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Whereas the rise of private space entrepreneurship is indisputable, we contend that contrary to the “NewSpace” narrative, the development of privately owned and operated human spacefaring does not dispel or fundamentally alter the American space dream, but rather implies continuity of the narrative of America as the dominant global space power, specifically regarding a return to the Moon and with the explicit aim of colonizing Mars. Herein, we analyze the continuity of the American space dream and how it is expressed by public and private space actors, as well as being supported by popular culture, entertainment, and an active space enthusiast community. We maintain that the continuity of the American space dream as a unifying national narrative is facilitated by how private spacefaring is dependent on the U.S. Government’s emphasis on the pivotal role of private space industry for space exploration. This dependent relationship provides incentives for private space entrepreneurs to share and leverage the established American space dream. The continuity of the American space dream is achieved through a prevailing, yet reconfigured, government-industrial complex.

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

BackgroundWhile the effectiveness of deep brain stimulation (DBS) in alleviating essential tremor (ET) is well-established, the underlying mechanisms of the treatment are unclear. ET, as characterised by tremor during action, is proposed to be driven by a dysfunction in the cerebello-thalamo-cerebral circuit that is evident not only during motor actions but also during rest.MethodsDBS effects on resting-state functional connectivity were investigated by functional MRI in 16 ET patients with fully implanted DBS in the caudal zona incerta during On and Off therapeutic stimulation, in a counterbalanced design. Functional connectivity was calculated between different constellations of sensorimotor as well as non-sensorimotor regions (as derived from seed-based and data-driven approaches), and compared between On and Off DBS.ResultsWe found that DBS did not modulate resting-state functional connectivity in ET.ConclusionsThe lack of DBS modulation during resting-state, in combination with previously demonstrated effects on the cerebello-thalamo-cerebral circuit during motor tasks, suggest an action-dependent modulation of DBS.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and East Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions, and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Cross-tissue analyses indicated that over a third of effector genes most likely act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis, and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9). Cannabis use disorder and cannabis use were genetically correlated (r g 0·50, p=1·50 × 10 −21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

Analytical methods and tools for the characterization of the human exposome by untargeted mass spectrometry approaches are advancing rapidly. Adductomics methods have been developed for untargeted screening of short-lived electrophiles, in the form of adducts to proteins or DNA

Preterm birth at very low birth weight (VLBW

PurposeThe InTraUterine sampling in early pregnancy (ITU) is a prospective pregnancy cohort study. The overarching aim of ITU is to unravel genomic, epigenomic, transcriptomic, endocrine, inflammatory and metabolic maternal-placental-fetal mechanisms involved in the programming of health and disease after exposure to prenatal environmental adversity, such as maternal malnutrition, cardiometabolic disorders, infections, medical interventions, mental disorders and psychosocial stress. This paper describes the study protocol, design and baseline characteristics of the cohort.ParticipantsWe included 944 pregnant Finnish women, their partners and children born alive between April 2012 and December 2017. The women were recruited through the national, voluntary trisomy 21 screening between 9+0 and 21+6 gestational weeks. Of the participating women, 543 were screen positive and underwent fetal chromosomal testing. Test result of these women suggested no fetal chromosomal abnormality. Further, we recruited 401 women who were screen negative and who did not undergo fetal chromosomal testing.Findings to dateWe have collected chorionic villi and amniotic fluid from the screen-positive women; blood, urine, buccal swabs and diurnal salivary samples from all women; blood and buccal swabs from all partners; and placenta, cord blood and buccal swabs from all newborns for analyses of the genome, epigenome, transcriptome, and endocrine, inflammatory and metabolic markers. These data are coupled with comprehensive phenotypes, including questions on demographic characteristics, health and well-being of the women and their partners during pregnancy and of the women and their children at the child’s age of 1.7 and 3 years. Data also come from patient records and nationwide registers covering health, lifestyle and medication data.Future plansMultiple layers of ITU data allow integrative data analyses, which translate to biomarker identification and allow risk stratification and understanding of the biological mechanisms involved in prenatal programming of health and disease.

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article.

