae). Hypertrophy of the principal sensory trigeminal nucleus in kiwi, Scolopacidae, and other tactile specialists appears to have co-evolved alongside bill-tip specializations, whereas hypertrophy of nucleus basorostralis may be influenced to a greater extent by other sensory inputs. We suggest that similarities between kiwi and scolopacid bill-tip organs and associated somatosensory brain regions are likely a result of similar ecological selective pressures, with inter-specific variations reflecting finer-scale niche differentiation

Self-Association of the glycan antibiotic teicoplanin A2 in aqueous solution studied by molecular hydrodynamics

The semi-synthetic glycan antibiotic teicoplanin is used for the treatment of serious Gram-positive related bacterial infections and can be administered intravenously, intramuscularly, topically (ocular infections), or orally. It has also been considered for targeting viral infection by SARS-CoV-2. The hydrodynamic properties of teicoplanin A2 (monomer molar mass ~ 1880 g/mol) were examined in phosphate chloride buffer (pH 6.8, I = 0.10 M) using sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge together with capillary (rolling ball) viscometry. In the concentration range, 0-10 mg/mL teicoplanin A2 was found to self-associate plateauing > 1 mg/mL to give a molar mass of (35400 ± 1000) g/mol corresponding to ~ (19 ± 1) mers, with a sedimentation coefficient s20,w = ~ 4.65 S. The intrinsic viscosity [h] was found to be (3.2 ± 0.1) mL/g: both this, the value for s20,w and the hydrodynamic radius from dynamic light scattering is consistent with a globular macromolecular assembly, with a swelling ratio through dynamic hydration processes of ~2

Mathematical practice, crowdsourcing, and social machines

The highest level of mathematics has traditionally been seen as a solitary endeavour, to produce a proof for review and acceptance by research peers. Mathematics is now at a remarkable inflexion point, with new technology radically extending the power and limits of individuals. Crowdsourcing pulls together diverse experts to solve problems; symbolic computation tackles huge routine calculations; and computers check proofs too long and complicated for humans to comprehend. Mathematical practice is an emerging interdisciplinary field which draws on philosophy and social science to understand how mathematics is produced. Online mathematical activity provides a novel and rich source of data for empirical investigation of mathematical practice - for example the community question answering system {\it mathoverflow} contains around 40,000 mathematical conversations, and {\it polymath} collaborations provide transcripts of the process of discovering proofs. Our preliminary investigations have demonstrated the importance of "soft" aspects such as analogy and creativity, alongside deduction and proof, in the production of mathematics, and have given us new ways to think about the roles of people and machines in creating new mathematical knowledge. We discuss further investigation of these resources and what it might reveal. Crowdsourced mathematical activity is an example of a "social machine", a new paradigm, identified by Berners-Lee, for viewing a combination of people and computers as a single problem-solving entity, and the subject of major international research endeavours. We outline a future research agenda for mathematics social machines, a combination of people, computers, and mathematical archives to create and apply mathematics, with the potential to change the way people do mathematics, and to transform the reach, pace, and impact of mathematics research.Comment: To appear, Springer LNCS, Proceedings of Conferences on Intelligent Computer Mathematics, CICM 2013, July 2013 Bath, U

Comparative hydrodynamic and nanoscale imaging study on the interactions of teicoplanin-A2 and bovine submaxillary mucin as a model ocular mucin

Glycopeptide antibiotics are regularly used in ophthalmology to treat infections of Gram-positive bacteria. Aggregative interactions of antibiotics with mucins however can lead to long exposure and increases the risk of resistant species. This study focuses on the evaluation of potential interactions of the last line of defence glycopeptide antibiotic teicoplanin with an ocular mucin model using precision matrix free hydrodynamic and microscopic techniques: sedimentation velocity in the analytical ultracentrifuge (SV-AUC), dynamic light scattering (DLS) and atomic force microscopy (AFM). For the mixtures of teicoplanin at higher doses (1.25 mg/mL and 12.5 mg/mL), it was shown to interact and aggregate with bovine submaxillary mucin (BSM) in the distributions of both sedimentation coefficients by SV-AUC and hydrodynamic radii by DLS. The presence of aggregates was confirmed by AFM for higher concentrations. We suggest that teicoplanin eye drop formulations should be delivered at concentrations of < 1.25 mg/mL to avoid potentially harmful aggregations

