Workflow for real-time in-vivo Cherenkov-excited luminescence imaging during radiotherapy

Radiotherapy is a common method for treating tumors, however, radiosensitivity can vary between tumor types or within the tumor microenvironment. The ability to deliver oxygen is crucial for the generation of reactive oxygen species resulting in increased localized cytotoxic effects. Alternatively, hypoxic tumors are thought to indicate a poor prognosis and may benefit from more aggressive treatments, yet identifying tumor hypoxia early in the course of a multi-week fractionated dose regimen is currently impractical. Using a time-gated imaging system and oxygen-sensitive phosphorescent compound (PtG4) we are able to estimate in vivo pO2 distribution at a rate of 2.6 estimates per second, which corresponds to 50+ values during a common 2Gy dose fraction. While our previous work has reported using Cherenkov-excited luminescence to estimate in vivo pO2 during external beam radiotherapy, the dose required was often greater than a standard fraction and camera acquisition parameters required modification during treatments, resulting in interrupted workflows. The current method utilizes custom control software which cycles through camera timing parameters during acquisition. Python code using the web-based user interface JupyterLab allows for interactive analysis of the resulting image stack without the need to pay expensive licensing fees for scientific computing packages. Using open source libraries, the analysis code is able to split the image stack into respective Cherenkov excitation and phosphorescence images, which can then be further automatically segmented to find regions of interest including the subject and phosphorescent region. The intensity of the regions in the phosphorescence images are used to estimate the compound lifetime, which can then be used in the Stern-Volmer relationship to estimate pO2. This entire process does not compromise clinical workflow and is able to provide a pO2 estimate within minutes after delivering the fractionated dose, providing clinicians early feedback about trends in tumor hypoxia. The current method has been validated with both direct injection of 50mM PtG4 in Matrigel in a mouse flank, and 24hrs post IV injection of mouse with MDA-MB-231 tumor implanted in the flank. The mouse with the direct injection was imaged under anesthesia and while awake and mobile to test the ability of the automated segmentation algorithm (Figure below). While the signal from the IV injection was less intense, simultaneous imaging using the previously reported method and current method resulted in similar lifetime estimates. While oxygen-sensitive PtG4 exhibits a lifetime between 16ms under atmospheric oxygen and 47ms when deprived of oxygen, other compounds have also been investigated. Europium chelate nanoparticle (~600ms), Iridium-based small molecules (~5ms), Si nanoparticles (~60ms), and UV-sensitive tattoo inks (~15ms) have all been imaged using Cherenkov-excitation. Camera time-gating can be utilized to discriminate these compound when mixed in the same field, allowing for additional tools in the realm of contrast enhancement during radiotherapy imaging. Ongoing studies with PtG4 and other compounds are being conducted to further improve system sensitivity and refine imaging workflows so they are more clinically translatable. Please click Additional Files below to see the full abstract

Experimental study of electrical heating to enhance oil production from oil-wet carbonate reservoirs

New approaches for enhanced oil recovery (EOR) with a reduced environmental footprint are required to improve recovery from mature oil fields, and when combined with carbon capture and storage (CCS) can provide useful options for resource maximisation during the net zero transition. Electrical heating is investigated as a potential EOR method in carbonate reservoirs. Samples were placed in an apparatus surrounded by a wire coil across which different DC (direct current) voltages were applied. Monitoring the imbibition of both deionized water (DW) and seawater (SW) into initially oil-wet Austin chalk showed that water imbibed into the rock faster when heated in the presence of a magnetic field. This was associated with a reduction in the water–air contact angle over time measured on the external surface of the sample. Without heating, the contact angle reduced from 127° approaching water-wet conditions, 90°, in 52 min, while in the presence of heating with 3 V, 6 V, and 9 V applied across a sample 17 mm in length, the time required to reach the same contact angle was only 47, 38 and 26 min, respectively, while a further reduction in contact angle was witnessed with SW. The ultimate recovery factor (RF) for an initially oil-wet sample imbibed by DW was 13% while by seawater (SW) the recorded RF was 26% in the presence of an electrical heating compared with 2.8% for DW and 11% for SW without heating. We propose heating as an effective way to improve oil recovery, enhancing capillary-driven natural water influx, and observe that renewable-powered heating for EOR with CCS may be one option to improve recovery from mature oil fields with low environmental footprint

Central Bank Announcements: Big News for Little People?

Little is known on how and whether central bank announcements affect consumers' beliefs about policy relevant economic figures. This paper focuses on consumers' perceptions and expectations of inflation and interest rates and confidence therein. Based on a sound identification (running surveys shortly before and after communication events), and relying on above 15 000 observations, spanning over 12 FOMC press conferences between December 2015 and June 2018, we document the impact of the central bank communication on ordinary people. While announcement events have little measurable direct effect on average beliefs, they make people more likely to receive news about the central bank's policy. In general, informed consumers tend to have lower perceptions and expectations, higher confidence and, to an extent, better quality beliefs

Potential Conservation Laws

We prove that potential conservation laws have characteristics depending only on local variables if and only if they are induced by local conservation laws. Therefore, characteristics of pure potential conservation laws have to essentially depend on potential variables. This statement provides a significant generalization of results of the recent paper by Bluman, Cheviakov and Ivanova [J. Math. Phys., 2006, V.47, 113505]. Moreover, we present extensions to gauged potential systems, Abelian and general coverings and general foliated systems of differential equations. An example illustrating possible applications of proved statements is considered. A special version of the Hadamard lemma for fiber bundles and the notions of weighted jet spaces are proposed as new tools for the investigation of potential conservation laws.Comment: 36 pages, extended versio

The globin gene family of the cephalochordate amphioxus: implications for chordate globin evolution

<p>Abstract</p> <p>Background</p> <p>The lancelet amphioxus (Cephalochordata) is a close relative of vertebrates and thus may enhance our understanding of vertebrate gene and genome evolution. In this context, the globins are one of the best studied models for gene family evolution. Previous biochemical studies have demonstrated the presence of an intracellular globin in notochord tissue and myotome of amphioxus, but the corresponding gene has not yet been identified. Genomic resources of <it>Branchiostoma floridae </it>now facilitate the identification, experimental confirmation and molecular evolutionary analysis of its globin gene repertoire.</p> <p>Results</p> <p>We show that <it>B. floridae </it>harbors at least fifteen paralogous globin genes, all of which reveal evidence of gene expression. The protein sequences of twelve globins display the conserved characteristics of a functional globin fold. In phylogenetic analyses, the amphioxus globin BflGb4 forms a common clade with vertebrate neuroglobins, indicating the presence of this nerve globin in cephalochordates. Orthology is corroborated by conserved syntenic linkage of <it>BflGb4 </it>and flanking genes. The kinetics of ligand binding of recombinantly expressed BflGb4 reveals that this globin is hexacoordinated with a high oxygen association rate, thus strongly resembling vertebrate neuroglobin. In addition, possible amphioxus orthologs of the vertebrate globin X lineage and of the myoglobin/cytoglobin/hemoglobin lineage can be identified, including one gene as a candidate for being expressed in notochord tissue. Genomic analyses identify conserved synteny between amphioxus globin-containing regions and the vertebrate <it>β-globin </it>locus, possibly arguing against a late transpositional origin of the <it>β-globin </it>cluster in vertebrates. Some amphioxus globin gene structures exhibit minisatellite-like tandem duplications of intron-exon boundaries ("mirages"), which may serve to explain the creation of novel intron positions within the globin genes.</p> <p>Conclusions</p> <p>The identification of putative orthologs of vertebrate globin variants in the <it>B. floridae </it>genome underlines the importance of cephalochordates for elucidating vertebrate genome evolution. The present study facilitates detailed functional studies of the amphioxus globins in order to trace conserved properties and specific adaptations of respiratory proteins at the base of chordate evolution.</p

Tails of probability density for sums of random independent variables

The exact expression for the probability density $p_{_N}(x)$ for sums of a finite number $N$ of random independent terms is obtained. It is shown that the very tail of $p_{_N}(x)$ has a Gaussian form if and only if all the random terms are distributed according to the Gauss Law. In all other cases the tail for $p_{_N}(x)$ differs from the Gaussian. If the variances of random terms diverge the non-Gaussian tail is related to a Levy distribution for $p_{_N}(x)$. However, the tail is not Gaussian even if the variances are finite. In the latter case $p_{_N}(x)$ has two different asymptotics. At small and moderate values of $x$ the distribution is Gaussian. At large $x$ the non-Gaussian tail arises. The crossover between the two asymptotics occurs at $x$ proportional to $N$. For this reason the non-Gaussian tail exists at finite $N$ only. In the limit $N$ tends to infinity the origin of the tail is shifted to infinity, i. e., the tail vanishes. Depending on the particular type of the distribution of the random terms the non-Gaussian tail may decay either slower than the Gaussian, or faster than it. A number of particular examples is discussed in detail.Comment: 6 pages, 4 figure

RegTransBase—a database of regulatory sequences and interactions in a wide range of prokaryotic genomes

RegTransBase is a manually curated database of regulatory interactions in prokaryotes that captures the knowledge in public scientific literature using a controlled vocabulary. Although several databases describing interactions between regulatory proteins and their binding sites are already being maintained, they either focus mostly on the model organisms Escherichia coli and Bacillus subtilis or are entirely computationally derived. RegTransBase describes a large number of regulatory interactions reported in many organisms and contains the following types of experimental data: the activation or repression of transcription by an identified direct regulator, determining the transcriptional regulatory function of a protein (or RNA) directly binding to DNA (RNA), mapping or prediction of a binding site for a regulatory protein and characterization of regulatory mutations. Currently, RegTransBase content is derived from about 3000 relevant articles describing over 7000 experiments in relation to 128 microbes. It contains data on the regulation of about 7500 genes and evidence for 6500 interactions with 650 regulators. RegTransBase also contains manually created position weight matrices (PWM) that can be used to identify candidate regulatory sites in over 60 species. RegTransBase is available at

The Random Nature of Genome Architecture: Predicting Open Reading Frame Distributions

Background: A better understanding of the size and abundance of open reading frames (ORFS) in whole genomes may shed light on the factors that control genome complexity. Here we examine the statistical distributions of open reading frames (i.e. distribution of start and stop codons) in the fully sequenced genomes of 297 prokaryotes, and 14 eukaryotes. Methodology/Principal Findings: By fitting mixture models to data from whole genome sequences we show that the size-frequency distributions for ORFS are strikingly similar across prokaryotic and eukaryotic genomes. Moreover, we show that i) a large fraction (60–80%) of ORF size-frequency distributions can be predicted a priori with a stochastic assembly model based on GC content, and that (ii) size-frequency distributions of the remaining “non-random” ORFs are well-fitted by log-normal or gamma distributions, and similar to the size distributions of annotated proteins. Conclusions/Significance: Our findings suggest stochastic processes have played a primary role in the evolution of genome complexity, and that common processes govern the conservation and loss of functional genomics units in both prokaryotes and eukaryotes.8 page(s