Laboratory mouse studies are paramount for understanding basic biological phenomena but also have limitations. These include conflicting results caused by divergent microbiota and limited ...translational research value. To address both shortcomings, we transferred C57BL/6 embryos into wild mice, creating "wildlings." These mice have a natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6 mice. The bacterial microbiome, mycobiome, and virome of wildlings affect the immune landscape of multiple organs. Their gut microbiota outcompete laboratory microbiota and demonstrate resilience to environmental challenges. Wildlings, but not conventional laboratory mice, phenocopied human immune responses in two preclinical studies. A combined natural microbiota- and pathogen-based model may enhance the reproducibility of biomedical studies and increase the bench-to-bedside safety and success of immunological studies.
Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate ...to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.
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EMUNI, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
3.
On the discovery of cementum Foster, B. L.
Journal of periodontal research,
August 2017, Volume:
52, Issue:
4
Journal Article
Peer reviewed
Open access
Though cementum of the tooth root is critical for periodontal structure and tooth attachment and function, this tissue was not discovered and characterized on human teeth until a full century later ...than enamel and dentin. Early observations from the seventeenth to the nineteenth centuries by Marcello Malpighi, Antonie van Leeuwenhoek, Robert Blake, Jacques Tenon and Georges Cuvier founded a confusing and conflicting nomenclature that obscured the nature of cementum, often conflating it with bone. Advances in microscopy and histological procedures yielded the first detailed descriptions of human cementum in the 1830s by Jan Purkinje and Anders Retzius, who identified for the first time acellular and cellular types of cementum, and the resident cementocytes embedded in the latter. Comparative anatomy studies by Richard Owen and others over the latter half of the nineteenth century identified coronal and radicular cementum varieties across the Reptilia and Mammalia. The functional importance of cementum was not appreciated until detailed anatomical studies of the periodontium were performed by G.V. Black and others in the late nineteenth and early twentieth centuries. These early studies on cementum laid the foundation for more advanced understanding of cementum ultrastructure, composition, development, physiology, disease, genetics, repair and regeneration throughout the twentieth and into the twenty‐first century.
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CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
The construction of an electron–positron collider ‘Higgs factory’ has been stalled for a decade, not because of feasibility but because of the cost of conventional radio-frequency (RF) ...acceleration. Plasma-wakefield acceleration promises to alleviate this problem via significant cost reduction based on its orders-of-magnitude higher accelerating gradients. However, plasma-based acceleration of positrons is much more difficult than for electrons. We propose a collider scheme that avoids positron acceleration in plasma, using a mixture of beam-driven plasma-wakefield acceleration to high energy for the electrons and conventional RF acceleration to low energy for the positrons. We emphasise the benefits of asymmetric energies, asymmetric bunch charges and asymmetric transverse emittances. The implications for luminosity and experimentation at such an asymmetric facility are explored and found to be comparable to conventional facilities; the cost is found to be much lower. Some of the areas in which R&D is necessary to make HALHF a reality are highlighted, including estimates for the improvement required in key technologies. These range from a factor of 10 to a factor of 1000.
To assess central venous catheter (CVC) harm in pediatric oncology patients, we explored risks for central-line-associated bloodstream infections (CLABSIs) and central-line-associated non-CLABSI ...complications (CLANCs).
Retrospective cohort study.
Midwestern US pediatric oncology program.
The study cohort comprised 592 pediatric oncology patients seen between 2006 and 2016.
CLABSIs were defined according to Centers for Disease Control and Prevention (CDC)/National Health Safety Network (NHSN) definitions. CLANCs were classified using a novel definition requiring CVC removal. Patient-level and central-line-level risks were calculated using a negative binomial model to adjust for correlations between total events and line numbers.
CVCs were inserted in 62% of patients, with 175,937 total catheter days. The inpatient CLABSI and CLANC rates were 5.8 and 8.5 times higher than outpatient rates. At the patient level, shared risks included acute myeloid leukemia (AML) and age <1 year at diagnosis. At the line level, shared risks included age <1 year at diagnosis, non-mediports, and >1 lumen. AML was a CLABSI-specific risk. CLANC-specific risks included non-brain-tumor diagnosis, younger age at diagnosis or central-line placement, and age <1 year at diagnosis or line placement. Multivariable risks were for CLABSI >1 lumen and for CLANC age <1 year at placement.
