Seeing Things Differently: Art, Law and Justice in the Scottish Feminist Judgments Project

This paper illustrates how turning to art rather than focusing solely on legal reform can form part of an alternative response to gender inequality that allows for deeper understandings of social (in)justice. We show how the Scottish Feminist Judgments Project – a collaborative endeavour by legal academics, practising lawyers, judges, artistic contributors and representatives from the third sector – can offer those who engage with our art the experience of hearing and seeing law in different ways. More specifically, we explore how art can open law up to scrutiny, render vivid the impact of legal decisions, and create richer and more democratic communities of understanding. At the same time, by discussing  knowledge differentials and the quandaries of creating art ethically, we also highlight some of the challenges involved in engaging in artistic-legal collaboration

Extracting detailed oncologic history and treatment plan from medical oncology notes with large language models

Both medical care and observational studies in oncology require a thorough understanding of a patient's disease progression and treatment history, often elaborately documented in clinical notes. Despite their vital role, no current oncology information representation and annotation schema fully encapsulates the diversity of information recorded within these notes. Although large language models (LLMs) have recently exhibited impressive performance on various medical natural language processing tasks, due to the current lack of comprehensively annotated oncology datasets, an extensive evaluation of LLMs in extracting and reasoning with the complex rhetoric in oncology notes remains understudied. We developed a detailed schema for annotating textual oncology information, encompassing patient characteristics, tumor characteristics, tests, treatments, and temporality. Using a corpus of 10 de-identified breast cancer progress notes at University of California, San Francisco, we applied this schema to assess the abilities of three recently-released LLMs (GPT-4, GPT-3.5-turbo, and FLAN-UL2) to perform zero-shot extraction of detailed oncological history from two narrative sections of clinical progress notes. Our team annotated 2750 entities, 2874 modifiers, and 1623 relationships. The GPT-4 model exhibited overall best performance, with an average BLEU score of 0.69, an average ROUGE score of 0.72, and an average accuracy of 67% on complex tasks (expert manual evaluation). Notably, it was proficient in tumor characteristic and medication extraction, and demonstrated superior performance in inferring symptoms due to cancer and considerations of future medications. The analysis demonstrates that GPT-4 is potentially already usable to extract important facts from cancer progress notes needed for clinical research, complex population management, and documenting quality patient care.Comment: Source code available at: https://github.com/MadhumitaSushil/OncLLMExtractio

Correction to:Feminist judgments projects at the intersection

On 25th and 26th July 2019, ten members of the African, Indian and Scottish Feminist Judgments Projects (FJPs), comprised of legal academics and legal practitioners, met at Edinburgh Law School in Scotland. We were also joined at various points in our discussions by a number of invited guests from the Scottish academic, legal and feminist activist communities. In the context of ongoing global conversations across diverse FJPs, the purpose of our meeting was to explore the connections between these three then in-progress FJPs, to reflect on the experience of being involved in an FJP within our respective jurisdictions, and to discuss both the pitfalls and possibilities for creating legacies in teaching, scholarship and practice (see also Cowan et al. 2018)

Evolution and extinction of Maastrichtian (Late Cretaceous) cephalopods from the López de Bertodano Formation, Seymour Island, Antarctica

One of the most expanded records to contain the final fortunes of ammonoid cephalopods is within the López de Bertodano Formation of Seymour Island, James Ross Basin, Antarctica. Located at 65° South now, and during the Cretaceous, this sequence is the highest southern latitude onshore outcrop containing the Cretaceous-Paleogene (K-Pg) transition. We present comprehensive new biostratigraphic range data for 14 ammonite and one nautiloid species based on the collection of >. 700 macrofossils from high-resolution sampling of parallel sedimentary sections, dated Maastrichtian to earliest Danian in age, across southern Seymour Island. We find evidence for only a single, abrupt pulse of cephalopod extinction at the end of the Cretaceous when the final seven ammonite species disappeared, consistent with most evidence globally. In the lead up to the K-Pg extinction in the James Ross Basin, starting during the Campanian, ammonite diversity decreased overall, but the number of endemic taxa belonging to the family Kossmaticeratidae actually increased. This pattern continued into the Maastrichtian and may be facies controlled, linked to changes in sea level and seawater temperature. During the early Maastrichtian, ammonite diversity dropped significantly with only two species recorded from the basal López de Bertodano Formation on Seymour Island. The subsequent diversification of endemic taxa and reappearance of long-ranging, widespread species into the basin resulted in an increase in ammonite diversity and abundance during the mid-Maastrichtian. This was coincident with an apparent period of warming temperatures and sea level rise interpreted from palynology and sedimentology, perhaps reflecting a high latitude expression of the Mid-Maastrichtian Event. Late Maastrichtian diversity levels remained stable despite reported climatic and environmental variation. Ammonite diversity patterns during the Maastrichtian parallel those of microfossil species such as nannofossil and planktonic foraminifera, suggesting that dynamic climatic and environmental changes affected many planktonic and nektonic organisms during the latest Cretaceous. However, we suggest that these perturbations had a minimal effect on overall diversity prior to the catastrophic extinction event at the K-Pg boundary

A novel approach to investigate tissue-specific trinucleotide repeat instability

Abstract Background In Huntington's disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors. Results Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG repeat instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability. Conclusion Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability

Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver

Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.

