Singly ionized ytterbium, with ultranarrow optical clock transitions at 467 and 436 nm, is a convenient system for the realization of optical atomic clocks and tests of present-day variation of ...fundamental constants. We present the first direct measurement of the frequency ratio of these two clock transitions, without reference to a cesium primary standard, and using the same single ion of Yb+171. The absolute frequencies of both transitions are also presented, each with a relative standard uncertainty of 6x10-16. Combining our results with those from other experiments, we report a threefold improvement in the constraint on the time variation of the proton-to-electron mass ratio, mu super(.)/ mu =0.2(1.1)x10-16 yr-1, along with an improved constraint on time variation of the fine structure constant, alpha super(.)/ alpha =-0.7(2.1)x10-17 yr-1
Cocaine addiction is a major public health problem that is particularly difficult to treat. Without medically proven pharmacological treatments, interventions to change the maladaptive behavior of ...addicted individuals mainly rely on psychosocial approaches. Here we report on impairment in cocaine-addicted patients to act purposefully toward a given goal and on the influence of extended training on their behavior. When patients were rewarded for their behavior, prolonged training improved their response rate toward the goal but simultaneously rendered them insensitive to the consequences of their actions. By contrast, overtraining of avoidance behavior had no effect on patient performance. Our findings illustrate the ineffectiveness of punitive approaches and highlight the potential for interventions that focus on improving goal-directed behavior and implementing more desirable habits to replace habitual drug-taking.
Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the ...mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.
Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review.
Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia.
Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual's health and ...social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.
Prion-like, trans-neuronal spread of tau pathology in humans is controversial. By evaluating tau burden and functional connectivity in living patients, Cope et al. demonstrate relationships ...consistent with this in Alzheimer's disease but not progressive supranuclear palsy. Tau distribution in the latter is better explained by metabolic demand and trophic support.
Abstract
Alzheimer's disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer's disease, neuropathology and atrophy preferentially affect 'hub' brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer's disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer's disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer's disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker 'small-world' properties. Conversely, in PSP, unlike in Alzheimer's disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer's disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.
Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale ...networks, and their joint influence on cognitive impairment. We combined
CPK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based "inflammetry" was used to extract principal components of
CPK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status.Patients showed significantly higher
CPK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this
CPK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia.
Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that
neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.
Rates of biodiversity loss are higher in freshwater ecosystems than in most terrestrial or marine ecosystems, making freshwater conservation a priority. However, prioritization methods are impeded by ...insufficient knowledge on the distribution and conservation status of freshwater taxa, particularly invertebrates. We evaluated the extinction risk of the world's 590 freshwater crayfish species using the IUCN Categories and Criteria and found 32% of all species are threatened with extinction. The level of extinction risk differed between families, with proportionally more threatened species in the Parastacidae and Astacidae than in the Cambaridae. Four described species were Extinct and 21% were assessed as Data Deficient. There was geographical variation in the dominant threats affecting the main centres of crayfish diversity. The majority of threatened US and Mexican species face threats associated with urban development, pollution, damming and water management. Conversely, the majority of Australian threatened species are affected by climate change, harvesting, agriculture and invasive species. Only a small proportion of crayfish are found within the boundaries of protected areas, suggesting that alternative means of long-term protection will be required. Our study highlights many of the significant challenges yet to come for freshwater biodiversity unless conservation planning shifts from a reactive to proactive approach.
The atmospheric methane burden is increasing rapidly, contrary to pathways compatible with the goals of the 2015 United Nations Framework Convention on Climate Change Paris Agreement. Urgent action ...is required to bring methane back to a pathway more in line with the Paris goals. Emission reduction from “tractable” (easier to mitigate) anthropogenic sources such as the fossil fuel industries and landfills is being much facilitated by technical advances in the past decade, which have radically improved our ability to locate, identify, quantify, and reduce emissions. Measures to reduce emissions from “intractable” (harder to mitigate) anthropogenic sources such as agriculture and biomass burning have received less attention and are also becoming more feasible, including removal from elevated‐methane ambient air near to sources. The wider effort to use microbiological and dietary intervention to reduce emissions from cattle (and humans) is not addressed in detail in this essentially geophysical review. Though they cannot replace the need to reach “net‐zero” emissions of CO2, significant reductions in the methane burden will ease the timescales needed to reach required CO2 reduction targets for any particular future temperature limit. There is no single magic bullet, but implementation of a wide array of mitigation and emission reduction strategies could substantially cut the global methane burden, at a cost that is relatively low compared to the parallel and necessary measures to reduce CO2, and thereby reduce the atmospheric methane burden back toward pathways consistent with the goals of the Paris Agreement.
Plain Language Summary
Methane is a powerful climate warmer, and the amount of methane in the air is growing rapidly. Reducing human‐caused methane emissions is urgent if the 2015 United Nations Paris Agreement to limit climate warming is to succeed. There is hope, though the problem of methane mitigation is very wide and complex. Much of the task is in finding, identifying, and quantifying emissions. Rapid technical advances are making it much easier to locate and thus cut emissions from fossil fuel industries (gas, coal, and oil). Assessing emissions from landfill and sewage facilities is also becoming easier. In particular, poorly regulated landfills in fast‐growing tropical megacities need attention. Agricultural emissions are less tractable but may also be reduced to some extent, especially by improving manure management. Many methane mitigation options offer cost‐effective approaches to cut global warming and bring the amount of methane in the air back to a pathway that is consistent with the aims of the Paris Agreement.
Key Points
The atmospheric methane burden is rising fast; this growth is an increasing threat to the Paris Agreement of the UN Framework Convention on Climate Change (UNFCCC)
New gas measurement technologies, on the ground and in the air, have greatly improved our ability to locate and quantify emissions and to identify mitigation targets
Emissions can be cut by ending fossil fuel emissions, cutting biomass burning, improving landfills, especially in the tropics, and changing cattle farming practice
Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model ...in which to test the specificity of in vivo binding of the putative tau ligand
FAV-1451, which is elevated in frontotemporal lobar degeneration tauopathies.
Seven patients (five with svPPA and two with 'right' semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with
FAV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BP
(non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BP
was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of
FAV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity.
FAV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for
FAV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed 'off target' binding sites for
FAV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of
FAV-1451 to differentiate and track different types of frontotemporal lobar degeneration.
Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The ...number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one‐quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair.
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Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.
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Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.
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