Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD

Estimands and their estimators for clinical trials Impacted by the COVID-19 pandemic: a report from the NISS Ingram Olkin Forum Series on unplanned clinical trial disruptions

The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be re-visited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions

Genomic epidemiology of NDM-1-encoding plasmids in latin American clinical isolates reveals insights into the evolution of multidrug resistance

Bacteria that produce the broad-spectrum Carbapenem antibiotic NewDelhi Metallo-b-lactamase (NDM) place a burden on health care systems worldwide, due to the limited treatment options for infections caused by them and the rapid global spread of this antibiotic resistancemechanism.Although it is believed that theassociated resistancegenebla NDM-1 originated inAcinetobacter spp., the role of Enterobacteriaceae in its dissemination remains unclear. In this study, we usedwhole genome sequencing to investigate the dissemination dynamics of blaNDM-1-positive plasmids in a set of 21 clinical NDM-1-positive isolates from Colombia and Mexico (Providencia rettgeri, Klebsiella pneumoniae, and Acinetobacter baumannii) aswell as six representative NDM-1-positive Escherichia coli transconjugants. Additionally, the plasmids from three representative P. rettgeri isolates were sequenced by PacBio sequencing and finished. Our results demonstrate the presence of previously reported plasmids from K. pneumoniae and A. baumannii in different genetic backgrounds and geographically distant locations in Colombia. Three new previously unclassified plasmids were also identified in P. rettgeri from Colombia and Mexico, plus an interesting genetic link between NDM-1-positive P. rettgeri from distant geographic locations (Canada, Mexico, Colombia, and Israel) without any reported epidemiological links was discovered. Finally, we detected a relationship between plasmids present in P. rettgeri and plasmids from A. baumannii and K. pneumoniae. Overall, our findings suggest a Russian dollmodel for the dissemination of blaNDM-1 in LatinAmerica,with P. rettgeri playing a central role in this process, andrevealnewinsights into the evolution and disseminationof plasmids carrying such antibiotic resistance genes

Broker Fixed: The Racialized Social Structure and the Subjugation of Indigenous Populations in the Andes

Responding to calls to return racial analysis to indigenous Latin America, this article moves beyond the prejudicial attitudes of dominant groups to specify how native subordination gets perpetuated as a normal outcome of the organization of society. I argue that a naturalized system of indirect rule racially subordinates native populations through creating the position of mestizo “authoritarian intermediary.” Natives must depend on these cultural brokers for their personhood, while maintaining this privileged position requires facilitating indigenous exploitation. Institutional structures combine with cultural practices to generate a vicious cycle in which increased village intermediary success increases native marginalization. This racialized social structure explains my ethnographic findings that indigenous villagers continued to support the same coterie of mestizos despite their regular and sometimes extreme acts of peculation. My findings about the primacy of race suggest new directions for research into indigenous studies, ethnic mobilizations, and the global dimensions of racial domination

Legumes as food ingredient: characterization, processing, and applications

Editores: Jiménez-López, José Carlos (CSIC); Clemente, Alfonso (CSIC

The Lipopolysaccharide Core of Brucella abortus Acts as a Shield Against Innate Immunity Recognition

Innate immunity recognizes bacterial molecules bearing pathogen-associated molecular patterns to launch inflammatory responses leading to the activation of adaptive immunity. However, the lipopolysaccharide (LPS) of the gram-negative bacterium Brucella lacks a marked pathogen-associated molecular pattern, and it has been postulated that this delays the development of immunity, creating a gap that is critical for the bacterium to reach the intracellular replicative niche. We found that a B. abortus mutant in the wadC gene displayed a disrupted LPS core while keeping both the LPS O-polysaccharide and lipid A. In mice, the wadC mutant induced proinflammatory responses and was attenuated. In addition, it was sensitive to killing by non-immune serum and bactericidal peptides and did not multiply in dendritic cells being targeted to lysosomal compartments. In contrast to wild type B. abortus, the wadC mutant induced dendritic cell maturation and secretion of pro-inflammatory cytokines. All these properties were reproduced by the wadC mutant purified LPS in a TLR4-dependent manner. Moreover, the core-mutated LPS displayed an increased binding to MD-2, the TLR4 co-receptor leading to subsequent increase in intracellular signaling. Here we show that Brucella escapes recognition in early stages of infection by expressing a shield against recognition by innate immunity in its LPS core and identify a novel virulence mechanism in intracellular pathogenic gram-negative bacteria. These results also encourage for an improvement in the generation of novel bacterial vaccines

The global spread of misinformation on spiders

In the internet era, the digital architecture that keeps us connected and informed may also amplify the spread of misinformation. This problem is gaining global attention, as evidence accumulates that misinformation may interfere with democratic processes and undermine collective responses to environmental and health crises1,2. In an increasingly polluted information ecosystem, understanding the factors underlying the generation and spread of misinformation is becoming a pressing scientific and societal challenge3. Here, we studied the global spread of (mis-)information on spiders using a high-resolution global database of online newspaper articles on spider–human interactions, covering stories of spider–human encounters and biting events published from 2010–20204. We found that 47% of articles contained errors and 43% were sensationalist. Moreover, we show that the flow of spider-related news occurs within a highly interconnected global network and provide evidence that sensationalism is a key factor underlying the spread of misinformation

APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The <it>APOE </it>ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (<it>APOE</it>) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the <it>APOE </it>ε4 allele on the risk and the age at onset of AD in this population.</p> <p>Methods</p> <p>376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the <it>APOE </it>alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.</p> <p>Results</p> <p>Odds Ratio (OR) for developing AD was significantly increased in carriers of the <it>APOE </it>ε4 allele compared to individuals with the <it>APOE </it>ε3/ε3 genotype. Individuals carrying <it>APOE </it>ε4/ε4 had OR of 12.9 for developing AD, while carriers of <it>APOE </it>ε2/ε4 and <it>APOE </it>ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the <it>APOE </it>ε4 allele was weaker with increasing age. Carrying the <it>APOE </it>ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the <it>APOE </it>ε4 allele, to 75.3 in carriers of one <it>APOE </it>ε4 allele and 72.9 in carriers of two <it>APOE </it>ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by <it>APOE </it>ε4 alleles.</p> <p>Conclusion</p> <p><it>APOE </it>ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.</p

The Transcriptome of Human Epicardial, Mediastinal and Subcutaneous Adipose Tissues in Men with Coronary Artery Disease

The biological functions of epicardial adipose tissue (EAT) remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases.Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina® HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT). The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects.Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD

An expert-curated global database of online newspaper articles on spiders and spider bites

Mass media plays an important role in the construction and circulation of risk perception associated with animals. Widely feared groups such as spiders frequently end up in the spotlight of traditional and social media. We compiled an expert-curated global database on the online newspaper coverage of human-spider encounters over the past ten years (2010-2020). This database includes information about the location of each human-spider encounter reported in the news article and a quantitative characterisation of the content-location, presence of photographs of spiders and bites, number and type of errors, consultation of experts, and a subjective assessment of sensationalism. In total, we collected 5348 unique news articles from 81 countries in 40 languages. The database refers to 211 identified and unidentified spider species and 2644 unique human-spider encounters (1121 bites and 147 as deadly bites). To facilitate data reuse, we explain the main caveats that need to be made when analysing this database and discuss research ideas and questions that can be explored with it.Peer reviewe