An extreme magneto-ionic environment associated with the fast radio burst source FRB 121102.

Fast radio bursts are millisecond-duration, extragalactic radio flashes of unknown physical origin. The only known repeating fast radio burst source-FRB 121102-has been localized to a star-forming region in a dwarf galaxy at redshift 0.193 and is spatially coincident with a compact, persistent radio source. The origin of the bursts, the nature of the persistent source and the properties of the local environment are still unclear. Here we report observations of FRB 121102 that show almost 100 per cent linearly polarized emission at a very high and variable Faraday rotation measure in the source frame (varying from +1.46 × 105 radians per square metre to +1.33 × 105 radians per square metre at epochs separated by seven months) and narrow (below 30 microseconds) temporal structure. The large and variable rotation measure demonstrates that FRB 121102 is in an extreme and dynamic magneto-ionic environment, and the short durations of the bursts suggest a neutron star origin. Such large rotation measures have hitherto been observed only in the vicinities of massive black holes (larger than about 10,000 solar masses). Indeed, the properties of the persistent radio source are compatible with those of a low-luminosity, accreting massive black hole. The bursts may therefore come from a neutron star in such an environment or could be explained by other models, such as a highly magnetized wind nebula or supernova remnant surrounding a young neutron star.

James Sharpe's Contributions to Neurology and Neuro-ophthalmology: A Posthumous Tribute 10 Years On.

Dr. Sharpe was a leading eye movement researcher who had also been the editor of this journal. We wish to mark the 10th anniversary of his death by providing a sense of what he had achieved through some examples of his research.

A direct localization of a fast radio burst and its host.

Fast radio bursts are astronomical radio flashes of unknown physical nature with durations of milliseconds. Their dispersive arrival times suggest an extragalactic origin and imply radio luminosities that are orders of magnitude larger than those of all known short-duration radio transients. So far all fast radio bursts have been detected with large single-dish telescopes with arcminute localizations, and attempts to identify their counterparts (source or host galaxy) have relied on the contemporaneous variability of field sources or the presence of peculiar field stars or galaxies. These attempts have not resulted in an unambiguous association with a host or multi-wavelength counterpart. Here we report the subarcsecond localization of the fast radio burst FRB 121102, the only known repeating burst source, using high-time-resolution radio interferometric observations that directly image the bursts. Our precise localization reveals that FRB 121102 originates within 100 milliarcseconds of a faint 180-microJansky persistent radio source with a continuum spectrum that is consistent with non-thermal emission, and a faint (twenty-fifth magnitude) optical counterpart. The flux density of the persistent radio source varies by around ten per cent on day timescales, and very long baseline radio interferometry yields an angular size of less than 1.7 milliarcseconds. Our observations are inconsistent with the fast radio burst having a Galactic origin or its source being located within a prominent star-forming galaxy. Instead, the source appears to be co-located with a low-luminosity active galactic nucleus or a previously unknown type of extragalactic source. Localization and identification of a host or counterpart has been essential to understanding the origins and physics of other kinds of transient events, including gamma-ray bursts and tidal disruption events. However, if other fast radio bursts have similarly faint radio and optical counterparts, our findings imply that direct subarcsecond localizations may be the only way to provide reliable associations.

A repeating fast radio burst.

Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.

Western diet increases cardiac ceramide content in healthy and hypertrophied hearts.

BACKGROUND AND AIMS: Obesity and cardiac left ventricular hypertrophy (LVH) are recognised independent risk factors in the development of heart failure (HF). However, the combination of these factors may exacerbate the onset of cardiovascular disease by mechanisms as yet unclear. LVH leads to significant cellular remodelling, including alterations in metabolism which may result in an inappropriate accumulation of lipids and eventual lipotoxicity and apoptosis. The aim of the study was to determine the impact of dietary manipulation on cardiac metabolism in the obese and hypertrophied heart. METHODS AND RESULTS: LVH was induced via aortic constriction (AC) in an experimental model of cardiac hypertrophy and animals subjected to 9 weeks of dietary manipulation with either a standard, high fat, or a sucrose containing Western-style diet (SD, HFD and WD, respectively). This latter diet resulted in accelerated weight gain in both LVH/AC and control animals. LVH was greater in AC animals fed a WD, and both control and AC animals from this diet showed a significant reduction in cardiac fatty acid oxidation and increased triacylglycerol content. Ceramide content was significantly increased in the WD groups, with no additional effect of LVH. Comparison with a model of HF induced by exposure to Doxorubicin and WD showed exacerbated remodelling of cardiac ceramide species leading to increased C16 and C18 content. CONCLUSIONS: These findings highlight the inappropriate accumulation and re-distribution of cardiac ceramide species in a diet-induced model of obesity and LVH, potentially increasing susceptibility to cell death. The combination of increased fat and sugar leads to greater pathological remodelling and may explain why this diet pattern is consistently linked with poor cardiovascular outcomes.

