A radio continuum study of planetary nebulae and extended emissions in the Magellanic Clouds

This thesis examines emissions from the interstellar medium (ISM) of the Small Magellanic Cloud (SMC) and reports the detection of planetary nebulae in the radio continuum (RC) from both Magellanic Clouds (MCs). New RC measurements of the planetary nebulae are used to calibrate a statistical distance scale based on the surface brightness–diameter relation (Σ–D) (defined as Σ = A × D-β). The correlation between far-infrared (FIR) and RC emissions from the ISM of the SMC was investigated over scales from 3 kpc to 0.01 kpc. Good far-infrared/radio continuum (FIR/RC) correlation down to ∼15 pc was seen. The reciprocal slope of the FIR/RC emission correlation, RC/FIR, in the SMC was shown to be greatest in the most active star–forming regions with a power law slope of ∼1.14 indicating that the RC emission increases faster than the FIR emission. The slope of the other regions and the entire SMC are much flatter and in the range of 0.63–0.85. The slopes tend to follow the thermal fractions of the regions with a range of 0.5– 0.95. It was found that the thermal fraction of the RC emission alone can provide the expected FIR/RC correlation. This result was consistent with a common source for ultraviolet (UV) photons which heat dust and which ionise Hi to produce thermal electrons leading to freefree (FF) radiation. The UV photons, which ionise the ISM and heat the dust, come from hot young stars, the largest of which will eventually become supernovae. Non-thermal emission, in the form of synchrotron radio emission, is from ultra-relativistic electrons accelerated by supernovae. These ultra-relativistic electrons interact with the galactic magnetic field and the acceleration produces the synchrotron radiation observed. The SMC results with minimal nonthermal contributions may not provide support for coupling between the local gas density and the magnetic field intensity. Planetary nebulae detected in the RC are frequently referred to by the shorthand “radio planetary nebulae”. A search for radio planetary nebulae in the SMC resulted in ten new RC detections reported here from the 105 catalogued planetary nebula positions in the SMC (SMP S6, LIN41, LIN142, SMPS13, SMP S14, SMP S16, J 18, SMP S18, SMPS19, and SMPS22). Six SMC radio planetary nebulae previously detected (LIN45, SMPS11, SMP S17, LIN321, LIN339, and SMP S24) were re-observed. These sixteen radio detections represent ∼15% of the total catalogued planetary nebula population in the SMC. Six of these objects, however, were shown to have characteristics that suggest they are likely planetary nebula mimics (LIN41, LIN45, SMPS11, LIN142, LIN321, and LIN339). The SMC radio planetary nebula population was also used in a (Σ–D) relation study. The results of this study were consistent with previous SMC and Large Magellanic Cloud (LMC) planetary nebula measurements of the (Σ-D) relation. This study contributed twenty-one new radio detections of planetary nebulae to the total of thirty-one radio planetary nebulae that have been detected in the LMC. The search for these radio planetary nebulae in the LMC began with the exploration of all 629 validated planetary nebula positions. All presently available data from the ATOA at 3, 6, 13, and 20 cm were examined at these positions. The newly detected planetary nebulae were: SMP L13, SMPL15, SMPL21, SMP L23, SMPL29, SMPL37, SMP L38, SMPL45, SMPL50, SMP L52, SMPL53, SMPL58, SMPL63, SMP L66, SMPL73, SMPL75, SMP L76, SMPL78, RP 659, SMPL85, and SMPL92. Seven previously detected radio planetary nebulae (Filipovic et al., 2009) were also detected: SMP L47, SMP L48, SMPL62, SMPL74, SMP L83, SMP L84, and SMP L89. An additional three planetary nebulae from the study by Filipovic et al. (2009): SMPL25, SMPL33, and SMPL39 were not detected in this study but were included in the complete catalogue compilation of radio planetary nebulae presented here. One of the previous detections from that study, SMP L8, had been reclassified as a planetary nebula mimic, a compact Hii region. With the available planetary nebula 6 cm surface brightness measurements and the corresponding planetary nebula diameter data, a bootstrap resampled sample was constructed from twenty-eight LMC radio planetary nebulae and nine SMC radio planetary nebulae which revealed that Magellanic Cloud (MC) planetary nebulae were not likely to follow linear evolutionary paths. The best fitting parameters from this resampled sample were comparable to previous results from the MCs and the Galactic planetary nebulae. A value of β = 2.9 ± 0.4 was obtained for MC planetary nebulae compared to β = 3.1 ± 0.4 for the Galaxy. The MC planetary nebula resampled sample was used to calibrate a planetary nebula (Σ–D) statistical distance model which resulted in a predicted statistical distance error of 17%. Since a value of β = 2.9±0.4 was found for the MC sample which is just below the minimum predicted theoretical value of β = 3, sensitivity selection effects were examined. To estimate the significance of the sensitivity selection effects, a Monte Carlo bootstrap resampled sample was created which included various sensitivity bias parameters. The best fitting parameters from the bias effects on the bootstrap resampled sample created in this way indicated that selection effects were significant for β values larger than β ∼ 2.6. The selection effect was shown to produce a measured value of β = 2.9 when the unbiased sample had a value of β ∼ 3.4. A continuous probability density function (PDF) was also constructed using a Monte Carlo bootstrap resampled sample with more advanced techniques. This approach resulted in an enhanced accuracy for the statistical distance calculation with a distance error of 16%. This error was comparable to a study by Frew et al. (2016b) which used the (SHα-r) relation and reported a distance measurement error of 18% with a calibration sample of 1100 planetary nebulae

