The ultimate arc: Differential displacement, oroclinal bending, and vertical axis rotation in the External Betic-Rif arc

The External Betic-Rif arc, which lies between the converging African and Iberian plates, is one of the tightest orogenic arcs on Earth. It is a thin-skinned fold and thrust belt formed in Miocene time around the periphery of the Alborán Domain, an older contractional orogen that underwent extensional collapse coevally with the formation of the thrust belt. Restoration of four sections across the thrust belt, together with kinematic and paleomagnetic analysis, allows a reconstruction of the prethrusting geometry of the Alborán Domain, and the identification of the following processes that contributed to the formation of the arc: (1) The Alborán Domain moved some 250 km westward relative to Iberia and Africa during the Miocene. This initiated the two limbs of the arc on its NW and SW margins, closing to the WSW in the region of Cherafat in northern Morocco. The overall convergence direction on the Iberian side of the arc was between 310° and 295°, and on the African side it was between 235° and 215°. The difference in convergence direction between the two sectors was primarily a result of the relative motion between Africa and Iberia. (2) Extensional collapse of the Alborán Domain during the Miocene modified the geometry of the western end of the arc: the Internal Rif rotated anticlockwise to form the present north trending sector of the arc, and additional components of displacement produced by extension were transferred into the external thrust belt along a series of strike-slip faults and shear zones. These allowed the limbs of the arc to rotate and extend, tightening the arc, and creating variations in the amounts and directions of shortening around the arc. The Betic sector of the arc rotated clockwise by 25° during this process, and the southern Rif rotated anticlockwise by ∼55°. (3) Oblique convergence on the two limbs of the arc, dextral in the Betics and sinistral in the southern Rif, resulted in strongly noncoaxial deformation. This had three related effects: (1) large rotations of individual thrust sheets resulted from the oblique propagation of thrusts away from the thrust front, followed by pinning and rotation as the thrust sheets peeled off, (2) continued oblique convergence resulted in distributed shear, particularly in the rear of the thrust wedge, causing rotation of stacks of thrust sheets on the scale of a few tens of kilometers, and (3) distributed shear in the orogen resulted in the rotation of folds as they amplified, the hinges migrating through the rock body, and rotating at a slower rate than the rock. These rotations were substantially larger than the bulk rotations of the limbs of the arc, and they strongly modified the orientations of folds, thrust traces, and the structural indicators of fault slip directions

A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging

The Translocase of Outer Mitochondrial Membrane 40 Homolog and Apolipoprotein E (TOMM40-APOE) locus has been associated with a number of age-related phenotypes in humans including nonpathologic cognitive aging, late-onset Alzheimer's disease, and longevity. Here, we investigate the influence of the TOMM40 intron 6 poly-T variant (rs10524523) on TOMM40 gene expression and cognitive abilities and decline in a cohort of 1613 community-dwelling elderly volunteers who had been followed for changes in cognitive functioning over a period of 14 years (range = 12–18 years). We showed that the shorter length poly-T variants were found to act as a repressor of luciferase gene expression in reporter gene constructs. Expression was reduced to approximately half of that observed for the very long variant. We further observed that the shorter poly-T variant was significantly associated with reduced vocabulary ability and a slower rate of vocabulary decline with age compared to the very long poly-T variants. No significant associations were observed for memory, fluid intelligence or processing speed, although the direction of effect, where the short variant was correlated with reduced ability and slower rate of decline was observed for all tests. Our results indicate that the poly-T variant has the ability to interact with transcription machinery and differentially modulate reporter gene expression and influence vocabulary ability and decline with age

Within-individual changes reveal increasing social selectivity with age in rhesus macaques

This is the final version. Available from National Academy of Sciences via the DOI in this record. Data, Materials, and Software Availability. Data are available from the Figshare Repository (https://doi.org/10.6084/m9.figshare.21551295).Accumulating evidence in humans and other mammals suggests older individuals tend to have smaller social networks. Uncovering the cause of these declines can inform how changes in social relationships with age affect health and fitness in later life. While age-based declines in social networks have been thought to be detrimental, physical and physiological limitations associated with age may lead older individuals to adjust their social behavior and be more selective in partner choice. Greater selectivity with age has been shown in humans, but the extent to which this phenomenon occurs across the animal kingdom remains an open question. Using longitudinal data from a population of rhesus macaques on Cayo Santiago, we provide compelling evidence in a nonhuman animal for within-individual increases in social selectivity with age. Our analyses revealed that adult female macaques actively reduced the size of their networks as they aged and focused on partners previously linked to fitness benefits, including kin and partners to whom they were strongly and consistently connected earlier in life. Females spent similar amounts of time socializing as they aged, suggesting that network shrinkage does not result from lack of motivation or ability to engage, nor was this narrowing driven by the deaths of social partners. Furthermore, females remained attractive companions and were not isolated by withdrawal of social partners. Taken together, our results provide rare empirical evidence for social selectivity in nonhumans, suggesting that patterns of increasing selectivity with age may be deeply rooted in primate evolution.National Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthKaufman Foundatio

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

What is the 'problem' that outreach work seeks to address and how might it be tackled? Seeking theory in a primary health prevention programme