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

Identification of Health Systems Science in a Problem-Based Learning Clinical Reasoning Exercise.

The creation of developmentally appropriate and meaningfully complex clinical reasoning exercises in the pre-clerkship curriculum is a common challenge for many medical schools. We provide an overview of one component of the pre-clerkship clinical reasoning curriculum at Case Western Reserve University School of Medicine, and present evidence that inclusion of Health Systems Science in this exercise facilitates integrated thinking in a Problem-Based Learning curriculum.

Reaching agreement for an Aboriginal e-health research agenda: the Aboriginal Telehealth Knowledge Circle consensus method.

INTRODUCTION: In Canada, telehealth has been successfully implemented in a number of Aboriginal communities with subsequent improvements to access to health care and quality of life. However, there are many knowledge gaps that limit our understanding of the broad range of Aboriginal e-health issues; a research agenda is urgently required. The objective of this research was to develop an Aboriginal e-health research agenda designed to address the substantial knowledge gaps that impede e-health deployment and adoption particularly in rural and remote Aboriginal communities in Canada. A consensus method based on Aboriginal culture, values and approaches to consensus was developed to achieve this. METHODS: In this consensus methodology, a core group of Aboriginal telehealth leaders, led by a research facilitator, engaged in an iterative process of individual and group review of research data. The reviewed data included stakeholder interview data, questionnaires, literature and other resources and was prioritized in order to develop recommendations for an Aboriginal e-health research agenda. RESULTS: A total of 40 stakeholders including Aboriginal Telehealth Knowledge Circle (ATKC) members, communities of practice and regional, provincial and federal leaders and policy-makers participated in the consensus process. The research recommendations showed a high degree of consistency among stakeholders. Participants reached consensus on 6 areas: research ethics, internet-based e-health services data, educational resources, sustainability models, best practices and exploration of innovative applications. CONCLUSIONS: An ATKC consensus process was successfully applied to reach consensus on an Aboriginal e-health research agenda, demonstrating the potential of Indigenous research approaches for defining levels of agreement on complex topics. The resulting conceptual map for e-health research can be used as a springboard for partnership-based research initiatives involving Aboriginal communities, governments and researchers, and may be of interest to Indigenous e-health researchers at an international level.

GARLA: Integrating Traditional and Modern Methodologies in Anatomy Education.

GARLA is an anatomy curriculum that combines dissection with applied anatomy. A two-week intensive dissection Boot-Camp is followed by a tripartite curriculum consisting of Gross Anatomy using a mixed reality headset, radiology, and physical exam/ultrasound skills. Student feedback has generally been positive.

Oncogenic forms of p53 inhibit p53-regulated gene expression.

Mutant forms of the gene encoding the tumor suppressor p53 are found in numerous human malignancies, but the physiologic function of p53 and the effects of mutations on this function are unknown. The p53 protein binds DNA in a sequence-specific manner and thus may regulate gene transcription. Cotransfection experiments showed that wild-type p53 activated the expression of genes adjacent to a p53 DNA binding site. The level of activation correlated with DNA binding in vitro. Oncogenic forms of p53 lost this activity. Moreover, all mutants inhibited the activity of coexpressed wild-type p53, providing a basis for the selection of such mutants during tumorigenesis.

Allelic variation at the C-reactive protein gene associates to both hand osteoarthritis severity and serum high sensitive C-reactive protein levels in the GARP study.

