Granger causality is a method for identifying directed functional connectivity based on time series analysis of precedence and predictability. The method has been applied widely in neuroscience, ...however its application to functional MRI data has been particularly controversial, largely because of the suspicion that Granger causal inferences might be easily confounded by inter-regional differences in the hemodynamic response function. Here, we show both theoretically and in a range of simulations, that Granger causal inferences are in fact robust to a wide variety of changes in hemodynamic response properties, including notably their time-to-peak. However, when these changes are accompanied by severe downsampling, and/or excessive measurement noise, as is typical for current fMRI data, incorrect inferences can still be drawn. Our results have important implications for the ongoing debate about lag-based analyses of functional connectivity. Our methods, which include detailed spiking neuronal models coupled to biophysically realistic hemodynamic observation models, provide an important ‘analysis-agnostic’ platform for evaluating functional and effective connectivity methods.
► GC is invariant to confounding times-to-peak in hemodynamic responses applied to fMRI. ► We integrate theoretical analysis, simple simulations, and detailed spiking models. ► Our spiking/balloon model provides a ‘analysis-agnostic’ simulation test-bed. ► GC can't be applied naively to fMRI since downsampling and noise affect inference. ► We establish constraints & principles for functional connectivity analysis of fMRI.
The aim of the UniProt Knowledgebase is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this publication ...we describe enhancements made to our data processing pipeline and to our website to adapt to an ever-increasing information content. The number of sequences in UniProtKB has risen to over 227 million and we are working towards including a reference proteome for each taxonomic group. We continue to extract detailed annotations from the literature to update or create reviewed entries, while unreviewed entries are supplemented with annotations provided by automated systems using a variety of machine-learning techniques. In addition, the scientific community continues their contributions of publications and annotations to UniProt entries of their interest. Finally, we describe our new website (https://www.uniprot.org/), designed to enhance our users' experience and make our data easily accessible to the research community. This interface includes access to AlphaFold structures for more than 85% of all entries as well as improved visualisations for subcellular localisation of proteins.
Abstract
The aim of the UniProt Knowledgebase is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this ...article, we describe significant updates that we have made over the last two years to the resource. The number of sequences in UniProtKB has risen to approximately 190 million, despite continued work to reduce sequence redundancy at the proteome level. We have adopted new methods of assessing proteome completeness and quality. We continue to extract detailed annotations from the literature to add to reviewed entries and supplement these in unreviewed entries with annotations provided by automated systems such as the newly implemented Association-Rule-Based Annotator (ARBA). We have developed a credit-based publication submission interface to allow the community to contribute publications and annotations to UniProt entries. We describe how UniProtKB responded to the COVID-19 pandemic through expert curation of relevant entries that were rapidly made available to the research community through a dedicated portal. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.
Abstract
The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations ...cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO—a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations—evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)—mechanistic models of molecular “pathways” (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project.
The natural distribution of the honeybee (Apis mellifera L.) has been changed by humans in recent decades to such an extent that the formerly widest-spread European subspecies, Apis mellifera ...mellifera, is threatened by extinction through introgression from highly divergent commercial strains in large tracts of its range. Conservation efforts for A. m. mellifera are underway in multiple European countries requiring reliable and cost-efficient molecular tools to identify purebred colonies. Here, we developed four ancestry-informative SNP assays for high sample throughput genotyping using the iPLEX Mass Array system. Our customized assays were tested on DNA from individual and pooled, haploid and diploid honeybee samples extracted from different tissues using a diverse range of protocols. The assays had a high genotyping success rate and yielded accurate genotypes. Performance assessed against whole-genome data showed that individual assays behaved well, although the most accurate introgression estimates were obtained for the four assays combined (117 SNPs). The best compromise between accuracy and genotyping costs was achieved when combining two assays (62 SNPs). We provide a ready-to-use cost-effective tool for accurate molecular identification and estimation of introgression levels to more effectively monitor and manage A. m. mellifera conservatories.
China Off Center Blum, Susan D; Jensen, Lionel M
2002, 2002., 20020930
eBook
China Off Center takes as its fundamental assumption that contemporary China can only be understood as a complex, decentralized place, where the view from above (Beijing) and from tourist buses is a ...skewed one. Instead of generalizing about China, it demonstrates that this diverse national terrain is better conceived as it is experienced by Chinese, as a set of many Chinas. To that end, this anthology of interpretive essays and ethnographic reports focuses on the everyday, the particular, the local, and the puzzling. Together with contextualizing introductions, the readings provide students with a compelling look at some little-known but significant aspects of China from the past decade; for those already familiar with China, they furnish an assortment of uncommon viewpoints in a single, convenient volume.
Dimethyl sulphoxide (DMSO) was tested for oral toxicity in rats and dogs, and dermal toxicity in rabbits and pigs. Oral administration was by gastric intubation as a 50% equeous solution, 5 days/week ...at levels equivalent to 9.0, 3.0 or 1.0 ml undiluted DMSO/hg/day. For dermal application 50% and 90% equeous solutions were used to give levels equivalent to 8.1, 4.5, 2.7 or 1.5 ml DMSO/hg/day, as one daily application for rabbits, and divided into two applications/day for pigs. Dogs were dosed for approximately 2 years and pigs for 1 year, although half the animals of both species were dosed for only 18 weeks. Rats were dosed for 18 months, but some were used for interim sacrifice after a year. Rabbits received applications to normal and abraded skin for 6 months. Minor changes in bodyweight and haematological values were observed, together with a physiological diuretic response to DMSO, but the target organ was the eye, principally the lenticular nucleus. Ocular effects in dogs started after 5-10 weeks dosing at 9 ml/kg and consisted of central (nuclear) lens changes with alteration of the refractive index (myopia); transitory equatorial opacities during the 5th month; central (nuclear) opalescence; and changes in the vitreous humour. Similar changes occurred more slowly at 3 ml/kg, the alterations to the vitreous being first observed after 9-10 months at this level. Progressive nuclear refractive changes occurred after dosing for considerably longer than 6 months at 1ml/kg, but none of the animals in this group manifested the opalescence. Biochemical investigation of the lenses revealed reduction of soluble protein (mainly alpha-crystallin), glutathione and water levels, and an increase of insoluble protein. Evidence of recovery was limited mainly to a reduction in the number of dioptres needed to correct nuclear refractive change. Cessation of dosing led to regression of refractive nuclear changes but did not prevent the appearance of opalescence at 3 ml/kg and above. Dogs were the most severely affected of the 4 species, with nuclear effects at 1ml/kg, extensive changes in the lens, and involvement of the vitreous. Pigs and rabbits were affected by dose levels of 2.7 ml/kg and 1.5 ml/kg respectively. Rats occasionally showed minimal changes at 9 ml/kg. The importance of the findings in dogs is discussed in relation to general toxicological protocols. It is emphasised that reversibility of signs, and adequate duration of administration, must both be considered when ascertaining whether changes occur at levels approximating to those of human intake.
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