Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch

GeneMatch: A novel recruitment registry using at‐home APOE genotyping to enhance referrals to Alzheimer’s prevention studies

IntroductionRecruitment for Alzheimer’s disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies.MethodsIndividuals aged 55‐75 years who live in the United States and self‐report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies.ResultsAs of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P < .001).DiscussionGeneMatch, the first trial‐independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152681/1/alzjjalz201812007.pd

Asteroid Ryugu before the Hayabusa2 encounter

Asteroid (162173) Ryugu is the target object of Hayabusa2, an asteroid exploration and sample return mission led by Japan Aerospace Exploration Agency (JAXA). Ground-based observations indicate that Ryugu is a C-type near-Earth asteroid with a diameter of less than 1 km, but the knowledge of its detailed properties is very limited prior to Hayabusa2 observation. This paper summarizes our best understanding of the physical and dynamical properties of Ryugu based on ground-based remote sensing and theoretical modeling before the Hayabusa2’s arrival at the asteroid. This information is used to construct a design reference model of the asteroid that is used for the formulation of mission operation plans in advance of asteroid arrival. Particular attention is given to the surface properties of Ryugu that are relevant to sample acquisition. This reference model helps readers to appropriately interpret the data that will be directly obtained by Hayabusa2 and promotes scientific studies not only for Ryugu itself and other small bodies but also for the solar system evolution that small bodies shed light on.Additional co-authors: Guy Libourel, Roy Lichtenheldt, Alessandro Maturilli, Scott R. Messenger, Tatsuhiro Michikami, Hideaki Miyamoto, Stefano Mottola, Thomas Müller, Akiko M. Nakamura, Larry R. Nittler, Kazunori Ogawa, Tatsuaki Okada, Ernesto Palomba, Naoya Sakatani, Stefan E. Schröder, Hiroki Senshu, Driss Takir, Michael E. Zolensky and International Regolith Science Group (IRSG) in Hayabusa2 projec

Prion protein interacts with bace1 and differentially regulates its activity towards wild type and swedish mutant amyloid precursor protein

In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. We have reported previously that the cellular prion protein (PrP(C)) inhibited the action of BACE1 toward human wild type APP (APP(WT)) in cellular models and that the levels of endogenous murine Aβ were significantly increased in PrP(C)-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrP(C) interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APP(WT) but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APP(Swe)). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APP(Swe,Ind)), PrP(C) deletion had no influence on APP proteolytic processing, Aβ plaque deposition, or levels of soluble Aβ or Aβ oligomers. In cells, although PrP(C) inhibited the action of BACE1 on APP(WT), it did not inhibit BACE1 activity toward APP(Swe). The differential subcellular location of the BACE1 cleavage of APP(Swe) relative to APP(WT) provides an explanation for the failure of PrP(C) deletion to affect Aβ accumulation in APP(Swe,Ind) mice. Thus, although PrP(C) exerts no control on cleavage of APP(Swe) by BACE1, it has a profound influence on the cleavage of APP(WT), suggesting that PrP(C) may be a key protective player against sporadic Alzheimer disease

Binding of Soluble Yeast β-Glucan to Human Neutrophils and Monocytes is Complement-Dependent

The immunomodulatory properties of yeast β-1,3/1,6 glucans are mediated through their ability to be recognized by human innate immune cells. While several studies have investigated binding of opsonized and unopsonized particulate β-glucans to human immune cells mainly via complement receptor 3 (CR3) or Dectin-1, few have focused on understanding the binding characteristics of soluble β-glucans. Using a well-characterized, pharmaceutical grade, soluble yeast β-glucan, this study evaluated and characterized the binding of soluble β-glucan to human neutrophils and monocytes. The results demonstrated that soluble β-glucan bound to both human neutrophils and monocytes in a concentration-dependent and receptor-specific manner. Antibodies blocking the CD11b and CD18 chains of CR3 significantly inhibited binding to both cell types, establishing CR3 as the key receptor recognizing the soluble β-glucan in these cells. Binding of soluble β-glucan to human neutrophils and monocytes required serum and was also dependent on incubation time and temperature, strongly suggesting that binding was complement-mediated. Indeed, binding was reduced in heat-inactivated serum, or in serum treated with methylamine or in serum reacted with the C3-specific inhibitor compstatin. Opsonization of soluble β-glucan was demonstrated by detection of iC3b, the complement opsonin on β-glucan-bound cells, as well as by the direct binding of iC3b to β-glucan in the absence of cells. Binding of β-glucan to cells was partially inhibited by blockade of the alternative pathway of complement, suggesting that the C3 activation amplification step mediated by this pathway also contributed to binding

