Association of the Matrix Attachment Region Recognition Signature with coding regions in Caenorhabditis elegans

<p>Abstract</p> <p>Background</p> <p>Matrix attachment regions (MAR) are the sites on genomic DNA that interact with the nuclear matrix. There is increasing evidence for the involvement of MAR in regulation of gene expression. The unsuitability of experimental detection of MAR for genome-wide analyses has led to the development of computational methods of detecting MAR. The MAR recognition signature (MRS) has been reported to be associated with a significant fraction of MAR in <it>C. elegans </it>and has also been found in MAR from a wide range of other eukaryotes. However the effectiveness of the MRS in specifically and sensitively identifying MAR remains unresolved.</p> <p>Results</p> <p>Using custom software, we have mapped the occurrence of MRS across the entire <it>C. elegans </it>genome. We find that MRS have a distinctive chromosomal distribution, in which they appear more frequently in the gene-rich chromosome centres than in arms. Comparison to distributions of MRS estimated from chromosomal sequences randomised using mono-, di- tri- and tetra-nucleotide frequency patterns showed that, while MRS are less common in real sequence than would be expected from nucleotide content alone, they are more frequent than would be predicted from short-range nucleotide structure. In comparison to the rest of the genome, MRS frequency was elevated in 5' and 3' UTRs, and striking peaks of average MRS frequency flanked <it>C. elegans </it>coding sequence (CDS). Genes associated with MRS were significantly enriched for receptor activity annotations, but not for expression level or other features.</p> <p>Conclusion</p> <p>Through a genome-wide analysis of the distribution of MRS in <it>C. elegans </it>we have shown that they have a distinctive distribution, particularly in relation to genes. Due to their association with untranslated regions, it is possible that MRS could have a post-transcriptional role in the control of gene expression. A role for MRS in nuclear scaffold attachment is not supported by these analyses.</p

A genomic study of the nuclear matrix attachment region recognition signature

Matrix attachment regions (MAR) are the sites on genomic DNA that interact with the nuclear matrix. A complex bipartite motif, the MAR recognition signature (MRS), has been proposed as a DNA sequence marker for MAR but its specificity and sensitivity remain unresolved. I describe here the distribution of the MRS in the genomes of a number of species from across animals and plants. The MRS is shown to have a distinctive, nonrandom distribution, with a particular relationship to genes. This relationship was studied in detail in the genome of Caenorhabditis elegans, revealing striking peaks of average MRS frequency in the regions flanking C. elegans genes. The occurrence of similar peaks in C. briggsae, Danio rerio, Arabidopsis thaliana, Drosophila melanogaster and Homo sapiens was also investigated. The nucleotide content in the vicinity of genes is examined and it too is shown to have striking peaks in regions surrounding genes. C. elegans genes associated with MRS were found to be significantly enriched for receptor activity annotations but not for some other features. Using this analysis of the genomic distribution of the MRS, the relevance of the MRS as a marker for MAR is discussed. The potential for MRS to play a functional role, as indicated by their peculiar frequency in the vicinity of genes, is also explored

Evaluation of four different small animal radiation plans on tumour and normal tissue dosimetry in a glioblastoma mouse model

Objective: Small animal radiotherapy research platforms such as XStrahl’s SARRP enable more precise irradiation of tumours and normal tissues in pre-clinical models of cancer. Using an orthotopic G7 glioblastoma xenograft model we studied the impact of four different radiotherapy plans on tumour and normal tissue dosimetry. Methods: Plans were created using four different approaches (single beam, parallel opposed pair, single plane arcs, couch rotation arcs) and dose volume histograms (DVH) for the tumour and the relevant organs at risk (OARs) (mouth, ipsilateral brain, contralateral brain, brain stem) were compared for a sample mouse subject. To evaluate the accuracy of delivery, treatment plans were recreated in solid-water phantoms and delivered to radiochromic film. Results: Favourable tumour dosimetry was achieved by all plans. DVH analysis showed that different plans could be used to spare specific OARs depending on the objectives of the study. The delivery accuracy of the various treatments was better than 2%/2mm (dose difference/distance to agreement) in terms of global γ analysis. Conclusion: Small animal radiotherapy research platforms are an exciting addition to the pre-clinical research environment. Such systems improve the conformality of irradiation of tumours and OARs while maintaining a high degree of accuracy and enable investigators to optimise experiments in terms of tumour coverage and inclusion or exclusion of relevant OARs. Advances in knowledge: This study confirms the utility of the SARRP in terms of the accuracy of plan delivery, and informs decisions on treatment planning to optimise the clinical relevance and scientific value of experiments

Representation of Maximally Regular Textures in Human Visual Cortex

This research was supported by National Science Foundation INSPIRE Grant 1248076, which was awarded to Y.L. and A.M.N.Peer reviewedPublisher PD

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study

Alemtuzumab; Disease-modifying therapy; Multiple sclerosisAlemtuzumab; Teràpia modificadora de la malaltia; Esclerosi múltipleAlemtuzumab; Terapia modificadora de la enfermedad; Esclerosis múltipleBackground and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants (‘alemtuzumab-only’) could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab (‘IFN-alemtuzumab’). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5–7 years (11–13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3–13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15–0.20] and IFN-alemtuzumab (0.14; 0.11–0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11–13 years, and most participants did not require more than one additional course.The TOPAZ study as well as writing and editorial support for this article were funded by Sanofi