Both prenatal and postnatal exposure to early life adversity is associated with increased risk for psychopathology. The impacts of those adversity exposures can also persist across generations, although the mechanisms for intergenerational transmission remain unclear. Emerging evidence from non-human animal models suggests that the gut microbiome (the collection of microorganisms living in the gastrointestinal tract) may be a biological mechanism underlying those increased transmitted risks, but this hypothesis has not been directly tested in humans. In a sample of 450 mother-child dyads, we examined how three adversity exposures experienced across two generations: maternal childhood maltreatment (generation 1), maternal prenatal anxiety (generation 1 and 2), and children’s exposure to stressful life events (generation 2), as well as the accumulation of adversity exposure across these time points, is associated with children’s gut microbiome composition at 2 years of age (generation 2). We then explored associations between second generation children’s gut microbiome at 2 years of age and socioemotional functioning at 2 and 4 years of age. We found distinct differences in gut microbiome composition as a function of each adversity exposure, some of which overlapped with microbiome profiles associated with concurrent and prospective child socioemotional functioning. These results highlight an intergenerational impact of adversity on the microbiome of children that may increase their vulnerability to future mental illness. That several of these taxonomic differences may reflect shared functional impacts, e.g. on immune system regulation, across adversity exposures, motivates future research characterizing microbiome functional potential in the context of intergenerational adversity.

Why is there a lack of grand, forward-looking vision in contemporary Russian space policy? Our study reveals nothing that compares with either ambitious Soviet goals or contemporary American goals of being first, reaching farthest, and being a dominant power in space; nor are there any clear explanations available of what goals Russia pursues in space. Notwithstanding the celebrational rhetoric on Russia being an ‘acknowledged leader’ which recurrently refers to its superpower past, the substance of contemporary Russian space policy is not focused on hegemony but rather on reaching equal status, catching up, being competitive, and strengthening independent access to space. Whether motivated by a shift to a less ambitious great power identity seeking equal status rather than dominance or departing from a perception of inferiority in comparison with the West, Russian space policy simultaneously seeks lasting space cooperation with the US and criticises the US for militarisation of space. This may seem paradoxical from a geopolitical perspective, but it makes sense from an identity perspective; for better or worse, the US remains Russia’s ‘significant other’ in space.

Markov chain Monte Carlo (MCMC) is a powerful methodology for the approximation of posterior distributions. However, the iterative nature of MCMC does not naturally facilitate its use with modern highly parallel computation on HPC and cloud environments. Another concern is the identification of the bias and Monte Carlo error of produced averages. The above have prompted the recent development of fully ('embarrassingly') parallel unbiased Monte Carlo methodology based on coupling of MCMC algorithms. A caveat is that formulation of effective coupling is typically not trivial and requires model-specific technical effort. We propose coupling of MCMC chains deriving from sequential Monte Carlo (SMC) by considering adaptive SMC methods in combination with recent advances in unbiased estimation for state-space models. Coupling is then achieved at the SMC level and is, in principle, not problem-specific. The resulting methodology enjoys desirable theoretical properties. A central motivation is to extend unbiased MCMC to more challenging targets compared to the ones typically considered in the relevant literature. We illustrate the effectiveness of the algorithm via application to two complex statistical models: (i) horseshoe regression; (ii) Gaussian graphical models., Comment: 18 pages, 9 figures

Cell types can be classified based on shared patterns of transcription. Variability in gene expression between individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. We asked whether long-term, heritable differences in transcription can impart diversity within a cell type. Studying clonal human lymphocytes and mouse brain cells, we uncover a vast diversity of heritable transcriptional states among different clones of cells of the same type in vivo. In lymphocytes we show that this diversity is coupled to clone specific chromatin accessibility, resulting in distinct expression of genes by different clones. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging and disease.

Analytical methods and tools for the characterization of the human exposome by untargeted mass spectrometry approaches are advancing rapidly. Adductomics methods have been developed for untargeted screening of short-lived electrophiles, in the form of adducts to proteins or DNA, in vivo. The identification of an adduct and its precursor electrophile in the blood is more complex than that of stable chemicals. The present work aims to illustrate procedures for the identification of an adduct to N-terminal valine in hemoglobin detected with adductomics, and pathways for the tracing of its precursor and possible exposure sources. Identification of the adduct proceeded via preparation and characterization of standards of adduct analytes. Possible precursor(s) and exposure sources were investigated by measurements in blood of adduct formation by precursors in vitro and adduct levels in vivo. The adduct was identified as hydroxypropanoic acid valine (HPA-Val) by verification with a synthesized reference. The HPA-Val was measured together with other adducts (from acrylamide, glycidamide, glycidol, and acrylic acid) in human blood (n = 51, schoolchildren). The HPA-Val levels ranged between 6 and 76 pmol/g hemoglobin. The analysis of reference samples from humans and rodents showed that the HPA-Val adduct was observed in all studied samples. No correlation of the HPA-Val level with the other studied adducts was observed in humans, nor was an increase in tobacco smokers observed. A small increase was observed in rodents exposed to glycidol. The formation of the HPA-Val adduct upon incubation of blood with glycidic acid (an epoxide) was shown. The relatively high adduct levels observed in vivo in relation to the measured reactivity of the epoxide, and the fact that the epoxide is not described as naturally occurring, suggest that glycidic acid is not the only precursor of the HPA-Val adduct identified in vivo. Another endogenous electrophile is suspected to contribute to the in vivo HPA-Val adduct level Analytical methods and tools for the characterization of the human exposome by untargeted mass spectrometry approaches are advancing rapidly. Adductomics methods have been developed for untargeted screening of short-lived electrophiles, in the form of adducts to proteins or DNA, in vivo. The identification of an adduct and its precursor electrophile in the blood is more complex than that of stable chemicals. The present work aims to illustrate procedures for the identification of an adduct to N-terminal valine in hemoglobin detected with adductomics, and pathways for the tracing of its precursor and possible exposure sources. Identification of the adduct proceeded via preparation and characterization of standards of adduct analytes. Possible precursor(s) and exposure sources were investigated by measurements in blood of adduct formation by precursors in vitro and adduct levels in vivo. The adduct was identified as hydroxypropanoic acid valine (HPA-Val) by verification with a synthesized reference. The HPA-Val was measured together with other adducts (from acrylamide, glycidamide, glycidol, and acrylic acid) in human blood (n = 51, schoolchildren). The HPA-Val levels ranged between 6 and 76 pmol/g hemoglobin. The analysis of reference samples from humans and rodents showed that the HPA-Val adduct was observed in all studied samples. No correlation of the HPA-Val level with the other studied adducts was observed in humans, nor was an increase in tobacco smokers observed. A small increase was observed in rodents exposed to glycidol. The formation of the HPA-Val adduct upon incubation of blood with glycidic acid (an epoxide) was shown. The relatively high adduct levels observed in vivo in relation to the measured reactivity of the epoxide, and the fact that the epoxide is not described as naturally occurring, suggest that glycidic acid is not the only precursor of the HPA-Val adduct identified in vivo. Another endogenous electrophile is suspected to contribute to the in vivo HPA-Val adduct level.

Background Responsible and efficient resource utilization are important factors in healthcare. The aim of this study was to investigate how total case time differs between two differently organized surgical departments. Methods This is a retrospective observational study of a cohort of patients undergoing elective surgery for breast cancer or malignant melanoma in a university hospital setting in Sweden. All patients were operated on by the same set of surgeons but in two different surgical departments: a general surgery (GS) and a cardiothoracic (CT) surgery department. Patients were selected to the two departments from a waiting list in the order of referral for surgery. The effect of being operated on at the CT department compared to the GS department was estimated by linear regression. Results The final study cohort comprised 349 patients in the GS department and 177 patients in the CT department. Both groups were similar regarding surgical procedures, American Society of Anesthesiologists’ score, body mass index, age, sex, and the skill level of the operating surgeon. These covariates were included in the linear regression model. The total case time, defined by the Procedural Time Glossary as room set-up start to room clean-up finish, was significantly shorter for the patients who underwent a surgical procedure at the CT department compared to the GS department, even after adjusting for the background characteristics of the patients and surgeon. After adjusting for the selected covariates, the average difference in total case time between the two departments was − 30.67 min (p = 0.001). Conclusions A significantly shorter total case time was measured for operations in the CT department. Plausible explanations may be more beneficial organizational factors, such as staffing ratio, skill mix in the operating room team, and working behavioral aspects regarding resource utilization.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

