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A number of no-go theorems have shown that Wigner’s Friend scenarios combined with various metaphysical assumptions lead to contradictions in any version of quantum theory. We present an alternative constructive approach that only assumes that agents make properly qualified true statements. Quantum observers are modeled rigorously, although simplistically, using quantum circuits. Terminology is suggested to help avoid contradictions. Our methodology is applied to the Frauchiger-Renner paradox and results in statements by all agents that are both true and consistent. Quantum theory evades the no-go theorems because they make an incorrect implicit assumption about how quantum agents behave.

Identification of modifiable factors associated with symptom intensity among people seeking care for Post-Acute Sequelae of SARS-CoV-2 infection (PASC) could help guide the development of comprehensive, whole-person care pathways to alleviate symptoms irrespective of potential underlying pathophysiologies. We aimed to better define the key contributors to PASC, and sought the factors associated with PASC symptom presence and intensity. In this cross-sectional study, 249 patients presenting for PASC care at a dedicated Post-COVID-19 clinic completed a standardized screening assessment prior to initial visit and evaluation by a general internist or nurse practitioner. We measured 46 symptoms based on the WHO's Global COVID-19 Clinical Platform Case Report Form for Post COVID Condition and performed a factor analysis and item response theory based 2-parameter logistic model to develop a population-based t-score to measure PASC symptom presence and intensity (PASC-SPI). A multivariable linear regression analysis was used to assess factors associated with PASC-SPI, accounting for demographics, comorbidities, COVID-19 infection duration and severity, and mental health. Greater PASC-SPI was associated with greater symptoms of anxiety, a longer duration of COVID-19 infection, and hypercholesterolemia. Lower PASC-SPI was associated with older age, self-reported 1-3 units of alcohol per week, and self-reported clinician confirmation of COVID-19 diagnosis. Symptoms of anxiety accounted for a considerably higher proportion of variation in PASC-SPI than other variables. Symptoms of anxiety were the strongest correlate of PASC-SPI, highlighting it as both a potential neuroinflammatory marker of PASC and a modifiable component of the illness. This emphasizes the need for comprehensive, whole person treatment strategies that integrate evidence-based interventions to address the multifaceted nature of PASC.

In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) are associated with improved survival. Lehmann et al. identified 4 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor (LAR)], and an immunomodulatory (IM) gene expression signature indicates the presence of TILs and modifies these subtypes. The association between TNBC subtype and TILs is not known. Also, the association between inflammatory breast cancer (IBC) and the presence of TILs is not known. Therefore, we studied the IM subtype distribution among different TNBC subtypes. We retrospectively analyzed patients with TNBC from the World IBC Consortium dataset. The molecular subtype and the IM signature [positive (IM+) or negative (IM-)] were analyzed. Fisher's exact test was used to analyze the distribution of positivity for the IM signature according to the TNBC molecular subtype and IBC status. There were 88 patients with TNBC in the dataset, and among them 39 patients (44%) had IBC and 49 (56%) had non-IBC. The frequency of IM+ cases differed by TNBC subtype (p = 0.001). The frequency of IM+ cases by subtype was as follows: BL1, 48% (14/29); BL2, 30% (3/10); LAR, 18% (3/17); and M, 0% (0/21) (in 11 patients, the subtype could not be determined). The frequency of IM+ cases did not differ between patients with IBC and non-IBC (23% and 33%, respectively; p = 0.35). In conclusion, the IM signature representing the underlying molecular correlate of TILs in the tumor may differ by TNBC subtype but not by IBC status.

Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data for 2,554 individuals from across the entire archipelago with geographically restricted ancestry, and performed population structure analyses and comparisons to ancient DNA. Extensive geographic structuring is revealed, from broad scales such as a NE to SW divide in mainland Scotland, through to the finest scale observed to date: across 3 km in the Northern Isles. Many genetic boundaries are consistent with Dark Age kingdoms of Gaels, Picts, Britons, and Norse. Populations in the Hebrides, the Highlands, Argyll, Donegal, and the Isle of Man show characteristics of isolation. We document a pole of Norwegian ancestry in the north of the archipelago (reaching 23 to 28% in Shetland) which complements previously described poles of Germanic ancestry in the east, and “Celtic” to the west. This modern genetic structure suggests a northwestern British or Irish source population for the ancient Gaels that contributed to the founding of Iceland. As rarer variants, often with larger effect sizes, become the focus of complex trait genetics, more diverse rural cohorts may be required to optimize discoveries in British and Irish populations and their considerable global diaspora.

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans. Genome-wide meta-analysis identifies >100 loci associated with hair color variation in humans of European ancestry. These loci explain a large portion of the heritability of this trait & provide insights into pathways regulating hair pigmentation.

Background Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. Methods Social-communication difficulties ( N  ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms ( N  ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data. Results In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait r g  ≤ 1, p min   =  3 × 10 −4 ) as those between repeated measures of the same trait (within-trait r g  ≤ 0.94, p min   =  7 × 10 −4 ). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes ( p -meta = 6.4 × 10 −4 ). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression R 2  = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder. Conclusions In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.

Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo David B. Ring 1 , Kirk W. Johnson 1 , Erik J. Henriksen 2 , John M. Nuss 1 , Dane Goff 1 , Tyson R. Kinnick 2 , Sylvia T. Ma 1 , John W. Reeder 1 , Isa Samuels 1 , Trina Slabiak 1 , Allan S. Wagman 1 , Mary-Ellen Wernette Hammond 1 and Stephen D. Harrison 1 1 From the Chiron Corporation, Emeryville, California 2 Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona Abstract Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K i < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at ∼100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30–48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db / db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes. Footnotes Address correspondence and reprint requests to Dr. Erik J. Henriksen, Department of Physiology, University of Arizona College of Medicine, P.O. Box 210093, Tucson, AZ 85721-0093. E-mail: ejhenrik{at}u.arizona.edu . Received for publication 30 April 2002 and accepted in revised form 20 November 2002. D.B.R., S.T.M., J.W.R., T.S., A.S.W., and S.D.H. are employed by and own stock in Chiron, a corporation that is involved in the research and development of potential therapeutics for the treatment of diabetes. K.W.J., J.M.N., D.G., I.S., and M.-E.W.H. are former employees of and hold stock in Chiron. E.J.H. and T.R.K. have received research support from Chiron. K.J.W.’s current affiliation is Genesoft Inc., South San Francisco, California. J.N.’s current affiliation is Exelixis, Inc., South San Francisco, California. D.G.’s current affiliation is Rigel, Inc., South San Francisco, California; I.S.’s current affiliation is Bayer Biotech, Berkeley, California. GS, glycogen synthase; GSK-3, glycogen synthase kinase 3; GTT, glucose tolerance test; ipGTT, intraperitoneal glucose tolerance test; IRS-1, insulin receptor substrate 1; oGTT, oral glucose tolerance test; PI, phosphatidylinositol; PKC, protein kinase C; RTK, receptor tyrosine kinase. DIABETES

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer – but not other cancers – explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter ). Ageing happens to us all, and as the cabaret singer Maurice Chevalier pointed out, \"old age is not that bad when you consider the alternative\". Yet, the growing ageing population of most developed countries presents challenges to healthcare systems and government finances. For many older people, long periods of ill health are part of the end of life, and so a better understanding of ageing could offer the opportunity to prolong healthy living into old age. Ageing is complex and takes a long time to study – a lifetime in fact. This makes it difficult to discern its causes, among the countless possibilities based on an individual’s genes, behaviour or environment. While thousands of regions in an individual’s genetic makeup are known to influence their risk of different diseases, those that affect how long they will live have proved harder to disentangle. Timmers et al. sought to pinpoint such regions, and then use this information to predict, based on their DNA, whether someone had a better or worse chance of living longer than average. The DNA of over 500,000 people was read to reveal the specific ‘genetic fingerprints’ of each participant. Then, after asking each of the participants how long both of their parents had lived, Timmers et al. pinpointed 12 DNA regions that affect lifespan. Five of these regions were new and had not been linked to lifespan before. Across the twelve as a whole several were known to be involved in Alzheimer’s disease, smoking-related cancer or heart disease. Looking at the entire genome, Timmers et al. could then predict a lifespan score for each individual, and when they sorted participants into ten groups based on these scores they found that top group lived five years longer than the bottom, on average. Many factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone. Nevertheless, Timmers et al. had hoped to narrow down their search and discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.

The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European ( n  = 2,249) and African ( n  = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19. Genetic and functional studies implicate allele-specific regulation of OAS1 splicing and nonsense-mediated decay in COVID-19 severity. The OAS1 risk haplotype is also associated with reduced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1.

Matthew Brown, John Reveille and colleagues report a genome-wide association study for ankylosing spondylitis. They identify four genetic loci outside of the MHC newly associated to AS susceptibility. To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10 −800 ), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10 −19 ) and 21q22 (rs2242944; P = 8.3 × 10 −20 ), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10 −8 ) and IL1R2 (rs2310173; P = 4.8 × 10 −7 ). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10 −14 ) and ERAP1 (rs27434; P = 5.3 × 10 −12 ). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.