Radio Planetary Nebulae in the Large Magellanic Cloud

We present 21 new radio-continuum detections at catalogued planetary nebula (PN) positions in the Large Magellanic Cloud (LMC) using all presently available data from the Australia Telescope Online Archive at 3, 6, 13 and 20 cm. Additionally, 11 previously detected LMC radio PNe are re-examined with $7$ detections confirmed and reported here. An additional three PNe from our previous surveys are also studied. The last of the 11 previous detections is now classified as a compact \HII\ region which makes for a total sample of 31 radio PNe in the LMC. The radio-surface brightness to diameter ($\Sigma$-D) relation is parametrised as $\Sigma \propto {D^{ - \beta }}$. With the available 6~cm $\Sigma$-$D$ data we construct $\Sigma$-$D$ samples from 28 LMC PNe and 9 Small Magellanic Cloud (SMC) radio detected PNe. The results of our sampled PNe in the Magellanic Clouds (MCs) are comparable to previous measurements of the Galactic PNe. We obtain $\beta=2.9\pm0.4$ for the MC PNe compared to $\beta = 3.1\pm0.4$ for the Galaxy. For a better insight into sample completeness and evolutionary features we reconstruct the $\Sigma$-$D$ data probability density function (PDF). The PDF analysis implies that PNe are not likely to follow linear evolutionary paths. To estimate the significance of sensitivity selection effects we perform a Monte Carlo sensitivity simulation on the $\Sigma$-$D$ data. The results suggest that selection effects are significant for values larger than $\beta \sim 2.6$ and that a measured slope of $\beta=2.9$ should correspond to a sensitivity-free value of $\sim 3.4$.Comment: 19 pages, 9 figures, 6 table

The past, present and future of gravitational wave astronomy

Gravitational Waves (GWs) have become a major source of insight in Multi Messenger Astronomy since their first direct detection in 2015 (Abbott et al. 2016) where the Nobel prize in Physics was awarded in 2017 to LIGO founders Barry C. Barish, Kip S. Thorne, and Rainer Weiss. They complement electromagnetic and particle measurements by providing cosmic scale evidence which cannot be detected in any other way. Their rise to prominence has not been straightforward since the founder of general relativity, Albert Einstein, who predicted GWs, was nevertheless skeptical of their existence and detectability. This skepticism put a damper on Gravitational Wave (GW) research that was not overcome until the 1950's, the decade of Einstein's death. Since then, ever more sensitive GW detectors have been designed for construction on earth and in space. Each of these detector approaches was designed to expand the types of cosmic events that could be detected

Radio Planetary Nebulae in the Small Magellanic Cloud

We present ten new radio continuum (RC) detections at catalogued planetary nebula (PN) positions in the Small Magellanic Cloud (SMC): SMPS6, LIN 41, LIN 142, SMP S13, SMP S14, SMP S16, J18, SMP S18, SMP S19 and SMP S22. Additionally, six SMC radio PNe previously detected, LIN 45, SMP S11, SMPS17, LIN321, LIN339 and SMPS24 are also investigated (re-observed) here making up a population of 16 radio detections of catalogued PNe in the SMC. These 16 radio detections represent ~15 % of the total catalogued PN population in the SMC. We show that six of these objects have characteristics that suggest that they are PN mimics: LIN 41, LIN 45, SMP S11, LIN 142, LIN 321 and LIN 339. We also present our results for the surface brightness - PN radius relation ({\Sigma}-D) of the SMC radio PN population. These are consistent with previous SMC and LMC PN measurements of the ({\Sigma}-D) relation.Comment: Accepted for publication in Astrophysics and Space Scienc

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimers disease patients.

INTRODUCTION: The A/T/N (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimers disease (AD) diagnosis and can encompass additional changes such as inflammation (I). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. HIGHLIGHTS: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate

Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response

An analysis of the FIR/RADIO Continuum Correlation in the Small Magellanic Cloud

The local correlation between far-infrared (FIR) emission and radio-continuum (RC) emission for the Small Magellanic Cloud (SMC) is investigated over scales from 3 kpc to 0.01 kpc. Here, we report good FIR/RC correlation down to ~15 pc. The reciprocal slope of the FIR/RC emission correlation (RC/FIR) in the SMC is shown to be greatest in the most active star forming regions with a power law slope of ~1.14 indicating that the RC emission increases faster than the FIR emission. The slope of the other regions and the SMC are much flatter and in the range of 0.63-0.85. The slopes tend to follow the thermal fractions of the regions which range from 0.5 to 0.95. The thermal fraction of the RC emission alone can provide the expected FIR/RC correlation. The results are consistent with a common source for ultraviolet (UV) photons heating dust and Cosmic Ray electrons (CRe-s) diffusing away from the star forming regions. Since the CRe-s appear to escape the SMC so readily, the results here may not provide support for coupling between the local gas density and the magnetic field intensity.Comment: 19 pages, 7 Figure

Neuropathological and Genetic Correlates of Survival and Dementia Onset in Synucleinopathies: A Retrospective Analysis

Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer\u27s disease pathology according to US National Institute on Aging–Alzheimer\u27s Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer\u27s disease neuropathology, 56 (26%) with low-level Alzheimer\u27s disease neuropathology, 45 (21%) with intermediate-level Alzheimer\u27s disease neuropathology, and 63 (30%) with high-level Alzheimer\u27s disease neuropathology. As levels of Alzheimer\u27s disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p \u3c 0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p \u3c 0·0001; R 2 0·22, p \u3c 0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, \u3c 0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer\u27s disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer\u27s disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer\u27s disease neuropathology

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson’s disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07