Numerical Model of Geochronological Tracers for Deposition and Reworking Applied to the Mississippi Subaqueous Delta

Measurements of naturally occurring, short-lived radioisotopes from sediment cores on the Mississippi subaqueous delta have been used to infer event bed characteristics such as depositional thicknesses and accumulation rates. Specifically, the presence of Beryllium-7 (Be-7) indicates recent riverine-derived terrestrial sediment deposition; while Thorium-234 (Th-234) provides evidence of recent suspension in marine waters. Sediment transport models typically represent coastal flood and storm deposition via estimated grain size patterns and deposit thicknesses, however, and do not directly calculate radioisotope activities and profiles, which leads to a disconnect between the numerical model and field observations. Here, observed radioisotopic profiles from the Mississippi subaqueous delta cores were directly related to a numerical model that represented resuspension and deposition using a new approach to account for the behavior of short-lived radioisotopes. Appropriate selection of parameters such as the bioditfusion coefficient, sediment accumulation rate, and radioisotopic source terms enabled a good match between the modeled and observed cores. Comparisons of modelled profiles with geochronological analytical models that estimate accumulation rate and flood layer thickness revealed potential avenues for refining these tools, and highlight the importance of constraining the biodiffusion coefficient

Spectral dynamic causal modelling in healthy women reveals brain connectivity changes along the menstrual cycle

Longitudinal menstrual cycle studies allow to investigate the effects of ovarian hormones on brain organization. Here, we use spectral dynamic causal modelling (spDCM) in a triple network model to assess effective connectivity changes along the menstrual cycle within and between the default mode, salience and executive control networks (DMN, SN, and ECN). Sixty healthy young women were scanned three times along their menstrual cycle, during early follicular, pre-ovulatory and mid-luteal phase. Related to estradiol, right before ovulation the left insula recruits the ECN, while the right middle frontal gyrus decreases its connectivity to the precuneus and the DMN decouples into anterior/posterior parts. Related to progesterone during the mid-luteal phase, the insulae (SN) engage to each other, while decreasing their connectivity to parietal ECN, which in turn engages the posterior DMN. When including the most confident connections in a leave-one out cross-validation, we find an above-chance prediction of the left-out subjects’ cycle phase. These findings corroborate the plasticity of the female brain in response to acute hormone fluctuations and may help to further understand the neuroendocrine interactions underlying cognitive changes along the menstrual cycle

Identification of a small molecule inhibitor of Ebolavirus genome replication and transcription using in silico screening.

Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen. Here, we describe a drug discovery pathway combining in silico screening of compounds predicted to bind to a hydrophobic pocket on the nucleoprotein (NP); with a robust and rapid EBOV minigenome assay for inhibitor validation at BSL2. One compound (MCCB4) was efficacious (EC50 4.8 μM), exhibited low cytotoxicity (CC50 > 100 μM) and was specific, with no effect on either a T7 RNA polymerase driven firefly luciferase or a Bunyamwera virus minigenome. Further investigations revealed that this small molecule inhibitor was able to outcompete established replication complexes, an essential aspect for a potential EBOV treatment

Direct load monitoring of rolling bearing contacts using ultrasonic time of flight

The load applied by each rolling element on a bearing raceway controls friction, wear and service life. It is possible to infer bearing load from load cells or strain gauges on the shaft or bearing housing. However, this is not always simply and uniquely related to the real load transmitted by rolling elements directly to the raceway. Firstly, the load sharing between rolling elements in the raceway is statically indeterminate, and secondly, in a machine with non-steady loading, the load path is complex and highly transient being subject to the dynamic behaviour of the transmission system. This study describes a method to measure the load transmitted directly by a rolling element to the raceway by using the time of flight (ToF) of a reflected ultrasonic pulse. A piezoelectric sensor was permanently bonded onto the bore surface of the inner raceway of a cylindrical roller bearing. The ToF of an ultrasonic pulse from the sensor to the roller-raceway contact was measured. This ToF depends on the speed of the wave and the thickness of the raceway. The speed of an ultrasonic wave changes with the state of the stress, known as the acoustoelastic effect. The thickness of the material varies when deflection occurs as the contacting surfaces are subjected to load. In addition, the contact stiffness changes the phase of the reflected signal and in simple peak-to-peak measurement, this appears as a change in the ToF. In this work, the Hilbert transform was used to remove this contact dependent phase shift. Experiments have been performed on both a model line contact and a single row cylindrical roller bearing from the planet gear of a wind turbine epicyclic gearbox. The change in ToF under different bearing loads was recorded and used to determine the deflection of the raceway. This was then related to the bearing load using a simple elastic contact model. Measured load from the ultrasonic reflection was compared with the applied bearing load with good agreement. The technique shows promise as an effective method for load monitoring in real-world bearing applications

Immuno-oncology combinations: raising the tail of the survival curve.