The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host's metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication

Characterization of Major Histocompatibility Complex (MHC) DRB Exon 2 and DRA Exon 3 Fragments in a Primary Terrestrial Rabies Vector (Procyon lotor)

The major histocompatibility complex (MHC) presents a unique system to explore links between genetic diversity and pathogens, as diversity within MHC is maintained in part by pathogen driven selection. While the majority of wildlife MHC studies have investigated species that are of conservation concern, here we characterize MHC variation in a common and broadly distributed species, the North American raccoon (Procyon lotor). Raccoons host an array of broadly distributed wildlife diseases (e.g., canine distemper, parvovirus and raccoon rabies virus) and present important human health risks as they persist in high densities and in close proximity to humans and livestock. To further explore how genetic variation influences the spread and maintenance of disease in raccoons we characterized a fragment of MHC class II DRA exon 3 (250bp) and DRB exon 2 (228 bp). MHC DRA was found to be functionally monomorphic in the 32 individuals screened; whereas DRB exon 2 revealed 66 unique alleles among the 246 individuals screened. Between two and four alleles were observed in each individual suggesting we were amplifying a duplicated DRB locus. Nucleotide differences between DRB alleles ranged from 1 to 36 bp (0.4–15.8% divergence) and translated into 1 to 21 (1.3–27.6% divergence) amino acid differences. We detected a significant excess of nonsynonymous substitutions at the peptide binding region (P = 0.005), indicating that DRB exon 2 in raccoons has been influenced by positive selection. These data will form the basis of continued analyses into the spatial and temporal relationship of the raccoon rabies virus and the immunogenetic response in its primary host

Stoichiometry of Base Excision Repair Proteins Correlates with Increased Somatic CAG Instability in Striatum over Cerebellum in Huntington's Disease Transgenic Mice

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of an unstable CAG repeat in the coding sequence of the Huntingtin (HTT) gene. Instability affects both germline and somatic cells. Somatic instability increases with age and is tissue-specific. In particular, the CAG repeat sequence in the striatum, the brain region that preferentially degenerates in HD, is highly unstable, whereas it is rather stable in the disease-spared cerebellum. The mechanisms underlying the age-dependence and tissue-specificity of somatic CAG instability remain obscure. Recent studies have suggested that DNA oxidation and OGG1, a glycosylase involved in the repair of 8-oxoguanine lesions, contribute to this process. We show that in HD mice oxidative DNA damage abnormally accumulates at CAG repeats in a length-dependent, but age- and tissue-independent manner, indicating that oxidative DNA damage alone is not sufficient to trigger somatic instability. Protein levels and activities of major base excision repair (BER) enzymes were compared between striatum and cerebellum of HD mice. Strikingly, 5′-flap endonuclease activity was much lower in the striatum than in the cerebellum of HD mice. Accordingly, Flap Endonuclease-1 (FEN1), the main enzyme responsible for 5′-flap endonuclease activity, and the BER cofactor HMGB1, both of which participate in long-patch BER (LP–BER), were also significantly lower in the striatum compared to the cerebellum. Finally, chromatin immunoprecipitation experiments revealed that POLβ was specifically enriched at CAG expansions in the striatum, but not in the cerebellum of HD mice. These in vivo data fit a model in which POLβ strand displacement activity during LP–BER promotes the formation of stable 5′-flap structures at CAG repeats representing pre-expanded intermediate structures, which are not efficiently removed when FEN1 activity is constitutively low. We propose that the stoichiometry of BER enzymes is one critical factor underlying the tissue selectivity of somatic CAG expansion

The miR-35-41 Family of MicroRNAs Regulates RNAi Sensitivity in Caenorhabditis elegans

RNA interference (RNAi) utilizes small interfering RNAs (siRNAs) to direct silencing of specific genes through transcriptional and post-transcriptional mechanisms. The siRNA guides can originate from exogenous (exo–RNAi) or natural endogenous (endo–RNAi) sources of double-stranded RNA (dsRNA). In Caenorhabditis elegans, inactivation of genes that function in the endo–RNAi pathway can result in enhanced silencing of genes targeted by siRNAs from exogenous sources, indicating cross-regulation between the pathways. Here we show that members of another small RNA pathway, the mir-35-41 cluster of microRNAs (miRNAs) can regulate RNAi. In worms lacking miR-35-41, there is reduced expression of lin-35/Rb, the C. elegans homolog of the tumor suppressor Retinoblastoma gene, previously shown to regulate RNAi responsiveness. Genome-wide microarray analyses show that targets of endo–siRNAs are up-regulated in mir-35-41 mutants, a phenotype also displayed by lin-35/Rb mutants. Furthermore, overexpression of lin-35/Rb specifically rescues the RNAi hypersensitivity of mir-35-41 mutants. Although the mir-35-41 miRNAs appear to be exclusively expressed in germline and embryos, their effect on RNAi sensitivity is transmitted to multiple tissues and stages of development. Additionally, we demonstrate that maternal contribution of miR-35-41 or lin-35/Rb is sufficient to reduce RNAi effectiveness in progeny worms. Our results reveal that miRNAs can broadly regulate other small RNA pathways and, thus, have far reaching effects on gene expression beyond directly targeting specific mRNAs