This cohort study investigates the life experiences, outdoor activity level, and adiposity changes in children in Singapore 1 year after COVID-19–related lockdown., Key Points Question What are typical lifestyle changes experienced by children after COVID-19–related lockdowns, and what are potential long-term outcomes? Findings In this cohort study of 604 children, one-third of parents and school-aged children reported elimination of outdoor play or exercise, and those with lower family income before and after lockdown were more likely to report elimination of outdoor play. Elimination of play was associated with increased adiposity 1 year after lockdown in school-aged children but not preschool-aged children. Meaning Outdoor play is an important part of children’s well-being, and efforts to mitigate avoidable negative outcomes of COVID-19 pandemic–related lockdowns should be considered., Importance Despite the potential for COVID-19 infection control–related events to have an effect on child well-being, comprehensive assessments of postlockdown changes and persistent outcomes are lacking. Objective To survey the extent of COVID-19 lockdown–related lifestyle changes, their differences by child age and family socioeconomic status, and the potential association with child adiposity 1 year after lockdown. Design, Setting, and Participants A self-administered, electronic survey was introduced to 2 ongoing child cohorts (the Singapore Preconception Study of Long-term Maternal and Child Outcomes [S-PRESTO] cohort of preschool children aged 1-4.5 years and the Growing Up in Singapore Towards Healthy Outcomes [GUSTO] cohort of primary school children aged 9-10.7 years) from July 8, 2020, to September 5, 2020, which was 1 to 3 months after the end of strict universal movement restrictions (duration of 73 days ending on June 19, 2020). All active participants from S-PRESTO and GUSTO, 2 population-based, longitudinal, parent-offspring cohorts in Singapore, were invited to participate and monitored through June 15, 2021. Exposures Exposures included family income before and after the COVID-19 lockdown, changes in child outdoor play or exercise, and COVID-19–related life events; all data were self-reported by parents and school-aged children 1 to 3 months after the lockdown. Main Outcomes and Measures Primary outcomes were self-reported COVID-19–related life events and changes in child online socialization, outdoor play or exercise, and intrafamily relationships. Study staff measured children’s weight, height, and skinfold thickness before and up to 1 year after lockdown. Body mass indices (calculated as weight in kilograms divided by height in meters squared) and World Health Organization–standardized scores were computed. Differences before and after lockdown were compared using baseline-adjusted linear regression. Results A total of 604 parents (53% of active cohort participants) and 356 school-aged children completed the survey and were similar to source cohorts. This represents 373 of 761 eligible children in the GUSTO cohort (mean [SD] age, 9.9 [0.4] years; 197 girls [52.8%]) and 231 of 370 eligible children in the S-PRESTO cohort (mean [SD] age, 2.6 [0.8] years; 121 boys [52.6%]). The COVID-19–related life changes were prevalent and varied (eg, 414 of 600 children [69.0%] reported changes in social activities). More than one-third of primary school–aged children (122 of 356 [34.3%]) and one-quarter of preschool-aged children (56 of 229 [24.5%]) eliminated any outdoor play after the lockdown. Lower family income before the lockdown was associated with increased odds of elimination of outdoor play (adjusted odds ratio per 1000 Singapore dollars [$730 US dollars] decrease, 1.09; 95% CI, 1.01-1.19). Complete elimination of outdoor activity (vs continued outdoor activity) was associated with an increase in body mass index of 0.48 (95% CI, 0.03-0.94) and a body mass index z score of 0.18 units (95% CI, 0-0.37) in school-aged children approximately 1 year after lockdown. Conclusions and Relevance Results of this cohort study suggest that 1 to 3 months after a brief, strict lockdown, a large proportion of parents and school-aged children reported elimination of outdoor play, which was more prevalent in lower-income families. Future research to better understand clinical implications and ways to mitigate lockdown outcomes is essential.

Two critical features of working memory are the identification and appropriate use of task-relevant information while avoiding distraction. Here, in 3 experiments, we explored if these features can be achieved also for nonconscious stimuli. Participants performed a delayed match-to-sample task in which task relevance of 2 competing stimuli was indicated by a cue, and continuous flash suppression was used to manipulate the conscious/nonconscious visual experience. Experiment 1 revealed better-than-chance performance with nonconscious stimuli, demonstrating goal-directed use of nonconscious task-relevant information. Experiment 2 demonstrated that the cue that defined task relevance must be conscious to allow such goal-directed use. In Experiment 3, multi-voxel pattern analyses of brain activity revealed that only the target was prioritized and maintained during conscious trials. Conversely, during nonconscious trials, both target and distractor were maintained. However, decoding of task relevance during the probe/test phase demonstrated identification of both target and distractor information. These results show that identification of task-relevant information can operate also on nonconscious material. However, they do not support the prioritization of nonconscious task-relevant information, thus suggesting a mismatch in the attentional mechanisms involved during conscious and nonconscious working memory.