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design

Biosemiotics, politics and Th.A. Sebeok’s move from linguistics to semiotics

This paper will focus on the political implications for the language sciences of Sebeok’s move from linguistics to a global semiotic perspective, a move that ultimately resulted in biosemiotics. The paper will seek to make more explicit the political bearing of a biosemiotic perspective in the language sciences and the human sciences in general. In particular, it will discuss the definition of language inherent in Sebeok’s project and the fundamental re-drawing of the grounds of linguistic debate heralded by Sebeok’s embrace of the concept of modelling. Thus far, the political co-ordinates of the biosemiotic project have not really been made explicit. This paper will therefore seek to outline 1. how biosemiotics enables us to reconfigure our understanding of the role of language in culture; 2. how exaptation is central to the evolution of language and communication, rather than adaptation; 3. how communication is the key issue in biosphere, rather than language, not just because communication includes language but because the language sciences often refer to language as if it were mere “chatter”, “tropes” and “figures of speech”; 4. how biosemiotics, despite its seeming “neutrality” arising from its transdisciplinarity, is thoroughly political; 5. how the failure to see the implications of the move from linguistics to semiotics arises from the fact that biosemiotics is devoid of old style politics, which is based on representation (devoid of experience) and “construction of [everything] in discourse” (which is grounded in linguistics, not communication study). In contrast to the post-“linguistic turn” idea that the world is “constructed in discourse”, we will argue that biosemiotics entails a reconfiguration of the polis and, in particular, offers the chance to completely reconceptualise ideology

Cloning and expression of activation induced cytidine deaminase from Bos taurus'

Activation induced cytidine deaminase is an enzyme crucial to somatic hypermutation and gene conversion, processes that are essential for the diversification of Ig V genes. The bovine Ig repertoire appears to be diversified by mechanisms that are significantly different to those that operate in humans and mice. This study set out to test the hypothesis that differences in the organization, coding sequence, expression or genomic location of the bovine AICDA gene enables the encoded enzyme to catalyse the unusual Ig diversification mechanism seen in cattle as well as conventional antigen-driven mutation. Characterization of bovine AICDA excluded the first two possibilities. AICDA expression was detected in lymphoid tissues from neonatal and older cattle, but AICDA cDNA could not be detected in muscle tissue. The pattern of gene expression did not therefore differ from that in other vertebrates. The AICDA cDNA was cloned and expressed successfully in Escherichia coli generating a phenotype consistent with the mutating action of this deaminase. Using a whole genome radiation hybrid panel, bovine AICDA was mapped to a region of bovine chromosome 5 syntenic with the location of human AICDA on chromosome 12. We conclude that the unusual nature of Ig diversification in cattle is unlikely to be attributable to the structure, sequence, activity or genomic location of bovine AICDA

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS

Molecular Structure and Confining Environment of Sn Sites in Single-Site Chabazite Zeolites

Chabazite (CHA) molecular sieves, which are industrial catalysts for the selective reduction of nitrogen oxides and the conversion of methanol into olefins, are also ideal materials in catalysis research because their crystalline frameworks contain one unique tetrahedral-site. The presence of a single lattice site allows for more accurate descriptions of experimental data using theoretical models, and consequently for more precise structure-function relationships of active sites incorporated into framework positions. A direct hydrothermal synthesis route to prepare pure-silica chabazite molecular sieves substituted with framework Sn atoms (Sn-CHA) is developed, which is required to predominantly incorporate Sn within the crystalline lattice. Quantitative titra-tion with Lewis bases (NH3, CD3CN, pyridine) demonstrates that framework Sn atoms behave as Lewis acid sites, which catalyze intermolecular propionaldehyde reduction and ethanol oxidation, as well as glucose-fructose isomerization. Aqueous-phase glucose isomerization turnover rates on Sn-CHA are four orders-of-magnitude lower than on Sn-Beta zeolites, but similar to those on amorphous Sn-silicates. Further analysis of Sn-CHA by dynamic nuclear polarization enhanced solid-state nuclear magnetic reso-nance (DNP NMR) spectroscopy enables measurement of 119Sn NMR chemical shift anisotropy (CSA) of Sn sites. Comparison of experimentally determined CSA parameters to those computed on cluster models using density functional theory supports the pres-ence of closed sites (Sn-(OSi)4) and defect sites ((HO)-Sn-(OSi)3) adjacent to a framework Si vacancy), which respectively be-come hydrated hydrolyzed-open sites and defect sites when Sn-CHA is exposed to ambient conditions or aqueous solution. Kinetic and spectroscopic data show that large substrates (e.g., glucose) are converted only on Sn sites located within disordered mesopo-rous voids of Sn-CHA, which are selectively detected and quantified in IR and 15N and 119Sn DNP NMR spectra using pyridine titrants. This integrated experimental and theoretical approach allows precise description of the primary coordination and secondary confining environments of Sn active sites isolated in crystalline silica frameworks, and clearly establishes the role of confinement within microporous voids for aqueous-phase glucose isomerization catalysis

Solvolyses of diarylmethyl chlorides. A comprehensive stability scale for diarylcarbenium ions

Eleven donor substituted diarylmethyl chlorides have been solvolyzed in ethanol. The rate constants, determined at 25°C, and additional ethanolysis data taken from the literature have been connected with solvolvsis rate constants, determined in other solvents, to construct a stability scale for 74 diarylcarbenium ions, covering a rate range of> 1012. Correlation equations are given which allow the calculation of solvolysis rates in other solvents, of equilibrium constants, and of rate constants for reactions involving diarylcarbenium ions