Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. ...However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.
Research in reintroduction biology has provided a greater understanding of the often limited success of species reintroductions and highlighted the need for scientifically rigorous approaches in ...reintroduction programs. We examined the recent genetic-based captive-breeding and reintroduction literature to showcase the underuse of the genetic data gathered. We devised a framework that takes full advantage of the genetic data through assessment of the genetic makeup of populations before (past component of the framework), during (present component), and after (future component) captive-breeding and reintroduction events to understand their conservation potential and maximize their success. We empirically applied our framework to two small fishes: Yarra pygmy perch (Nannoperca obscura) and southern pygmy perch (Nannoperca australis). Each of these species has a locally adapted and geographically isolated lineage that is endemic to the highly threatened lower Murray-Darling Basin in Australia. These two populations were rescued during Australia's recent decade-long Millennium Drought, when their persistence became entirely dependent on captive-breeding and subsequent reintroduction efforts. Using historical demographic analyses, we found differences and similarities between the species in the genetic impacts of past natural and anthropogenic events that occurred in situ, such as European settlement (past component). Subsequently, successful maintenance of genetic diversity in captivity—despite skewed brooder contribution to offspring—was achieved through carefully managed genetic-based breeding (present component). Finally, genetic monitoring revealed the survival and recruitment of released captive-bred offspring in the wild (future component). Our holistic framework often requires no additional data collection to that typically gathered in genetic-based breeding programs, is applicable to a wide range of species, advances the genetic considerations of reintroduction programs, and is expected to improve with the use of next-generation sequencing technology. Investigaciones sobre biología de la reintroducción han proporcionado un mejor entendimiento del, a menudo, éxito limitado de las reintroducciones de especies y han resaltado la necesidad de aproximaciones rigorosas científicamente en los programas de reintroducción. Examinamos la literatura reciente sobre reproducción en cautiverio basada en genética y reintroducción para exhibir la subutilización de los datos genéticos. Diseñamos un marco de referencia que obtiene la mayor ventaja de los datos genéticos mediante la evaluación de la composición genética de las poblaciones antes (componente pasado del marco de referencia), durante (componente presente), y después (componente futuro) de eventos de reproducción en cautiverio y de reintroducción para entender su potencial de conservación y maximizar su éxito. Aplicamos nuestro marco de referencia empíricamente con dos especies de peces pequeños: Nannoperca obscura y N. australis. Cada especie tiene un linaje adaptado localmente y aislado geográficamente endémico de la muy amenazada Cuenca Baja Murray-Darling, Australia. Las dos poblaciones fueron rescatadas durante la reciente Sequía del Milenio que duró diez años en Australia, cuando su persistencia se volvió totalmente dependiente de esfuerzos de reproducción en cautiverio y subsecuente reintroducción. Mediante análisis demográficos históricos, encontramos diferencias y similitudes entre las especies en los impactos genéticos de eventos naturales y antropogénicos pasados que ocurrieron in situ, como el asentamiento europeo (componente pasado). Subsecuentemente, el mantenimiento exitoso de la diversidad genética en cautiverio - no obstante la contribución de reproductores sesgada - fue posible por el manejo cuidadoso de la reproducción basada en genética (componente presente). Finalmente, el monitoreo genético reveló la supervivencia y reclutamiento de crías obtenidas en cautiverio liberadas en el medio silvestre. Nuestro marco de referencia holístico a menudo no requiere de datos adicionales a los obtenidos típicamente en programas de reproducción basados en genética, es aplicable a un rango amplio de especies, es un avance en las consideraciones genéticas de los programas de reintroducción, y mejorará con el uso de tecnología de secuenciación de última generación.
Abstract
Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological ...traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.
Rationale
Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.
Objectives
Here, we report on safety and efficacy outcomes ...for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.
Methods
Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.
Results
Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s
d
= 2.2 at week 1 and 2.3 at week 5, both
p
< 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s
d
= 1.5 and 1.4, respectively, both
p
< 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.
Conclusions
Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
There is a need to develop robust and clinically applicable gene expression signatures. Hypoxia is a key factor promoting solid tumour progression and resistance to therapy; a hypoxia signature has ...the potential to be not only prognostic but also to predict benefit from particular interventions.
An approach for deriving signatures that combine knowledge of gene function and analysis of in vivo co-expression patterns was used to define a common hypoxia signature from three head and neck and five breast cancer studies. Previously validated hypoxia-regulated genes (seeds) were used to generate hypoxia co-expression cancer networks.
A common hypoxia signature, or metagene, was derived by selecting genes that were consistently co-expressed with the hypoxia seeds in multiple cancers. This was highly enriched for hypoxia-regulated pathways, and prognostic in multivariate analyses. Genes with the highest connectivity were also the most prognostic, and a reduced metagene consisting of a small number of top-ranked genes, including VEGFA, SLC2A1 and PGAM1, outperformed both a larger signature and reported signatures in independent data sets of head and neck, breast and lung cancers.
Combined knowledge of multiple genes' function from in vitro experiments together with meta-analysis of multiple cancers can deliver compact and robust signatures suitable for clinical application.
It is 20 years since the identification of PKD1, the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), followed closely by the cloning of PKD2. These major breakthroughs ...have led in turn to a period of intense investigation into the function of the two proteins encoded, polycystin-1 and polycystin-2, and how defects in either protein lead to cyst formation and nonrenal phenotypes. In this review, we summarize the major findings in this area and present a current model of how the polycystin proteins function in health and disease.
Abstract
Aims
Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to ...undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys.
Methods
The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women.
Results
Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2–110.8, interquartile range = 6.0–19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1–2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs.
Conclusions
Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.
In a trial involving 304 veterans with stable PTSD, prazosin did not alleviate distressing dreams and did not improve sleep quality or overall clinical symptoms over 10 or 26 weeks. This result is in ...contrast to findings in several previous smaller or briefer trials.
Many interesting but practically intractable problems can be reduced to that of finding the ground state of a system of interacting spins; however, finding such a ground state remains computationally ...difficult. It is believed that the ground state of some naturally occurring spin systems can be effectively attained through a process called quantum annealing. If it could be harnessed, quantum annealing might improve on known methods for solving certain types of problem. However, physical investigation of quantum annealing has been largely confined to microscopic spins in condensed-matter systems. Here we use quantum annealing to find the ground state of an artificial Ising spin system comprising an array of eight superconducting flux quantum bits with programmable spin-spin couplings. We observe a clear signature of quantum annealing, distinguishable from classical thermal annealing through the temperature dependence of the time at which the system dynamics freezes. Our implementation can be configured in situ to realize a wide variety of different spin networks, each of which can be monitored as it moves towards a low-energy configuration. This programmable artificial spin network bridges the gap between the theoretical study of ideal isolated spin networks and the experimental investigation of bulk magnetic samples. Moreover, with an increased number of spins, such a system may provide a practical physical means to implement a quantum algorithm, possibly allowing more-effective approaches to solving certain classes of hard combinatorial optimization problems.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used ...linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.
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