OBJECTIVE: To gain more insight into the role of genetic variation of the C-reactive protein (CRP) gene in serum CRP levels and osteoarthritis (OA). METHODS: Serum high sensitive CRP (S-HsCRP) levels were measured in the Genetics of osteoARthritis and Progression (GARP) study. Furthermore, to assess genetic variation of the CRP gene, genotypes of five tagging single nucleotide polymorphisms were assessed in the GARP study and a random control sample. RESULTS: A significant and consistent relation between S-HsCRP levels and observed haplotypes was identified. Additionally, a CRP haplotype, which also associated to a significantly higher expected phenotypic mean S-HsCRP level, was associated to severe hand OA. This haplotype was tagged by a single nucleotide polymorphism (rs3091244). Carriers of this allele have an increased risk for the presence of severe hand OA with an OR of 2.3 (95% confidence interval 1.2 to 4.3, p = 0.009). CONCLUSIONS: A haplotype of the CRP gene, associated to high basal S-HsCRP level, is also associated to severity of hand OA, indicating that innate high basal S-HsCRP levels may influence OA onset.

Extreme testing of undiluted e-cigarette aerosol in vitro using an Ames air-agar-interface technique.

There is a growing consensus that e-cigarettes hold the potential for reducing the harm associated with cigarette smoking. Recently published studies have reported in vitro testing of e-cigarettes, demonstrating reduced toxicological and biological effects. Few studies however have reported the use of e-cigarettes under extreme testing conditions. To assess the full mutagenic potential of a commercially available electronic-cigarette (Vype ePen), this study investigated the delivery of aerosol under extreme conditions, using a scaled-down 35 mm plate Ames bacterial reverse mutagenicity assay. S. typhimurium strains TA98, TA100, TA97, TA104 and E. coli WP2 uvrA pKM101 with or without metabolic activation (S9), were employed. Using a modified Vitrocell VC 10 exposure system 0, 180, 360, 540, 720 or 900 puffs of undiluted e-cigarette aerosol was generated and delivered to bacterial cultures aligned to reported human consumption data. The results demonstrate that no mutagenic activity was observed in any strain under any test condition even when exposed to 900 puffs of undiluted e-cigarette aerosols +/- S9. Positive control responses were observed in all strains +/- S9. Nicotine assessments demonstrated an increased and consistent aerosol delivery, with calculated maximum doses of ∼1 mg/mL delivery of nicotine. These data demonstrate the validity of this unique testing approach and adds further information to the growing weight of evidence that e-cigarettes offer substantially reduced exposure when compared to conventional cigarette smoke. For future in vitro assessments of next generation tobacco and nicotine products, the generation, delivery and testing of undiluted aerosols can now be considered.

Impairment of cardiac function and energetics in experimental renal failure.

Cardiac function and energetics in experimental renal failure in the rat (5/6 nephrectomy) have been investigated by means of an isolated perfused working heart preparation and an isometric Langendorff preparation using 31P nuclear magnetic resonance (31P NMR). 4 wk after nephrectomy cardiac output of isolated hearts perfused with Krebs-Henseleit buffer was significantly lower (P < 0.0001) at all levels of preload and afterload in the renal failure groups than in the pair-fed sham operated control group. In control hearts, cardiac output increased with increases in perfusate calcium from 0.73 to 5.61 mmol/liter whereas uremic hearts failed in high calcium perfusate. Collection of 31P NMR spectra from hearts of renal failure and control animals during 30 min normoxic Langendorff perfusion showed that basal phosphocreatine was reduced by 32% to 4.7 mumol/g wet wt (P < 0.01) and the phosphocreatine to ATP ratio was reduced by 32% (P < 0.01) in uremic hearts. During low flow ischemia, there was a substantial decrease in phosphocreatine in the uremic hearts and an accompanying marked increase in release of inosine into the coronary effluent (14.9 vs 6.1 microM, P < 0.01). We conclude that cardiac function is impaired in experimental renal failure, in association with abnormal cardiac energetics and increased susceptibility to ischemic damage. Disordered myocardial calcium utilization may contribute to these derangements.

Automated detection and enumeration of marine wildlife using unmanned aircraft systems (UAS) and thermal imagery.

Estimating animal populations is critical for wildlife management. Aerial surveys are used for generating population estimates, but can be hampered by cost, logistical complexity, and human risk. Additionally, human counts of organisms in aerial imagery can be tedious and subjective. Automated approaches show promise, but can be constrained by long setup times and difficulty discriminating animals in aggregations. We combine unmanned aircraft systems (UAS), thermal imagery and computer vision to improve traditional wildlife survey methods. During spring 2015, we flew fixed-wing UAS equipped with thermal sensors, imaging two grey seal (Halichoerus grypus) breeding colonies in eastern Canada. Human analysts counted and classified individual seals in imagery manually. Concurrently, an automated classification and detection algorithm discriminated seals based upon temperature, size, and shape of thermal signatures. Automated counts were within 95-98% of human estimates; at Saddle Island, the model estimated 894 seals compared to analyst counts of 913, and at Hay Island estimated 2188 seals compared to analysts' 2311. The algorithm improves upon shortcomings of computer vision by effectively recognizing seals in aggregations while keeping model setup time minimal. Our study illustrates how UAS, thermal imagery, and automated detection can be combined to efficiently collect population data critical to wildlife management.