Among patients with CVCs, CLABSI and CLANC rates were similar, higher among inpatients than outpatients. For both CLABSIs and CLANCs, infants and patients with AML were at higher risk. In both univariate and multivariate models, lines with >1 lumen were associated with CLABSIs and placement during infancy with CLANCs.
Significance Within the cell nucleus, the genetic material is organized into loop domains that transiently bring together genes separated by various distances along linear DNA. We asked whether the ...insulin ( INS ) gene in human pancreatic beta cells, which secrete the insulin protein, makes contact with other genes that play some role in insulin function. We show that the INS promoter contacts the anoctamin 1 (ANO1) gene, located far away on the same chromosome, stimulating its expression, and that ANO1, a chloride ion channel protein, plays a role in insulin secretion. Measurements of long-range interactions detect regulatory pathways not evident from other kinds of studies. In this case, such experiments reveal previously unrecognized mechanisms that could affect susceptibility to human diabetes.
We used circular chromatin conformation capture (4C) to identify a physical contact in human pancreatic islets between the region near the insulin ( INS ) promoter and the ANO1 gene, lying 68 Mb away on human chromosome 11, which encodes a Ca ²⁺-dependent chloride ion channel. In response to glucose, this contact was strengthened and ANO1 expression increased, whereas inhibition of INS gene transcription by INS promoter targeting siRNA decreased ANO1 expression, revealing a regulatory effect of INS promoter on ANO1 expression. Knockdown of ANO1 expression caused decreased insulin secretion in human islets, establishing a physical proximity-dependent feedback loop involving INS transcription, ANO1 expression, and insulin secretion. To explore a possible role of ANO1 in insulin metabolism, we carried out experiments in Ano1 ⁺/⁻ mice. We observed reduced serum insulin levels and insulin-to-glucose ratios in high-fat diet–fed Ano1 ⁺/⁻ mice relative to Ano1 ⁺/⁺ mice fed the same diet. Our results show that determination of long-range contacts within the nucleus can be used to detect novel and physiologically relevant mechanisms. They also show that networks of long-range physical contacts are important to the regulation of insulin metabolism.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
We have observed 37 Infrared Dark Clouds (IRDCs), containing a total of 159 clumps, in high-density molecular tracers at 3 mm using the 22 m ATNFMopra Telescope located in Australia. The most ...commonly detected molecular lines are Nsub 2Hsup +, HNC, HNsup 13C, HCOsup +, Hsup 13COsup +, HCN, Csub 2H, HCsub 3N, HNCO, and SiO. We investigate the behavior of the different molecular tracers and look for chemical variations as a function of an evolutionary sequence based on Spitzer IRAC and MIPS emission. We find that the molecular tracers behave differently through the evolutionary sequence and some of them can be used to yield useful relative age information. Total column densities of the different molecules, except Csub 2H, increase with the evolutionary stage of the clumps. Molecular abundances increase with the evolutionary stage for Nsub 2Hsup + and HCOsup +. The Nsub 2Hsup +/HCOsup + and Nsub 2Hsup +/HNC abundance ratios act as chemical clocks, increasing with the evolution of the clumps.
How do you love and not like the same thing at the same time? This was the riddle that met Mississippi writer B. Brian Foster when he returned to his home state to learn about Black culture and found ...himself hearing about the blues. One moment, Black Mississippians would say they knew and appreciated the blues. The next, they would say they didn't like it. For five years, Foster listened and asked: "How?" "Why not?" "Will it ever change?" This is the story of the answers to his questions.In this illuminating work, Foster takes us where not many blues writers and scholars have gone: into the homes, memories, speculative visions, and lifeworlds of Black folks in contemporary Mississippi to hear what they have to say about the blues and all that has come about since their forebears first sang them. In so doing, Foster urges us to think differently about race, place, and community development and models a different way of hearing the sounds of Black life, a method that he calls listening for the backbeat.