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data

Alemtuzumab; Product surveillance; Risk assessmentAlemtuzumab; Vigilancia de productos; Evaluación de riesgosAlemtuzumab; Vigilància de productes; Avaluació de riscosDoes preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The CAMMS223 and CARE-MS studies, and their extensions, were supported by Sanofi and Bayer Healthcare Pharmaceuticals. Editorial and writing assistance was supported by Sanofi

Stable isotopes of oxygen and hydrogen in meteoric water during the Cryogenian Period

We measured δ18O and δ2H values of muscovite and carbonate mineral separates from metamorphosed carbonate-bearing mudstone layers in late Tonian to early Cryogenian strata, including Sturtian glacial deposits, which were deposited in a coastal setting at an approximate paleolatitude of 30-35°S and now crop out on Islay and the Garvellach Islands, Scotland. From these values, we calculated δ18O and δ2H values of meteoric water that equilibrated with clay at diagenetic conditions which we infer were reached shortly after deposition (i.e. before the end of the Cryogenian Period) because sediment accumulation was rapid due to fast subsidence at that time. This calculation required removal of the effects of exchange with reservoir rocks, metamorphic volatilization and mixing with metamorphic fluids on δ18O and δ2H values. The values we calculated for meteoric water fall within the 2σ ranges δ18O = -1 to -4 ‰ and δ2H = 0 to -23 ‰, respectively. These ranges are similar to present day values at equivalent latitudes. This finding is consistent with sediment accumulation in the Cryogenian Period having occurred in a climate similar to present day (Ice Age) conditions. This conclusion is not at odds with the Snowball Earth hypothesis because one of its predictions is that sediment accumulation occurred as the climate warmed at the end of panglaciation, a prediction supported by sedimentological evidence of multiple glacial advances and retreats in our study area and elsewhere

Fluids or vasopressors for the initial resuscitation of septic shock

Intravenous fluid resuscitation is recommended first-line treatment for sepsis-associated hypotension and/or hypoperfusion. The rationale is to restore circulating volume and optimize cardiac output in the setting of shock. Nonetheless, there is limited high-level evidence to support this practice. Over the past decade emerging evidence of harm associated with large volume fluid resuscitation among patients with septic shock has led to calls for a more conservative approach. Specifically, clinical trials undertaken in Africa have found harm associated with initial fluid resuscitation in the setting of infection and hypoperfusion. While translating these findings to practice in other settings is problematic, there has been a re-appraisal of current practice with some recommending earlier use of vasopressors rather than repeated fluid boluses as an alternative to restore perfusion in septic shock. There is consequently uncertainty and variation in practice. The question of fluids or vasopressors for initial resuscitation in septic shock is the subject of international multicentre clinical trials

Seeking the Holy Grail: robust chronologies from archaeology and radiocarbon dating combined

The strengths of formal Bayesian chronological modelling are restated, combining as it does knowledge of the archaeology with the radiocarbon dating of carefully chosen samples of known taphonomy in association with diagnostic material culture. The risks of dating bone samples are reviewed, along with a brief history of the development of approaches to the radiocarbon dating of bone. In reply to Strien (2017), selected topics concerned with the emergence and aftermath of the LBK are discussed, as well as the early Vin≠a, Ra∫i∏te and Hinkelstein sequences. The need for rigour in an approach which combines archaeology and radiocarbon dating is underlined

The parenting hub of the hypothalamus is a focus of imprinted gene action

Imprinted genes are subject to germline epigenetic modification resulting in parental-specific allelic silencing. Although genomic imprinting is thought to be important for maternal behaviour, this idea is based on serendipitous findings from a small number of imprinted genes. Here, we undertook an unbiased systems biology approach, taking advantage of the recent delineation of specific neuronal populations responsible for controlling parental care, to test whether imprinted genes significantly converge to regulate parenting behaviour. Using single-cell RNA sequencing datasets, we identified a specific enrichment of imprinted gene expression in a recognised “parenting hub”, the galanin-expressing neurons of the preoptic area. We tested the validity of linking enriched expression in these neurons to function by focusing on MAGE family member L2 (Magel2), an imprinted gene not previously linked to parenting behaviour. We confirmed expression of Magel2 in the preoptic area galanin expressing neurons. We then examined the parenting behaviour of Magel2-null(+/p) mice. Magel2-null mothers, fathers and virgin females demonstrated deficits in pup retrieval, nest building and pup-directed motivation, identifying a central role for this gene in parenting. Finally, we show that Magel2-null mothers and fathers have a significant reduction in POA galanin expressing cells, which in turn contributes to a reduced c-Fos response in the POA upon exposure to pups. Our findings identify a novel imprinted gene that impacts parenting behaviour and, moreover, demonstrates the utility of using single-cell RNA sequencing data to predict gene function from expression and in doing so here, have identified a purposeful role for genomic imprinting in mediating parental behaviour