Ventromedial Frontal Lobe Damage Disrupts Value Maximization in Humans

Recent work in neuroeconomics has shown that regions in orbitofrontal and medial prefrontal cortex encode the subjective value of different options during choice. However, these electrophysiological and neuroimaging studies cannot demonstrate whether such signals are necessary for value-maximizing choices. Here we used a paradigm developed in experimental economics to empirically measure and quantify violations of utility theory in humans with damage to the ventromedial frontal lobe (VMF). We show that people with such damage are more likely to make choices that violate the generalized axiom of revealed preference, which is the one necessary and sufficient condition for choices to be consistent with value maximization. These results demonstrate that the VMF plays a critical role in value-maximizing choice

Heliophysics and Amateur Radio:Citizen Science Collaborations for Atmospheric, Ionospheric, and Space Physics Research and Operations

The amateur radio community is a global, highly engaged, and technical community with an intense interest in space weather, its underlying physics, and how it impacts radio communications. The large-scale observational capabilities of distributed instrumentation fielded by amateur radio operators and radio science enthusiasts offers a tremendous opportunity to advance the fields of heliophysics, radio science, and space weather. Well-established amateur radio networks like the RBN, WSPRNet, and PSKReporter already provide rich, ever-growing, long-term data of bottomside ionospheric observations. Up-and-coming purpose-built citizen science networks, and their associated novel instruments, offer opportunities for citizen scientists, professional researchers, and industry to field networks for specific science questions and operational needs. Here, we discuss the scientific and technical capabilities of the global amateur radio community, review methods of collaboration between the amateur radio and professional scientific community, and review recent peer-reviewed studies that have made use of amateur radio data and methods. Finally, we present recommendations submitted to the U.S. National Academy of Science Decadal Survey for Solar and Space Physics (Heliophysics) 2024–2033 for using amateur radio to further advance heliophysics and for fostering deeper collaborations between the professional science and amateur radio communities. Technical recommendations include increasing support for distributed instrumentation fielded by amateur radio operators and citizen scientists, developing novel transmissions of RF signals that can be used in citizen science experiments, developing new amateur radio modes that simultaneously allow for communications and ionospheric sounding, and formally incorporating the amateur radio community and its observational assets into the Space Weather R2O2R framework. Collaborative recommendations include allocating resources for amateur radio citizen science research projects and activities, developing amateur radio research and educational activities in collaboration with leading organizations within the amateur radio community, facilitating communication and collegiality between professional researchers and amateurs, ensuring that proposed projects are of a mutual benefit to both the professional research and amateur radio communities, and working towards diverse, equitable, and inclusive communities

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

A systematic study of 7 MHz greyline propagation using amateur radio beacon signals

This paper investigates 7 MHz ionospheric radio wave propagation between pairs of distant countries that simultaneously lie on the terminator. This is known as greyline propagation. Observations of amateur radio beacon transmitters recorded in the Weak Signal Propagation Reporter (WSPR) database are used to investigate the times of day that beacon signals were observed during the year 2017. The WSPR beacon network consists of thousands of automated beacon transmitters and observers distributed over the globe. The WSPR database is a very useful resource for radio science as it offers the date and time at which a propagation path was available between two radio stations, as well as their precise locations. This paper provides the first systematic study of grey-line propagation between New Zealand/Eastern Australia and UK/Europe. The study shows that communications were predominantly made from the United Kingdom (UK) to New Zealand at around both sunset and sunrise times, whereas from New Zealand to the UK, communication links occurred mainly during UK sunrise hours. The lack of observations at the UK sunset time was particularly evident during the UK summer. The same pattern was found in the observations of propagation from Eastern Australia to UK, and from New Zealand and Eastern Australia to Italy and the surrounding regions in Europe. The observed asymmetry in reception pattern could possibly be due to the increase in electromagnetic noise across Europe in the summer afternoon/evening from thunderstorm

The landscape of recombination in African Americans

Recombination, together with mutation, is the ultimate source of genetic variation in populations. We leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing-over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P<10(−245)). We identify a 17 base pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of African-enriched alleles of PRDM9

Meta-analysis of breast cancer microarray studies in conjunction with conserved <it>cis</it>-elements suggest patterns for coordinate regulation

<p>Abstract</p> <p>Background</p> <p>Gene expression measurements from breast cancer (BrCa) tumors are established clinical predictive tools to identify tumor subtypes, identify patients showing poor/good prognosis, and identify patients likely to have disease recurrence. However, diverse breast cancer datasets in conjunction with diagnostic clinical arrays show little overlap in the sets of genes identified. One approach to identify a set of consistently dysregulated candidate genes in these tumors is to employ meta-analysis of multiple independent microarray datasets. This allows one to compare expression data from a diverse collection of breast tumor array datasets generated on either cDNA or oligonucleotide arrays.</p> <p>Results</p> <p>We gathered expression data from 9 published microarray studies examining estrogen receptor positive (ER+) and estrogen receptor negative (ER-) BrCa tumor cases from the Oncomine database. We performed a meta-analysis and identified genes that were universally up or down regulated with respect to ER+ versus ER- tumor status. We surveyed both the proximal promoter and 3' untranslated regions (3'UTR) of our top-ranking genes in each expression group to test whether common sequence elements may contribute to the observed expression patterns. Utilizing a combination of known transcription factor binding sites (TFBS), evolutionarily conserved mammalian promoter and 3'UTR motifs, and microRNA (miRNA) seed sequences, we identified numerous motifs that were disproportionately represented between the two gene classes suggesting a common regulatory network for the observed gene expression patterns.</p> <p>Conclusion</p> <p>Some of the genes we identified distinguish key transcripts previously seen in array studies, while others are newly defined. Many of the genes identified as overexpressed in ER- tumors were previously identified as expression markers for neoplastic transformation in multiple human cancers. Moreover, our motif analysis identified a collection of specific <it>cis</it>-acting target sites which may collectively play a role in the differential gene expression patterns observed in ER+ versus ER- breast cancer tumors. Importantly, the gene sets and associated DNA motifs provide a starting point with which to explore the mechanistic basis for the observed expression patterns in breast tumors.</p

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P &lt; 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis