The opportunity prior: a proof-based prior for criminal cases

One of the greatest challenges to the use of probabilistic reasoning in the assessment of criminal evidence is the ‘problem of the prior’, i.e. the difficulty in establishing an acceptable prior probability of guilt. Even strong supporters of a Bayesian approach have often preferred to ignore priors and focus on the likelihood ratio (LR) of the evidence. But to calculate if the probability of guilt, given the evidence reaches the probability required for conviction (the standard of proof), the LR has to be combined with a prior. In this article, we propose a solution to the ‘problem of the prior’: the defendant shall be treated as a member of the set of ‘possible perpetrators’ defined as the people who had the same or better opportunity as the defendant to commit the crime. For this purpose, we introduce the concept of an ‘extended crime scene’. The number of people who had the same or better opportunity as the defendant is the number of people who were just as close or closer to the crime scene, in time and space. We demonstrate how the opportunity prior is incorporated into a generic Bayesian network model that allows us to integrate other evidence about the case

Datafied female health: Sociotechnical imaginaries of femtech in Danish public discourse

The digitalization of health promises individual empowerment while raising the threat of collective surveillance. Conceptualizing these threats and promises as sociotechnical imaginaries, we explore how issues of datafied female health are articulated in Danish public discourse. Empirically, we work with a large data set of Danish news media coverage of algorithmic technologies in the past 10 years (2011–2021). We locate coverage of female-oriented health technologies (or femtech) by using the data sprint methodology to track the emergence of such technologies as a topic of public concern. Across the data, we identify two broad sociotechnical imaginaries: one zooming in on individual uses of femtech, the other focusing on the collective benefits of public health initiatives. We conclude that sociotechnical imaginaries of femtech are increasingly entangled in everyday life, making female bodies knowable through algorithms and data. As such, female health becomes subject to instrumental rationality, not lived reality

Assimilation of atmospheric infrasound data to constrain tropospheric and stratospheric winds

This data assimilation study exploits infrasound from explosions to probe an atmospheric wind component from the ground up to stratospheric altitudes. Planned explosions of old ammunition in Finland generate transient infrasound waves that travel through the atmosphere. These waves are partially reflected back towards the ground from stratospheric levels, and are detected at a receiver station located in northern Norway at 178 km almost due North from the explosion site. The difference between the true horizontal direction towards the source and the backazimuth direction(the horizontal direction of arrival) of the incoming infrasound wave-fronts, in combination with the pulse propagation time, are exploited to provide an estimate of the average cross-wind component in the penetrated atmosphere. We perform offline assimilation experiments with an ensemble Kalman filter and these observations, using the ERA5 ensemble reanalysis atmospheric product as background(prior) for the wind at different vertical levels. We demonstrate that information from both source scan be combined to obtain analysis (posterior) estimates of cross-winds at different vertical levels of the atmospheric slice between the explosion site and the recording station. The assimilation makes greatest impact at the 12−60 km levels, with some changes with respect to the prior of the order of 0.1−1.0 m/s, which is a magnitude larger than the typical standard deviation of the ERA5 background. The reduction of background variance in the higher levels often reached 2−5%. This is the first published study demonstrating techniques to implement assimilation of infrasound data into atmospheric models. It paves the way for further exploration in the use of infrasound observations– especially natural and continuous sources – to probe the middle atmospheric dynamics and to assimilate these data into atmospheric model products

Adipose tissue pathways involved in weight loss of cancer cachexia

White adipose tissue (WAT) constitutes our most expandable tissue and largest endocrine organ secreting hundreds of polypeptides collectively termed adipokines. Changes in WAT mass induce alterations in adipocyte secretion and function, which are linked to disturbed whole-body metabolism. Although the mechanisms controlling this are not clear they are dependent on changes in gene expression, a complex process which is regulated at several levels. Results in recent years have highlighted the role of small non-coding RNA molecules termed microRNAs (miRNAs), which regulate gene expression via post-transcriptional mechanisms. The aim of this thesis was to characterize global gene expression levels and describe novel miRNAs and adipokines controlling the function of human WAT in conditions with pathological increases or decreases in WAT mass. Obesity and cancer cachexia were selected as two models since they are both clinically relevant and characterized by involuntary changes in WAT mass. In Study I, expressional analyses were performed in subcutaneous WAT from cancer patients with or without cachexia and obese versus non-obese subjects. In total, 425 transcripts were found to be regulated in cancer cachexia. Pathway analyses based on this set of genes revealed that processes involving extracellular matrix, actin cytoskeleton and focal adhesion were significantly downregulated, whereas fatty acid metabolism was upregulated comparing cachectic with weight-stable cancer subjects. Furthermore, by overlapping these results with microarray data from an obesity study, many transcripts were found to be reciprocally regulated comparing the two conditions. This suggests that WAT gene expression in cancer cachexia and obesity are regulated by similar, albeit opposing, mechanisms. In Study II, the focus was on the family of fibroblast growth factors (FGFs), members of which have recently been implicated in the development of obesity and insulin resistance. A retrospective analysis of global gene expression data identified several FGFs (FGF1/2/7/9/13/18) to be expressed in WAT. However, only one, FGF1, was actively secreted from WAT and predominantly so from the adipocyte fraction. Moreover, FGF1 release was increased in obese compared to non-obese subjects, but was not normalized by weight loss. Although the clinical significance of these findings is not yet clear, it can be hypothesized that FGF1 may play a role in WAT growth, possibly by promoting fat cell proliferation and/or differentiation. In Study III, we identified adipose miRNAs regulated in obesity. Out of eleven miRNAs regulated by changes in body fat mass, ten controlled the production of the pro-inflammatory chemoattractant chemokine (C-C motif) ligand 2 (CCL2) when overexpressed in fat cells and for two, miR-126 and -193b, signaling circuits were defined. In Study IV, a novel adipokine, semaphorin 3C (SEMA3C), was identified by combining transcriptome and secretome data. Detailed studies focusing on SEMA3C revealed that this factor was secreted from adipocytes and induced the expression of extracellular matrix and matricellular genes in preadipocytes. Furthermore, SEMA3C mRNA levels correlated with interstitial fibrosis and insulin resistance in WAT derived from subjects with a wide range in BMI. In summary, the results presented in this thesis have delineated transcriptional alterations in WAT in two clinically relevant conditions, obesity and cancer cachexia. This has allowed the identification of novel adipokines and microRNAs with potential pathophysiological importance. These findings form the basis for further studies aiming at understanding the central role of WAT in disorders associated with metabolic complications

Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue

Proceedings of the National Academy of Sciences of the United States of America112144363-436

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor

Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study

<p>Abstract</p> <p>Background</p> <p>Liver X receptor alpha <it>(LXRA</it>) and beta (<it>LXRB</it>) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in <it>LXRA </it>and <it>LXRB </it>associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.</p> <p>Methods</p> <p>Eight common single nucleotide polymorphisms in <it>LXRA </it>and <it>LXRB </it>were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMA_IRas measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal <it>LXRB </it>promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to <it>in silico </it>analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.</p> <p>Results</p> <p>Genotypes at two <it>LXRB </it>promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No <it>LXRA </it>or <it>LXRB </it>SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the <it>LXRB </it>gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.</p> <p>Conclusion</p> <p>Variations in the <it>LXRB </it>gene promoter may be part of the aetiology of T2D. However, the association between <it>LXRB </it>rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in <it>LXRA </it>is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.</p

Could sound be used as a strategy for reducing symptoms of perceived motion sickness?

<p>Abstract</p> <p>Background</p> <p>Working while exposed to motions, physically and psychologically affects a person. Traditionally, motion sickness symptom reduction has implied use of medication, which can lead to detrimental effects on performance. Non-pharmaceutical strategies, in turn, often require cognitive and perceptual attention. Hence, for people working in high demand environments where it is impossible to reallocate focus of attention, other strategies are called upon. The aim of the study was to investigate possible impact of a mitigation strategy on perceived motion sickness and psychophysiological responses, based on an artificial sound horizon compared with a non-positioned sound source.</p> <p>Methods</p> <p>Twenty-three healthy subjects were seated on a motion platform in an artificial sound horizon or in non-positioned sound, in random order with one week interval between the trials. Perceived motion sickness (Mal), maximum duration of exposure (ST), skin conductance, blood volume pulse, temperature, respiration rate, eye movements and heart rate were measured continuously throughout the trials.</p> <p>Results</p> <p>Mal scores increased over time in both sound conditions, but the artificial sound horizon, applied as a mitigation strategy for perceived motion sickness, showed no significant effect on Mal scores or ST. The number of fixations increased with time in the non-positioned sound condition. Moreover, fixation time was longer in the non-positioned sound condition compared with sound horizon, indicating that the subjects used more time to fixate and, hence, assumingly made fewer saccades.</p> <p>Conclusion</p> <p>A subliminally presented artificial sound horizon did not significantly affect perceived motion sickness, psychophysiological variables or the time the subjects endured the motion sickness triggering stimuli. The number of fixations and fixation times increased over time in the non-positioned sound condition.</p

Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue

PLEXIN D1 (PLXND1) has been implicated in body fat distribution and type 2 diabetes by genome-wide association studies, but the mechanism is unknown. We show here that Plxnd1 regulates body fat distribution in zebrafish by controlling the visceral adipose tissue (VAT) growth mechanism. Plxnd1 deficiency in zebrafish resulted in induction of a hyperplastic state and reduced lipid deposition in VAT. Regulation of VAT was dependent on the induction of the type V collagen, col5a1, suggesting that Plxnd1 controls body fat distribution by determining the status of VAT extracellular matrix. Plxnd1-deficient zebrafish were protected from high-fat-induced insulin resistance, and human PLXND1 mRNA was positively associated with type 2 diabetes. These results suggest that the role of Plxnd1 in body fat distribution and insulin signaling is conserved from zebrafish to humans

A Transcriptional Enhancer from the Coding Region of ADAMTS5

The revelation that the human genome encodes only approximately 25,000 genes and thus cannot account for phenotypic complexity has been one of the biggest surprises in the post-genomic era. However, accumulating evidence suggests that transcriptional regulation may be in large part responsible for this observed mammalian complexity. Consequently, there has been a strong drive to locate cis-regulatory regions in mammalian genomes in order to understand the unifying principles governing these regions, including their genomic distribution. Although a number of systematic approaches have been developed, these all discount coding sequence.Using the computational tool PRI (Pattern-defined Regulatory Islands), which does not mask coding sequence, we identified a regulatory region associated with the gene ADAMTS5 that encompasses the entirety of the essential coding exon 2. We demonstrate through a combination of chromatin immunoprecipitation and reporter gene studies that this region can not only bind the myogenic transcription factors MYOD and myogenin and the E-protein HEB but can also function as a very strong myogenic transcriptional enhancer.Thus, we report the identification and detailed characterization of an exonic enhancer. Ultimately, this leads to the interesting question of why evolution would be so parsimonious in the functional assignment of sequence