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EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

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Signal Transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： Keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell Jun Okabe Ishant Khurana Thomas Karagiannis julia J.Liang Lina Mariana Thomas Loudovaris Thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release *** type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-*** of these cells leads to a lifelong dependence on exogenous insulin administration for ***,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell *** and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation *** transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 *** the present study,we show that transient stimulation of exocrine cells,derived from juvenile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell *** transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin *** EZH2 is fundamental toβ-cell regenerative *** pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex *** pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

Probiotics and prebiotics in chronic inflammatory bowel diseases

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World Journal of Gastroenterology 2006年第37期12卷 5941-5950页

作者： julia b Ewaschuk Levinus A Dieleman Centre of Excellence for Gastrointestinal Inflammation and Immunity Research Uni-versity of Alberta Edmonton Alberta Canada

The prokaryotic and eukaryotic cells of the colon exist in a highly complex, but harmonious relationship. Disturbances in this remarkable symbiosis can result in the development of inflammatory bowel diseases (IbD). Although the etiology of IbD is not entirely understood, it is known that the chronic inflammation of Crohn’s disease, ulcerative colitis and chronic pouchitis are a result of an overly aggressive immune response to the commensal intestinal flora in genetically susceptible hosts. Recent studies have enhanced our ability to understand the interaction between the host and its intestinal microflora and the role the microflora plays in maintaining intestinal homeostasis. As we begin to understand the benefi ts conferred to the intestine by the microflora, the notion of modifying the composition of the bacterial load to improve human health has arisen. A signifi cant body of research now exists investigating the role of probiotics and prebiotics in ameliorating chronic intestinal inflammation. This article will begin with an overview of the role of the commensal microflora in maintaining mucosal immune homeostasis, and how a dysregulated immune response to the intestinal microflora results in IbD. This will be followed by a summary of the use of probiotics and prebiotics in experimental and human IbD.

关键词： Colitis Crohn's disease Microflora Immunity Probiotics Prebiotics

Ca^(2+) binding to the C_(2)E domain of otoferlin is required for hair cell exocytosis and hearing

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Protein & Cell 2024年第4期15卷 305-312页

作者： Han Chen Mehar Monga Qinghua Fang Loujin Slitin Jakob Neef Shashank S.Chepurwar Regina Célia Mingroni Netto Karina Lezirovitz Alfredo Tabith,Jr. Fritz benseler Nils brose Kathrin Kusch Carolin Wichmann Nicola Strenzke barbara Vona julia Preobraschenski Tobias Moser Institute for Auditory Neuroscience and InnerEarLab University Medical Center Göttingen37075 GöttingenGermany Collaborative Research Center 889 University of Göttingen37075 GöttingenGermany Auditory Neuroscience and Synaptic Nanophysiology Group Max Planck Institute for Multidisciplinary Sciences37075 GöttingenGermany Göttingen Graduate Center for Neurosciences Biophysics and Molecular BiosciencesUniversity of Göttingen37075 GöttingenGermany biochemistry of Membrane Dynamics Group Institute for Auditory NeuroscienceUniversity Medical Center Göttingen37075 GöttingenGermany Molecular Architecture of Synapses Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Center for biostructural Imaging of Neurodegeneration University Medical Center Göttingen37075 GöttingenGermany Auditory Systems Physiology Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Departamento de Genética e biologia Evolutiva Centro de Pesquisas sobre o Genoma Humano e Células-TroncoInstituto de BiociênciasUniversidade de São PauloSão Paulo 05508-220Brazil Laboratório de Otorrinolaringologia/LIM32 Faculdade de MedicinaHospital das ClínicasUniversidade de São PauloSão PauloSP 05508-220Brazil DERDIC Pontifícia Universidade Católica de São PauloSão Paulo 05508-220Brazil Department of Molecular Neurobiology Max Planck Institute for Multidisciplinary Sciences37075 GöttingenGermany Multiscale bioimaging Cluster of Excellence(MbExC) University of Göttingen37075 GöttingenGermany Functional Auditory Genomics Group Auditory Neuroscience and Optogenetics LaboratoryGerman Primate Center37077 GöttingenGermany Hearing Genomics Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Institute of Human Genetics University Medical Center Göttingen37075 GöttingenGermany

Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and Starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C_(2)-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein family involved in membrane trafficking and repair that are of major disease relevance(Pangršičet al.,2012),also see Supplementary *** is distributed broadly within IHCs(Fig.2Ai-Aiii;Pangrsic et al.,2010;Roux et al.,2006).

关键词： auditory hair

Microbiota alterations in acute and chronic gastrointestinal inflammation of cats and dogs

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World Journal of Gastroenterology 2014年第44期20卷 16489-16497页

作者： julia b honne.fe. Yasushi Minamoto Jan S Suchodolski Gastrointestinal Laboratory Department of Small Animal Clini-cal Sciences College of Veterinary Medicine and Biomedical Science Texas A & M University College Station TX 77843 United States

The intestinal microbiota is the collection of the living microorganisms(bacteria, fungi, protozoa, and viruses) inhabiting the gastrointestinal tract. Novel bacterial identification approaches have revealed that the gastrointestinal microbiota of dogs and cats is, similarly to humans, a highly complex ecosystem. Studies in dogs and cats have demonstrated that acute and chronic gastrointestinal diseases, including inflammatory bowel disease(IbD), are associated with alterations in the small intestinal and fecal microbial communities. Of interest is that these alterations are generally similar to the dysbiosis observed in humans with IbD or animal models of intestinal inflammation, suggesting that microbial responses to inflammatory conditions of the gut are conserved across mammalian host types. Studies have also revealed possible underlying susceptibilities in the innate immune system of dogs and cats with IbD, which further demonstrate the intricate relationship between gut microbiota and host health. Commonly identified microbiome changes in IbD are decreases in bacterial groups within the phyla Firmicutes and bacteroidetes, and increases within Proteobacteia. Furthermore, a reduction in the diversity of Clostridium clusters XIVa and IV(i.e., Lachnospiraceae and Clostridium coccoides subgroups) are associated with IbD, suggesting that these bacterial groups may play an important role in maintenance of gastrointestinal health. