Acetylcholine modifies neuronal acoustic rate-level functions in guinea pig auditory cortex by an action at muscarinic receptors

ABSTRACT Cholinergic modification of neuronal responsiveness in auditory cortex includes alteration of spontaneous and tone-evoked neuronal discharge. Previously it was suggested that the effects of acetylcholine (ACh) and muscarinic agonists on neuronal discharge resembled those due to increases in the intensity of acoustic stimuli Acet lcholine (ACh) modifies spontaneous and Often the effects of ACh result in systematic modification of the receptive field of the neuron (for recent reviews, see Ashe and Weinberger, 1990; Weinberger et evoke B discharge of neurons in sensory koniocortex. consist of a change in of responses to different frequencies of acoustic stimuli bethods of recordin single unit dischar e, acoustic logical agents used were similar to those previously reporte

Patchy Progress On Obesity Prevention: Emerging Exemplars, Entrenched Barriers, and New Thinking

Although there have been positive pockets of change, no country has yet turned around its obesity epidemic. Preventing an increase in obesity prevalence will require urgent actions from government as well as a broader spectrum of stakeholders than previously emphasized. In this paper, we review a number of regulatory and non-regulatory actions taken around the world to address obesity and discuss some of the reasons for the patchy progress. In addition, we preview the papers in this Lancet series, which each identify priority actions on key obesity issues and challenge some of the entrenched dichotomies that present obesity and its solutions in “either/or” terms. Although obesity is acknowledged as a complex issue, many debates about its causes and solutions are centered around overly simple dichotomies that present seemingly competing perspectives. Examples of such dichotomies explored in this series include: individual versus environmental causes of obesity, personal versus collective responsibilities for actions, supply versus demand explanations for consumption of unhealthy food, government regulation versus industry self-regulation, top down versus bottom up drivers for change, treatment versus prevention priorities, and under versus over nutrition focus. In the current paper, we explore the dichotomy of individual versus environmental drivers of obesity, which lay out two truths: people bear some personal responsibility for their health and environmental factors can readily support or undermine the ability of people to act in their self-interest. We propose a re-framing of obesity that emphasizes the reciprocal nature of the interaction between the environment and individual. Current food environments exploit people’s biological, psychological, social, and economic vulnerabilities, making it easier for them to eat unhealthful foods. This leads to preferences and demands for foods of poor nutritional quality, thus sustaining the unhealthful food environments. Breaking these vicious cycles will need regulatory actions from governments and greater efforts from industry and civil society

Mobilisation of Public Support for Policy Actions to Prevent Obesity

Public mobilisation is needed to enact obesity prevention policies and to mitigate backlash against their implementation. However, current approaches in public health focus primarily on dialogue between public health professionals and political leaders. Strategies to increase popular demand for obesity prevention policies include refining and streamlining public information, identifying effective frames for each population, enhancing media advocacy, building citizen protest and engagement, and developing a receptive political environment with change agents embedded across organisations and sectors. Long-term support and investment in collaboration among diverse stakeholders to create shared value is also important. Each actor in an expanded coalition for obesity prevention can make specific contributions to engaging, mobilising and coalescing the public. Shifting from a top-down to an integrated bottom-up and top-down approach would require an overhaul of current strategies and re-prioritisation of resources

Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

SummaryThe accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer’s disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo

Attributional style, self-esteem, and celebrity worship

Two studies were carried out to investigate the relationship between attributional style (Study 1), self-esteem (Study 2), and different forms of celebrity worship. Entertainment social celebrity worship (the most normal form considered) was unrelated to attributional style or self-esteem; intense personal celebrity worship was related positively to self-esteem but also to a propensity toward stable and globalattributions; and borderline pathological celebrity worship (the most negative form considered) was related to external, stable, and global attributions. These results were independent of whether participants were located in Europe or North America, and are discussed in terms of whether celebrity worship should be regarded as positive or negative and as a unitary concept

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Iminosugar-Based Inhibitors of Glucosylceramide Synthase Increase Brain Glycosphingolipids and Survival in a Mouse Model of Sandhoff Disease

The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects

Substrate Reduction Augments the Efficacy of Enzyme Therapy in a Mouse Model of Fabry Disease

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease

A deep learning approach to photo–identification demonstrates high performance on two dozen cetacean species

We thank the countless individuals who collected and/or processed the nearly 85,000 images used in this study and those who assisted, particularly those who sorted these images from the millions that did not end up in the catalogues. Additionally, we thank the other Kaggle competitors who helped develop the ideas, models and data used here, particularly those who released their datasets to the public. The graduate assistantship for Philip T. Patton was funded by the NOAA Fisheries QUEST Fellowship. This paper represents HIMB and SOEST contribution numbers 1932 and 11679, respectively. The technical support and advanced computing resources from University of Hawaii Information Technology Services—Cyberinfrastructure, funded in part by the National Science Foundation CC* awards # 2201428 and # 2232862 are gratefully acknowledged. Every photo–identification image was collected under permits according to relevant national guidelines, regulation and legislation.Peer reviewedPublisher PD