Self-association of the glycopeptide antibiotic teicoplanin A2 in aqueous solution studied by molecular hydrodynamics

AbstractThe natural glycopeptide antibiotic teicoplanin is used for the treatment of serious Gram-positive related bacterial infections and can be administered intravenously, intramuscularly, topically (ocular infections), or orally. It has also been considered for targeting viral infection by SARS-CoV-2. The hydrodynamic properties of teicoplanin A2 (M1 = 1880 g/mol) were examined in phosphate chloride buffer (pH 6.8, I = 0.10 M) using sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge together with capillary (rolling ball) viscometry. In the concentration range, 0–10 mg/mL teicoplanin A2 was found to self-associate plateauing &gt; 1 mg/mL to give a molar mass of (35,400 ± 1000) g/mol corresponding to ~ (19 ± 1) mers, with a sedimentation coefficient s20, w =  ~ 4.65 S. The intrinsic viscosity [$$\eta$$ η ] was found to be (3.2 ± 0.1) mL/g: both this, the value for s20,w and the hydrodynamic radius from dynamic light scattering are consistent with a globular macromolecular assembly, with a swelling ratio through dynamic hydration processes of ~ 2. </jats:p

Portación de Staphylococcus aureus en manipuladores de alimentos de la ciudad de Gualeguaychú

Food handlers in the community who do not have good personal hygiene can be vehicles for transmission of Staphylococcus aureus (SAU). Their strains have become increasingly resistant to beta-lactam antibiotics, which is a problem for food safety. Isolation was performed on samples of hands and nostrils of 49 ice cream dispensers and 43 food handlers. Methicillin resistance was determined in the positive samples using the cefoxitin disk diffusion technique (30 μg) and 24 positive SAU samples were also subjected to enterotoxin detection using VIDAS Staph enterotoxy reagents. Hygienic habits were evaluated, applying a questionnaire. Of the ice cream sellers, 19 were carriers (39%); for the handlers at educational institutions this percentage was 47% (n = 20). Habits and knowledge found have flaws. For the first sampling (n = 30), a resistance in nostrils of 13% (n = 4) and for hands of 7% was obtained, and in the second (n = 20), of 20% (n = 4) and of 5% (n = 1) respectively and for educational institutions (n ​​= 43), of 25% (n = 11) for nostrils and of 19% (n = 8) for hands. They were enterotoxigenic (33%) of the strains. The results showed the presence of MRSA among these handlers and the risk of being disseminators. Courses should focus on preventive measures of contamination of food and talk about the importance of this issue working interdisciplinary with professionals in the field and with those responsible for public health.Los elaboradores que preparan alimentos y no mantienen una buena higiene personal pueden ser vehículos de transmisión de Staphylococcus aureus (SAU); microorganismo causante de intoxicaciones alimentarias que últimamente se ha tornado más resistente a antibióticos betalactámicos, representando un problema en salud pública. Se lo aisló e identificó en muestras de manos y narinas de 49 expendedores de helados y 43 elaboradores de alimentos en instituciones educativas, se empleó la técnica de difusión con disco de cefoxitina (30 µg) propuesta por CLSI (Clinical &amp; Laboratory Standards Institute) para determinar su resistencia a meticilina. Se evaluaron los hábitos higiénicos aplicando un cuestionario de autoinforme y a 24 cepas extraidas de 24 muestras seleccionadas al azar que fueron SAU positivas, se les realizó la detección de enterotoxinas utilizando reactivos VIDAS Staph enterotoxin. Se obtuvo que un 39% de los expendedores y un 47% de los elaboradores resultaron portadores. El primer muestreo (n=30), marcó una resistencia en narinas del 13% y manos de 7%, en los muestreos siguientes se observó un incremento de SARM (Staphylococcus aureus resistente a meticilina). Respecto a la detección de toxinas de las 24 cepas investigadas, 8 resultaron enterotoxigénicas (33%). Los hábitos y conocimientos evaluados marcaron falencias en puntos críticos, los resultados mostraron la presencia de SARM entre los manipuladores con riesgo de ser diseminadores de dichas cepas. Se deberían programar cursos haciendo énfasis en medidas preventivas que eviten la contaminación alimentaria, realizando un plan de concientización a la población y utilizando estos datos como punto de partida. Es necesario trabajar en forma interdisciplinaria con profesionales afines y responsables de salud pública