<b>Background</b> Preventive approaches to health are disproportionately accessed by the more affluent and recent health improvement policy advocates the use of targeted preventive primary care to reduce risk factors in poorer individuals and communities. Outreach has become part of the health service response. Outreach has a long history of engaging those who do not otherwise access services. It has, however, been described as eclectic in its purpose, clientele and mode of practice; its effectiveness is unproven. Using a primary prevention programme in the UK as a case, this paper addresses two research questions: what are the perceived problems of non-engagement that outreach aims to address; and, what specific mechanisms of outreach are hypothesised to tackle these.<p></p> <b>Methods</b> Drawing on a wider programme evaluation, the study undertook qualitative interviews with strategically selected health-care professionals. The analysis was thematically guided by the concept of 'candidacy' which theorises the dynamic process through which services and individuals negotiate appropriate service use.<p></p> <b>Results</b> The study identified seven types of engagement 'problem' and corresponding solutions. These 'problems' lie on a continuum of complexity in terms of the challenges they present to primary care. Reasons for non-engagement are congruent with the concept of 'candidacy' but point to ways in which it can be expanded.<p></p> <b>Conclusions</b> The paper draws conclusions about the role of outreach in contributing to the implementation of inequalities focused primary prevention and identifies further research needed in the theoretical development of both outreach as an approach and candidacy as a conceptual framework

Enteroaggregative escherichia coli have evolved independently as distinct complexes within the E. Coli population with varying ability to cause disease

Enteroaggregative E. Coli (EAEC) is an established diarrhoeagenic pathotype. The association with virulence gene content and ability to cause disease has been studied but little is known about the population structure of EAEC and how this pathotype evolved. Analysis by Multi Locus Sequence Typing of 564 EAEC isolates from cases and controls in Bangladesh, Nigeria and the UK spanning the past 29 years, revealed multiple successful lineages of EAEC. The population structure of EAEC indicates some clusters are statistically associated with disease or carriage, further highlighting the heterogeneous nature of this group of organisms. Different clusters have evolved independently as a result of both mutational and recombination events; the EAEC phenotype is distributed throughout the population of E. coli

Ageing in a collective: the impact of ageing individuals on social network structure

This is the final version. Available on open access from the Royal Society via the DOI in this recordData accessibility: All data are available from the Figshare Repository: https://doi.org/10.6084/m9.figshare.21936426 [97]. The data are provided in the electronic supplementary material [98].Ageing affects many phenotypic traits, but its consequences for social behaviour have only recently become apparent. Social networks emerge from associations between individuals. The changes in sociality that occur as individuals get older are thus likely to impact network structure, yet this remains unstudied. Here we use empirical data from free-ranging rhesus macaques and an agent-based model to test how age-based changes in social behaviour feed up to influence: (i) an individual's level of indirect connectedness in their network and (ii) overall patterns of network structure. Our empirical analyses revealed that female macaques became less indirectly connected as they aged for some, but not for all network measures examined. This suggests that indirect connectivity is affected by ageing, and that ageing animals can remain well integrated in some social contexts. Surprisingly, we did not find evidence for a relationship between age distribution and the structure of female macaque networks. We used an agent-based model to gain further understanding of the link between age-based differences in sociality and global network structure, and under which circumstances global effects may be detectable. Overall, our results suggest a potentially important and underappreciated role of age in the structure and function of animal collectives, which warrants further investigation. This article is part of a discussion meeting issue ‘Collective behaviour through time’.National Institutes of HealthKaufman Foundatio

Efficacy and Safety of Upadacitinib Treatment in Adolescents With Moderate-to-Severe Atopic Dermatitis

Importance: Atopic dermatitis onset usually occurs in childhood. Persistence of disease into adolescence and adulthood is common. It is important to evaluate new treatment options in adolescents because of the high unmet need in this population. Objective: To assess the efficacy and safety of upadacitinib to treat moderate-to-severe atopic dermatitis in adolescents. Design, setting, and participants: Prespecified analysis of adolescents enrolled in 3 randomized, double-blind, placebo-controlled phase 3 clinical trials in more than 20 countries across Europe, North and South America, Oceania, the Middle East, and the Asia-Pacific region from July 2018 through December 2020. Participants were adolescents aged 12 to 17 years with moderate-to-severe atopic dermatitis. Data analysis was performed from April to August 2021. Interventions: Patients were randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo alone (Measure Up 1 and Measure Up 2) or with topical corticosteroids (AD Up). Main outcomes and measures: Safety and efficacy, including at least a 75% improvement in the Eczema Area and Severity Index from baseline and validated Investigator Global Assessment for Atopic Dermatitis score of 0 (clear) or 1 (almost clear) at week 16 (coprimary end points). Results: A total of 552 adolescents (290 female; 262 male) were randomized. Mean (SD) age was 15.4 (1.8), 15.5 (1.7), and 15.3 (1.8) years for adolescents in Measure Up 1, Measure Up 2, and AD Up, respectively. In Measure Up 1, Measure Up 2, and AD Up, respectively, a greater proportion of adolescents (% [95% CI]) achieved at least 75% improvement in the Eczema Area and Severity Index at week 16 with upadacitinib 15 mg (73% [63%-84%], 69% [57%-81%], 63% [51%-76%]), and upadacitinib 30 mg (78% [68%-88%], 73% [62%-85%], 84% [75%-94%]), than with placebo (12% [4%-20%], 13% [5%-22%], 30% [19%-42%]; nominal P < .001 for all comparisons vs placebo). Similarly, a greater proportion of adolescents treated with upadacitinib achieved a validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 at week 16 and improvements in quality of life with upadacitinib than with placebo. Upadacitinib was generally well tolerated in adolescents. Acne was the most common adverse event, and all acne events were mild or moderate. Conclusions and relevance: In this analysis of 3 randomized clinical trials, upadacitinib was an effective treatment for adolescents with moderate-to-severe atopic dermatitis, with an acceptable safety profile.info:eu-repo/semantics/publishedVersio