Allelotype of pancreatic adenocarcinoma.

Knowledge of the patterns of allelic loss has been useful in identifying the spectrum of the tumor suppressor genes involved in various tumor types. Such analyses in pancreatic carcinoma have been difficult due to the characteristic host desmoplastic reaction to the neoplasm. We have assembled the first allelotype of pancreatic adenocarcinoma, a survey for allelic loss among each chromosomal arm, using seven cryostat-dissected neoplasms. The fractional allelic loss in these seven neoplasms was 0.18, a value similar to that seen previously in colorectal carcinoma. Alleles of chromosome 18q (lost in five of six informative tumors) and of chromosome 17p (lost in four of five informative tumors) were commonly affected. Neither APC mutations (33 neoplasms), allelic shifts of dinucleotide repeats (26 neoplasms), nor immunohistochemical evidence of retinoblastoma protein underexpression (7 neoplasms) were found. Further evaluation of allelic loss in pancreatic cancer would benefit from improved methods for the analysis of lost genetic material which overcome the problems posed by the high admixture of nonneoplastic stromal and inflammatory cells in these tumors.

p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions.

Pancreatic adenocarcinoma is a major cause of cancer death, and yet little is known about its molecular pathogenesis. We identified p53 mutations in 19 (70%) of 27 primary pancreatic adenocarcinomas. Most were missense point mutations, and the mutations were distributed primarily within the evolutionarily conserved domains. Transitions predominated over transversions, and many of the transitions were at CpG dinucleotides. Intragenic deletions accounted for 32% of mutations and were associated with decreased survival (P = 0.0016). A review of 1937 published p53 mutations revealed that the occurrence of small (1-2 base pairs) microdeletions varied among different types of human neoplasms and that pancreatic adenocarcinoma had one of the highest frequencies (13% of 47 mutations, P = 0.0036). Many small deletions occurred in iterations of single bases, but this did not fully account for their pattern of distribution, and there was evidence for the involvement of homocopolymer (polypurine:polypyrimidine) tracts. This may represent a more widespread phenomenon, because microdeletions occur in similar sequence patterns in reports of somatic and germ line mutations among genes other than p53.

Allelotype of pancreatic adenocarcinoma using xenograft enrichment.

p53 and MTS1 are known to be mutationally inactivated in pancreatic adenocarcinoma. Other tumor suppressor genes are likely also to play a role. To define chromosomal arms which may harbor additional tumor suppressor genes, we performed an extensive allelotype on pancreatic cancer utilizing a xenograft enrichment technique. Eighty-eight percent (28/32) of primary tumors gave rise to xenografts. Eighteen cases were used in a PCR-based allelotype using 283 polymorphic markers, over 2800 informative assays, and an average coverage of 4.1 informative markers per chromosomal arm per case. Highly frequent allelic loss (> 60%) was seen at chromosomes 1p, 9p, 17p, and 18q. Moderately frequent allelic loss (40-60%) was seen at 3p, 6p, 6q, 8p, 10q, 12q, 13q, 18p, 21q, and 22q. The average fractional allelic loss was 0.36. Allelic and sequence stability was demonstrated among 64 parallel and second-passage xenografts derived from 12 cases of pancreatic adenocarcinoma with the ascertainment of over 3000 single alleles. The findings were confirmed in primary tumors. In only two instances were discrepancies revealed between the allelic loss data obtained from corresponding parallel xenografts, probably due to the xenografting of minor subpopulations, reflecting genetic heterogeneity of the primary tumor.

Homozygous deletion map at 18q21.1 in pancreatic cancer.