F4‐02‐04: The Alzheimer’s Prevention Initiative (API) Program: Genetic Testing and Disclosure Strategies

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152610/1/alzjjalz201606595.pd

Unfamiliar Territory: Emerging Themes for Ecological Drought Research and Management

Novel forms of drought are emerging globally, due to climate change, shifting teleconnection patterns, expanding human water use, and a history of human influence on the environment that increases the probability of transformational ecological impacts. These costly ecological impacts cascade to human communities, and understanding this changing drought landscape is one of today\u27s grand challenges. By using a modified horizon-scanning approach that integrated scientists, managers, and decision-makers, we identified the emerging issues in ecological drought that represent key challenges to timely and effective responses. Here we review the themes that most urgently need attention, including novel drought conditions, the potential for transformational drought impacts, and the need for anticipatory drought management. This horizon scan and review provides a roadmap to facilitate the research and management innovations that will support forward-looking, co-developed approaches to reduce the risk of drought to our socio-ecological systems during the 21st century. We used a modified horizon-scanning approach that brought together scientists, managers, and decision-makers to identify the emerging issues around the ecological impacts from drought that represent key challenges to effective response. We found three broad themes within ecological drought that need attention, including novel drought conditions, transformational drought impacts, and anticipatory drought management. This horizon scan and integrated review provides a roadmap to inspire the needed research and management innovations to reduce the risk of 21st century droughts

Effects of supplemental creatine and guanidinoacetic acid on spatial memory and the brain of weaned Yucatan miniature pigs

The emergence of creatine as a potential cognitive enhancement supplement for humans prompted an investigation as to whether supplemental creatine could enhance spatial memory in young swine. We assessed memory performance and brain concentrations of creatine and its precursor guanidinoacetic acid (GAA) in 14-16-week-old male Yucatan miniature pigs supplemented for 2 weeks with either 200 mg/kg∙d creatine (+Cr; n = 7) or equimolar GAA (157 mg/kg∙d) (+GAA; n = 8) compared to controls (n = 14). Spatial memory tests had pigs explore distinct sets of objects for 5 min. Objects were spatially controlled, and we assessed exploration times of previously viewed objects relative to novel objects in familiar or novel locations. There was no effect of either supplementation on memory performance, but pigs successfully identified novel objects after 10 (p < 0.01) and 20 min (p < 0.01) retention intervals. Moreover, pigs recognized spatial transfers after 65 min (p < 0.05). Regression analyses identified associations between the ability to identify novel objects in memory tests and concentrations of creatine and GAA in cerebellum, and GAA in prefrontal cortex (p < 0.05). The concentration of creatine in brain regions was not influenced by creatine supplementation, but GAA supplementation increased GAA concentration in cerebellum (p < 0.05), and the prefrontal cortex of +GAA pigs had more creatine/g and less GAA/g compared to +Cr pigs (p < 0.05). Creatine kinase activity and maximal reaction velocity were also higher with GAA supplementation in prefrontal cortex (p < 0.05). In conclusion, there appears to be a relationship between memory performance and guanidino compounds in the cerebellum and prefrontal cortex, but the effects were unrelated to dietary supplementation. The cerebellum is identified as a target site for GAA accretion