We have observed the Infrared Dark Cloud (IRDC) G028.23-00.19 at 3.3 mm using the Combined Array for Research in Millimeter-wave Astronomy. In its center, the IRDC hosts one of the most massive ...(~1520 M sub(middot in circle)) quiescent, cold (12 K) clumps known (MM1). The low temperature, high NH sub(2)D abundance, narrow molecular line widths, and absence of embedded infrared sources (from 3.6 to 70 mu m) indicate that the clump is likely prestellar. Strong SiO emission with broad line widths (6-9 km s super(-1)) and high abundances ((0.8-4) x 10 super(-9)) is detected in the northern and southern regions of the IRDC, unassociated with MM1. We suggest that SiO is released to the gas phase from the dust grains through shocks produced by outflows from undetected intermediate-mass stars or clusters of low-mass stars deeply embedded in the IRDC. A weaker SiO component with narrow line widths (~2 km s super(-1)) and low abundances (4.3 x 10 super(-11)) is detected in the center-west region, consistent with either a "subcloud-subcloud" collision or an unresolved population of a few low-mass stars. We report widespread CH sub(3)OH emission throughout the whole IRDC and the first detection of extended narrow methanol emission (~2 km s super(-1)) in a cold, massive prestellar clump (MM1). We suggest that the most likely mechanism releasing methanol into the gas phase in such a cold region is the exothermicity of grain-surface reactions. HN super(13)C reveals that the IRDC is actually composed of two distinct substructures ("subclouds") separated in velocity space by ~1.4 km s super(-1). The narrow SiO component arises where the subclouds overlap. The spatial distribution of C sub(2)H resembles that of NH sub(2)D, which suggests that C sub(2)H also traces cold gas in this IRDC.
The periodontal complex is essential for tooth attachment and function and includes the mineralized tissues, cementum and alveolar bone, separated by the unmineralized periodontal ligament (PDL). To ...gain insights into factors regulating cementum-PDL and bone-PDL borders and protecting against ectopic calcification within the PDL, we employed a proteomic approach to analyze PDL tissue from progressive ankylosis knock-out (Ank−/−) mice, featuring reduced PPi, rapid cementogenesis, and excessive acellular cementum. Using this approach, we identified the matrix protein osteopontin (Spp1/OPN) as an elevated factor of interest in Ank−/− mouse molar PDL. We studied the role of OPN in dental and periodontal development and function. During tooth development in wild-type (WT) mice, Spp1 mRNA was transiently expressed by cementoblasts and strongly by alveolar bone osteoblasts. Developmental analysis from 14 to 240days postnatal (dpn) indicated normal histological structures in Spp1−/− comparable to WT control mice. Microcomputed tomography (micro-CT) analysis at 30 and 90dpn revealed significantly increased volumes and tissue mineral densities of Spp1−/− mouse dentin and alveolar bone, while pulp and PDL volumes were decreased and tissue densities were increased. However, acellular cementum growth was unaltered in Spp1−/− mice. Quantitative PCR of periodontal-derived mRNA failed to identify potential local compensators influencing cementum in Spp1−/− vs. WT mice at 26dpn. We genetically deleted Spp1 on the Ank−/− mouse background to determine whether increased Spp1/OPN was regulating periodontal tissues when the PDL space is challenged by hypercementosis in Ank−/− mice. Ank−/−; Spp1−/− double deficient mice did not exhibit greater hypercementosis than that in Ank−/− mice. Based on these data, we conclude that OPN has a non-redundant role regulating formation and mineralization of dentin and bone, influences tissue properties of PDL and pulp, but does not control acellular cementum apposition. These findings may inform therapies targeted at controlling soft tissue calcification.
•Osteopontin (Spp1/OPN) was identified as increased in periodontal tissues of the Ank-/-mouse model of hypercementosis.•Spp1 is transiently expressed by cementoblasts and strongly expressed by alveolar bone osteoblasts during tooth development.•Spp1 knockout in mice causes increased volumes and densities of dentin and alveolar bone•Acellular cementum growth is unaltered in Spp1-/- mice.•Knock-out of Spp1/OPN on the Ank-/- mouse background does not exacerbate hypercementosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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