Absolute genetic differences between neoplastic and nonneoplastic cells can be discerned at sites of homozygous deletions. These deletions are of critical interest because they might be useful in the identification of defective biochemical pathways in neoplastic cells, and subsequently for the development of new treatment strategies in human cancer. We identified an area at 18q21.1 involved by homozygous deletions in 30% of pancreatic carcinomas. To characterize the homozygous deletions, we constructed a detailed physical map of nearly 2 Mb, containing yeast artificial chromosomes, P1-derived artificial chromosomes, cosmids and 24 sequence-tagged sites. The homozygously deleted are contained a new candidate tumor-suppressor gene (DPC4). To date, 23 (64%) of 35 pancreatic carcinomas carry at least one homozygous deletion at a published locus. The study of the total gene content of these loci, facilitated by the sequence-tagged site markers and maps of these regions, should help to reveal the absolute biochemical differences between neoplastic and nonneoplastic cells for a common human tumor.

The mutagenic assessment of an electronic-cigarette and reference cigarette smoke using the Ames assay in strains TA98 and TA100.

Salmonella typhimurium strains TA98 and TA100 were used to assess the mutagenic potential of the aerosol from a commercially available, rechargeable, closed system electronic-cigarette. Results obtained were compared to those for the mainstream smoke from a Kentucky reference (3R4F) cigarette. Two different test matrices were assessed. Aerosol generated from the e-cigarette was trapped on a Cambridge filter pad, eluted in DMSO and compared to cigarette smoke total particulate matter (TPM), which was generated in the same manner for mutagenicity assessment in the Salmonella assay. Fresh e-cigarette and cigarette smoke aerosols were generated on the Vitrocell® VC 10 smoking robot and compared using a modified scaled-down 35mm air agar interface (AAI) methodology. E-cigarette aerosol collected matter (ACM) was found to be non-mutagenic in the 85mm plate incorporation Ames assay in strains TA98 and TA100 conducted in accordance with OECD 471, when tested up to 2400µg/plate. Freshly generated e-cigarette aerosol was also found to be negative in both strains after an AAI aerosol exposure, when tested up to a 1L/min dilution for up to 3h. Positive control responses were observed in both strains, using benzo[a]pyrene, 2-nitrofluorene, sodium azide and 2-aminoanthracene in TA98 and TA100 in the presence and absence of metabolic activation respectively. In contrast, cigarette smoke TPM and aerosol from 3R4F reference cigarettes were found to be mutagenic in both tester strains, under comparable test conditions to that of e-cigarette exposure. Limited information exists on the mutagenic activity of captured e-cigarette particulates and whole aerosol AAI approaches. With the lower toxicant burden of e-cigarette aerosols compared to cigarette smoke, it is clear that a more comprehensive Ames package of data should be generated when assessing e-cigarettes, consisting of the standard OECD-five, TA98, TA100, TA1535, TA1537 (or TA97) and E. coli (or TA102). In addition, TA104 which is more sensitive to the carbonyl based compounds found in e-cigarette aerosols under dry-wicking conditions may also prove a useful addition in a testing battery. Regulatory standard product testing approaches as used in this study will become important when determining whether e-cigarette aerosols are in fact less biologically active than cigarette smoke, as this study suggests. Future studies should be supported by in vitro dosimetry approaches to draw more accurate comparisons between cigarette smoke, e-cigarette aerosol exposure and human use.

Reproductive Regulation of Gene Expression in the Hypothalamic Supraoptic and Paraventricular Nuclei.

Oxytocin secretion is required for successful reproduction. Oxytocin is synthesised by magnocellular neurones of the hypothalamic supraoptic and paraventricular nuclei and the physiological demand for oxytocin synthesis and secretion is increased for birth and lactation. Therefore, we used a polymerase chain reaction (PCR) array screen to determine whether genes that might be important for synthesis and/or secretion of oxytocin are up- or down-regulated in the supraoptic and paraventricular nuclei of late-pregnant and lactating rats, compared to virgin rats. We then validated the genes that were most highly regulated using real time-quantitative PCR. Among the most highly regulated genes were those that encode for suppressors of cytokine signalling, which are intracellular inhibitors of prolactin signalling. Prolactin receptor activation changes gene expression via phosphorylation of signal transducer and activator of transcription 5 (STAT5). Using double-label immunohistochemistry, we found that phosphorylated STAT5 was expressed in almost all oxytocin neurones of late-pregnant and lactating rats but was almost absent from oxytocin neurones of virgin rats. We conclude that increased prolactin activation of oxytocin neurones might contribute to the changes in gene expression by oxytocin neurones required for normal birth and lactation.