Background and objective: We recently reported improvements of working memory across 10 years post stroke among middle-aged individuals. However, the mechanisms underlying working-memory recovery are largely unknown. This study investigated the associations between long-term improvement of working memory and resting-state functional connectivity in two frontoparietal networks: the frontoparietal network and the dorsal attention network. Methods: Working memory was repeatedly assessed by the Digit Span Backwards task in 21 persons, within 1 year after stroke onset and again 10 years post stroke onset. Brain functional connectivity was examined by resting state functional magnetic resonance imaging at the 10-year follow-up. Results: A significant improvement of working memory was found among 21 persons after stroke (median age = 64) at the 10-year follow-up compared to the within-one-year assessment. The magnitude of performance improvement on the Digit Span Backwards task was significantly positively correlated with stronger brain connectivity in the frontoparietal network (r = 0.51, p = 0.018) measured at the 10-year follow-up only. A similar association was observed in the dorsal attention network (r = 0.43, p = 0.052) but not in a visual network (r = -0.17, p = 0.46) that served as a control network. The association between functional connectivity within the above-mentioned networks and Digit Span Backwards scores at 10-year after stroke was in the same direction but did not reach significance. Conclusions: The present work relate stronger long-term performance improvement on the Digit Span Backwards task with higher integrity of frontoparietal network connectivity.

Carbamazepine (CBZ) is an anticonvulsant medication with highly persistent properties in the aquatic environment, where it has the potential to affect nontarget biota. Because CBZ and many other pharmaceuticals are not readily removed in conventional sewage treatment plants (STP), additional STP effluent treatment technologies are being evaluated and implemented. Whole effluent ozonation is a prospective method to remove pharmaceuticals such as CBZ, yet knowledge on the toxicity of CBZ ozonation byproducts (OBPs) is lacking. This study presents, for the first time, in vivo individual and mixture toxicity of four putative OBPs, that is, carbamazepine 10,11-epoxide, 10,11-Dihydrocarbamazepine, 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one (BQM), and 1-(2-benzaldehyde)-(1H,3H)-quinazoline-2,4-dione (BQD) in developing zebrafish (Danio rerio) embryos. BQM and BQD were isolated from the ozonated solution as they were not commercially available. The study confirmed that the OBP mixture caused embryotoxic responses comparable to that of ozonated CBZ. Individual compound embryotoxicity assessment further revealed that BQM and BQD were the drivers of embryotoxicity. OBP chemical stability in ozonated CBZ water solution during 2 week dark storage at 22 °C was also assessed. The OBP concentrations remained over time, except for BQD which decreased by 94%. Meanwhile, ozonated CBZ persistently induced embryotoxicity over 2 week storage, potentially illustrating environmental concern.

After two decades of quiescence, clinical psychedelic research re-started in the 1990s and is rapidly accelerating. Early evidence for effectiveness is promising, but understanding of the psychological processes of change underlying observed benefits is limited. This paper outlines contextual behavioral science (CBS) as an ideal framework for understanding psychedelic experiences and the psychological processes of change involved in psychedelic assisted therapy. This paper argues that CBS-based therapies, such as Acceptance and Commitment Therapy (ACT), can contribute to deepening and maintaining the often profound acute effects of psychedelics. The paper begins by briefly outlining the current state of clinical psychedelic research. It then progresses to outlining why CBS may be uniquely positioned to potentially increase the efficacy of psychedelic-assisted therapy, how this scientific model fits with existing data on psychedelic-assisted therapy, as well as with leading neuroscientific theories such as the entropic brain theory. Finally, it concludes by suggesting avenues for future research on how CBS could contribute to psychedelic science, and vice versa.

This paper argues that conflicts tend to be intractable if collective victimhood has become a component of national identity, and when conflicting communities claim to be the ‘real’ or ‘onl...

This pedestrian and cycle bridge spans the river in Eskilsuna connecting the historic, industrial area of Munktellstaden with the town centre, forming part of a rehabilitation of the area. The bridge was completed in 2016 on behalf of the City of Eskilstuna. The final design was chosen from three alternatives: the Landmark, the Industrial and the Transparent. All three options proposed were of steel, and all designs had to provide a 4.5m free deck width, maintain an unobstructed navigation channel of 5.0m wide by 3.35m high and a maximum slope of 5%. The Landmark proposal was an asymmetric cable stayed bridge with a 27m high, A- shaped, inclined steel pylon located on one bank with two planes of cables towards the steel deck and one plane of cables towards the back anchorage. The Industrial proposal was a variable height optimized truss, inclined outwards to provide a sensation of openness to the bridge user. The design finally chosen by the client was the Transparent. This bridge, unlike the other two, has two supports within the river that allows for a very slender deck. There is a central, low arch spanning 32m and an overall length of 65m. The arches are formed from two inclined box sections which are slightly curved on plan towards the supports. The railing is made up of a series of thin, steel plates connected via a stainless-steel handrail. The overall effect of transparency thus allows for a largely unobstructed view along the river. Due to the slender deck section a detailed dynamic analysis was carried out to check for possible pedestrian-induced vibrations.

BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

This chapter provides an overview of the literature on technology and International Relations (IR) theory. First, the chapter considers how technology is treated in more general IR theory, including what role technology plays in the wider paradigmatic debates of IR. Second, the chapter scrutinizes attempts to develop specific theories on technology and international relations. Third, the chapter discusses the advantages and disadvantages of different approaches, including whether there are some areas that are amply theorized while others remain under-researched. In particular, the chapter addresses how and to what extent various approaches have been able to analyze the relationship between technological and societal change, both including the rapid development of new technologies (concerning, for example, cyber, nano, space, robotics and AI technologies), and how technologies and critical infrastructures are becoming increasingly interconnected. Finally, the chapter suggests new horizons for empirically grounded theory on the relationship between technology and international society

The FREIA Laboratory at Uppsala University focuses on superconducting technology and accelerator development. It actively supports the development of the European Spallation Source, CERN, and MAX IV, among others. FREIA has developed test facilities for superconducting accelerator technology such as a double-cavity horizontal test cryostat, a vertical cryostat with a novel magnetic field compensation scheme, and a test stand for short cryomodules. Accelerating cavities have been tested in the horizontal cryostat, crab-cavities in the vertical cryostat, and cryomodules for ESS on the cryomodule test stand. High power radio-frequency amplifier prototypes based on vacuum tube technology were developed for driving spoke cavities. Solid-state amplifiers and power combiners are under development for future projects. We present the status of the FREIA Laboratory complemented with results of recent projects and future prospects., Comment: 30 pages, 18 figures

This chapter addresses the technological megashift and implications for security and accountability within the EU. Digitalised interconnectivity of increasingly ‘embedded’ systems, infrastructures and societal functions are megashift features. Although the EU hardly lacks technological strategies, accountability structures beg improvement, and there are multiple expert groups with insufficient coordination and societal focus. The EU suffers from techno-optimism—coupled to powerful objectives of fuelling economic growth—which can lead to broadly conceived and represented security issues falling in shadow and struggles between interests being inadequately addressed. This chapter analyses how the EU deals with the megashift with respect to threats, surveillance systems, infrastructural vulnerability and public-private accountability. It is suggested that the EU take (i) a holistic grip on the megashift and implications, (ii) abandon optimistic techno-determinism for nuanced and contextual understanding and (iii) avoid outsourcing management of sensitive data and critical infrastructures.

International audience; The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8+ T cell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8+ T cell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human T cell response to acute viral infections.

The CD8

The novel tyrosine kinase inhibitor AKN028 has demonstrated promising results in preclinical trials. An expedient protocol for the synthesis of the compound at kilogram scale is described, includin...

This paper argues that past research has overlooked how the way problems and solutions are framed contribute to a prevailing gap in the global governance of climate and energy. Empirically, this pa...

A compact single-stage 8-1 Gysel Combiner in planar technology for operation with 352-MHz pulses with peak output power of 10 kW has been designed, manufactured, and tested. The module has 0.2-dB insertion loss when operated at nominal power, and the return loss of all ports is 20 dB or better. The module was operated using 3.3-ms pulses at 14-Hz repetition rate without any signs of degradation, thermal heating, or arcing. The new design makes use of inclusions of weakly coupled lines in the common point section of the Gysel combiner. It is possible to adjust port imbalances caused by parasitic line coupling in the system for optimum performance at a given frequency by adjusting the coupling.

Corporatisation of critical information infrastructure (CII) is rooted inthe ‘privatisation wave’ of the 1980s-90s, when the ground was laidfor outsourcing public utilities. Despite well-known risks relating toreliability, resilience, and accountability, commitment to efficiencyimperatives have driven governments to outsource key publicservices and infrastructures. A recent illustrative case with enormousimplications is the 2017 Swedish ICT scandal, where outsourcing ofCII caused major security breaches. With the transfer of the SwedishTransport Agency’s ICT system to IBM and subcontractors, classifieddata and protected identities were made accessible to non-vettedforeign private employees – sensitive data could thus now be inanyone’s hands. This case clearly demonstrates accountability gapsthat can arise in public-private governance of CII. QC 20220228

Freedom is an a priori condition for the way in which Freudian psychoanalysis thematizes the development, the structure and the dynamics of our psychic life; the human psyche is essentially constituted by freedom. What this really means is that psychoanalysis lacks a foundation or ground – both as a psychological science and as a kind of clinical treatment. Freedom is the abyssal ground of psychoanalysis.

The National Mapping Agency in Sweden has conducted an airborne laser scanning (ALS) campaign covering almost the entire country for the purpose of creating a new national Digital Elevation Model (DEM). The ALS data were collected between 2009 and 2015 using Leica, Optech, Riegl, and Trimble scanners and have a point density of 0.5–1.0 pulses/m2. A high resolution national raster database (12.5 m × 12.5 m cell size) with forest variables was produced by combining the ALS data with field data from the Swedish National Forest Inventory (NFI). Approximately 11500 NFI plots (10 meter radius) located on productive forest land, inventoried between 2009 and 2013, were used to create linear regression models relating selected forest variables, or transformations of the variables, to metrics derived from the ALS data. The resulting stand level relative RMSEs for predictions of stem volume, basal area, basal-area weighted mean tree height, and basal-area weighted mean stem diameter were in the ranges of 17.2–22.0%, 13.9–18.2%, 5.4–9.5%, and 8.7–13.1%, respectively. It was concluded that the predictions had an accuracy that were at least as good as data typically used in forest management planning. Above ground tree biomass was also included in the national raster database but not validated on a stand-level. An important part of the project was to make the raster database available to private forest owners, forest associations, forest companies, authorities, researchers, and the general public. Thus, all predicted forest variables can be viewed and downloaded free of charge at the Swedish Forest Agency's homepage ( http://www.skogsstyrelsen.se/skogligagrunddata ).

What is “threat framing”? It concerns how something or someone is perceived, labeled, and communicated as a threat to something or someone. The designation “threat,” notably, belongs to the wider family of negative concerns such as danger, risk, or hazard. Research on threat framing is not anchored in a single or specific field but rather is scattered across three separate and largely disconnected bodies of literature: framing theory, security studies, and crisis studies. It is noteworthy that whereas these literatures have contributed observations on how and under what consequences something is framed as a threat, none of them have sufficiently problematized the concept of threat. Crisis analysis considers the existence or perception of threat essential for a crisis to emerge, along with a perception of urgency and uncertainty, yet crisis studies focus on the meaning of “crisis” without problematizing the concept of threat. Likewise, security studies have spent a lot of ink defining “security,” typically understood as the “absence of threat,” but leave the notion of “threat” undefined. Further, framing theory is concerned with “problem definition” as a main or first function of framing but generally pays little or no attention to the meaning of “threat.” Moreover, cutting across these bodies of literature is the distinction between constructivist and rationalist approaches, both of which have contributed to the understanding of threat framing. Constructivist analyses have emphasized how threat framing can be embedded in a process of socialization and acculturation, making some frames appear normal and others highly contested. Rationalist approaches, on the other hand, have shown how threat framing can be a conscious strategic choice, intended to accomplish certain political effects such as the legitimization of extraordinary means, allocation of resources, or putting issues high on the political agenda. Although there are only a handful of studies explicitly combining insights across these fields, they have made some noteworthy observations. These studies have shown for example how different types of framing may fuel amity or enmity, cooperation, or conflict. These studies have also found that antagonistic threat frames are more likely to result in a securitizing or militarizing logic than do structural threat frames. Institutionalized threat frames are more likely to gain and maintain saliency, particularly if they are associated with policy monopolies. In the post-truth era, however, the link between evidence and saliency of frames is weakened, leaving room for a much more unpredictable politics of framing.

