VAC14 Gene‐Related Parkinsonism‐Dystonia With Response to Deep Brain Stimulation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150504/1/mdc312797-sup-0001-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150504/2/mdc312797.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150504/3/mdc312797_am.pd

The potential to narrow uncertainty in projections of stratospheric ozone over the 21st century

Future stratospheric ozone concentrations will be determined both by changes in the concentration of ozone depleting substances (ODSs) and by changes in stratospheric and tropospheric climate, including those caused by changes in anthropogenic greenhouse gases (GHGs). Since future economic development pathways and resultant emissions of GHGs are uncertain, anthropogenic climate change could be a significant source of uncertainty for future projections of stratospheric ozone. In this pilot study, using an "ensemble of opportunity" of chemistry-climate model (CCM) simulations, the contribution of scenario uncertainty from different plausible emissions pathways for ODSs and GHGs to future ozone projections is quantified relative to the contribution from model uncertainty and internal variability of the chemistry-climate system. For both the global, annual mean ozone concentration and for ozone in specific geographical regions, differences between CCMs are the dominant source of uncertainty for the first two-thirds of the 21st century, up-to and after the time when ozone concentrations return to 1980 values. In the last third of the 21st century, dependent upon the set of greenhouse gas scenarios used, scenario uncertainty can be the dominant contributor. This result suggests that investment in chemistry-climate modelling is likely to continue to refine projections of stratospheric ozone and estimates of the return of stratospheric ozone concentrations to pre-1980 levels

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder

To assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls

Male gays in the female gaze: women who watch m/m pornography

This paper draws on a piece of wide-scale mixed-methods research that examines the motivations behind women who watch gay male pornography. To date there has been very little interdisciplinary research investigating this phenomenon, despite a recent survey by PornHub (one of the largest online porn sites in the world) showing that gay male porn is the second most popular choice for women porn users out of 25+ possible genre choices. While both academic literature and popular culture have looked at the interest that (heterosexual) men have in lesbian pornography, considerably less attention has been paid to the consumption of gay male pornography by women. Research looking at women's consumption of pornography from within the Social Sciences is very focused around heterosexual (and, to a lesser extent, lesbian) pornography. Research looking more generally at gay pornography/erotica (and the subversion of the ‘male gaze’/concept of ‘male as erotic object’) often makes mention of female interest in this area, but only briefly, and often relies on anecdotal or observational evidence. Research looking at women's involvement in slashfic (primarily from within media studies), while very thorough and rich, tends to view slash writing as a somewhat isolated phenomenon (indeed, in her influential article on women's involvement in slash, Bacon-Smith talks about how ‘only a small number’ of female slash writers and readers have any interest in gay literature or pornography more generally, and this phenomenon is not often discussed in more recent analyses of slash); so while there has been a great deal of very interesting research done in this field, little attempt has been made to couch it more generally within women's consumption and use of pornography and erotica or to explore what women enjoy about watching gay male pornography. Through a series of focus groups, interviews, and an online questionnaire (n = 275), this exploratory piece of work looks at what women enjoy about gay male pornography, and how it sits within their consumption of erotica/pornography more generally. The article investigates what this has to say about the existence and nature of a ‘female gaze’

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe