Early Cementation of the Short Creek Oolite Member, Boone Formation (Osagean, Lower Mississippian), Northern Arkansas

The Short Creek Oolite is the only formally named member of the Boone Formation in northern Arkansas. It lacks bedding features, and oolith concentrations that would suggest a shoal environment, and it occurs at variable stratigraphic horizons within the upper Boone Formation consistent with episodic deposition as grainflow slurries. As with modern oolite examples, such as Joulters Cays, Bahamas, the Short Creek preserves numerous intraclasts, and at least one large olistolith indicating an early cementation history

Targeted Next-Generation Sequencing Validates the Use of Diagnostic Biopsies as a Suitable Alternative to Resection Material for Mutation Screening in Colorectal Cancer

Background: Mutation testing in the context of neoadjuvant therapy must be performed on biopsy samples. Given the issue of tumour heterogeneity, this raises the question of whether the biopsies are representative of the whole tumour. Here we have compared the mutation profiles of colorectal biopsies with their matched resection specimens. Methods: We performed next-generation sequencing (NGS) analysis on 25 paired formalin-fixed, paraffin-embedded colorectal cancer biopsy and primary resection samples. DNA was extracted and analysed using the TruSight tumour kit, allowing the interrogation of 26 cancer driver genes. Samples were run on an Illumina MiSeq. Mutations were validated using quick-multiplex-consensus (QMC)-polymerase chain reaction (PCR) in conjunction with high resolution melting (HRM). The paired biopsy and resection tumour samples were assessed for presence or absence of mutations, mutant allele frequency ratios, and allelic imbalance status. Results: A total of 81 mutations were detected, in ten of the 26 genes in the TruSight kit. Two of the 25 paired cases were wild-type across all genes. The mutational profiles, allelic imbalance status, and mutant allele frequency ratios of the paired biopsy and resection samples were highly concordant (88.75–98.85%), with all but three (3.7%) of the mutations identified in the resection specimens also being present in the biopsy specimens. All 81 mutations were confirmed by QMC-PCR and HRM analysis, although four low-level mutations required a co-amplification at lower denaturation temperature (COLD)-PCR protocol to enrich for the mutant alleles. Conclusions: Diagnostic biopsies are adequate and reliable materials for molecular testing by NGS. The use of biopsies for molecular screening will enhance targeted neoadjuvant therapy

Innovationsfähigkeit: Empirische Befunde zur Rolle reflexiver Verfahren

Dieser Beitrag faßt einige Befunde aus den standardisierten Erhebungen sowie den Fallstudien des Projekts "Innovationsfähigkeit durch Institutionelle Reflexivität“ zusammen und stellt zunächst nochmals Grundzüge des zugrundeliegenden theoretischen Ansatzes vor. Es handelt sich hier um eine selektive Vorabveröffentlichung wesentlich umfangreicherer Befunde und Interpretationen, die in Kürze als Buch erscheinen werden. --

Characterisation of the UK high energy proton research beamline for high and ultra-high dose rate (FLASH) irradiation

Objective. This work sets out the capabilities of the high energy proton research beamline developed in the Christie proton therapy centre for Ultra-High Dose Rate (UHDR) irradiation and FLASH experiments. It also characterises the lower limits of UHDR operation for this Pencil Beam Scanning (PBS) proton hardware. Approach. Energy dependent nozzle transmission was measured using a Faraday Cup beam collector. Spot size was measured at the reference plane using a 2D scintillation detector. Integrated depth doses (IDDs) were measured. EBT3 Gafchromic film was used to compare UHDR and conventional dose rate spots. Our beam monitor calibration methodolgy for UHDR is described. A microDiamond detector was used to determine dose rates at zref. Instantaneous depth dose rates were calculated for 70–245 MeV. PBS dose rate distributions were calculated using Folkerts and Van der Water definitions. Main results. Transmission of 7.05 ± 0.1% is achieveable corresponding to a peak instantaneous dose rate of 112.7 Gy s−1. Beam parameters are comparable in conventional and UHDR mode with a spot size of σx = 4.6 mm, σy = 6.6 mm. Dead time in the beam monitoring electonics warrants a beam current dependent MU correction in the present configuration. Fast beam scanning of 26.4 m s−1 (X) and 12.1 m s−1 (Y) allows PBS dose rates of the order tens of Grays per second. Significance. UHDR delivery is possible for small field sizes and high energies enabling research into the FLASH effect with PBS protons at our facility. To our knowledge this is also the first thorough characterisation of UHDR irradiation using the hardware of this clinical accelerator at energies less than 250 MeV. The data set out in this publication can be used for designing experiments at this UK research facility and inform the possible future clinical translation of UHDR PBS proton therapy

The evolution of mammalian brain size

Relative brain size has long been considered a reflection of cognitive capacities and has played a fundamental role in developing core theories in the life sciences. Yet, the notion that relative brain size validly represents selection on brain size relies on the untested assumptions that brain-body allometry is restrained to a stable scaling relationship across species and that any deviation from this slope is due to selection on brain size. Using the largest fossil and extant dataset yet assembled, we find that shifts in allometric slope underpin major transitions in mammalian evolution and are often primarily characterized by marked changes in body size. Our results reveal that the largest-brained mammals achieved large relative brain sizes by highly divergent paths. These findings prompt a reevaluation of the traditional paradigm of relative brain size and open new opportunities to improve our understanding of the genetic and developmental mechanisms that influence brain size

High-Resolution Characterization of Toxoplasma gondii Transcriptome with a Massive Parallel Sequencing Method†

For the last couple of years, a method that permits the collection of precise positional information of transcriptional start sites (TSSs) together with digital information of the gene-expression levels in a high-throughput manner was established. We applied this novel method, ‘tss-seq’, to elucidate the transcriptome of tachyzoites of the Toxoplasma gondii, which resulted in the identification of 124 000 TSSs, and they were clustered into 10 000 transcription regions (TRs) with a statistics-based analysis. The TRs and annotated ORFs were paired, resulting in the identification of 30% of the TRs and 40% of the ORFs without their counterparts, which predicted undiscovered genes and stage-specific transcriptions, respectively. The massive data for TSSs make it possible to execute the first systematic analysis of the T. gondii core promoter structure, and the information showed that T. gondii utilized an initiator-like motif for their transcription in the major and novel motif, the downstream thymidine cluster, which was similar to the Y patch observed in plants. This encyclopaedic analysis also suggested that the TATA box, and the other well-known core promoter elements were hardly utilized

Discovery of Mycobacterium Tuberculosis Protein Tyrosine Phosphatase A (MptpA) Inhibitors Based on Natural Products and a Fragment-Based Approach

Naturally inspired or fragment based. Mcyobacterium tuberculosis has two functional phosphatases, protein tyrosine phosphates A and B (MptpA and B), which are thought to mediate mycobacterial survival in the host. Here we describe the first inhibitors of MptpA (see scheme). Initial hits were identified in screening collections that were inspired by natural products and composed by fragment-based approach