Carbamazepine (CBZ) is an anticonvulsant medication with highly persistent properties in the aquatic environment, where it has the potential to affect nontarget biota. Because CBZ and many other pharmaceuticals are not readily removed in conventional sewage treatment plants (STP), additional STP effluent treatment technologies are being evaluated and implemented. Whole effluent ozonation is a prospective method to remove pharmaceuticals such as CBZ, yet knowledge on the toxicity of CBZ ozonation byproducts (OBPs) is lacking. This study presents, for the first time, in vivo individual and mixture toxicity of four putative OBPs, that is, carbamazepine 10,11-epoxide, 10,11-Dihydrocarbamazepine, 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one (BQM), and 1-(2-benzaldehyde)-(1H,3H)-quinazoline-2,4-dione (BQD) in developing zebrafish (Danio rerio) embryos. BQM and BQD were isolated from the ozonated solution as they were not commercially available. The study confirmed that the OBP mixture caused embryotoxic responses comparable to that of ozonated CBZ. Individual compound embryotoxicity assessment further revealed that BQM and BQD were the drivers of embryotoxicity. OBP chemical stability in ozonated CBZ water solution during 2 week dark storage at 22 °C was also assessed. The OBP concentrations remained over time, except for BQD which decreased by 94%. Meanwhile, ozonated CBZ persistently induced embryotoxicity over 2 week storage, potentially illustrating environmental concern.

Field emission and vacuum breakdown limit performance in many classes of electronic devices, including rf systems in particle accelerators. Although there are general explanations of both processes, a large correction factor is systematically needed to explain observations, and experimental evidence to establish the breakdown mechanism is limited. This study elucidates both issues, using a high-voltage electrode system that can operate down to cryogenic temperatures. Measurements of temperature-dependent field emission and breakdown with this system reveal remarkable effects that yield insight into both processes, which in turn will enable further development of high-field technology.

CD8+ T cells play essential roles in immunity to viral and bacterial infections, and to guard against malignant cells. The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogenous repertoire of phenotypically and functionally distinct effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout an immune response is key to understand immunity but remains largely unknown. Here, we longitudinally tracked hundreds of CD8+ T cell clones expanding in response to yellow fever virus vaccination at the single cell level in humans. We show that only a fraction of the clones detected in the acute phase of the response are detected as circulating memory T cells later, indicative of clonal selection shaping the memory repertoire. Clones persisting in the memory phase displayed biased differentiation trajectories along a gradient from stem cell memory to terminally differentiated effector memory fates. Reactivation of single memory CD8+ T cell clones revealed that they were poised to recapitulate skewed differentiation trajectories in secondary responses, and this was generalizable across individuals for both yellow fever and influenza virus. Together, we show that the sum of distinct clonal differentiation repertoires results in the multifaceted T cell response to acute viral infections in humans.

In this contribution, a data-driven control approach was developed and applied experimentally to a pharmaceutical batch cooling crystallization process. In this approach, a radial basis functions (RBF) network model was trained in real-time with experimental data (time varied temperature and chord length distribution) with two different input data update strategies. The control objective was to optimize the cooling profile with the aid of trained RBF to achieve the desired crystal population profile throughout the process. The robustness of the proposed control strategy was tested with 10 comprehensive experiments in the presence of several disturbances (initial supersaturation, impeller speed, water composition and seed size). The presented control strategy was able to easily handle all the case scenarios. In 8 cases, the experimental crystal population profile followed successfully the reference with less than 10% offset. In the remaining 2 cases, the offset was 17% that was due to the absence of the supersaturation. The proposed RBF network-driven control is a promising strategy that is easy to implement, fully-automated and relies on relatively limited data for training. Therefore, the RBF control is expected to contribute to quick process development and control, especially when there is a lack of comprehensive process understanding and historical data especially in the pharmaceutical industry.

Symbolic execution allows us to observe and assert properties of program code executing under (partially) unknown inputs and state. In this work we present a case study demonstrating that safety functions implemented in the Rust programming language can be verified by an assertion based approach. To this end, we leverage on previous developments adopting LLVM-KLEE for symbolic execution of Rust programs.In particular we show that reliability can be ensured by proven absence of undefined behavior and that safety properties (expressed as assertions) can be ensured for all reachable paths of the underlying implementation (under symbolic inputs). Moreover, the verification (besides stating assertions) is fully automatic and can be applied without any changes made to the implementation. While assertions have the advantage of being familiar to the mainstream programmer, they lack the expressiveness of dedicated logic developed for model checking. The paper also discusses complexity issues arising from path/state explosion inherent to symbolic execution. The feasibility of the approach is demonstrated on a representative use case implementing a safety function (equality) from the PLCopen library. We obtain complete path- (466) and state- (8) coverage in under 2 seconds for the given example on an i7-7700 laptop computer.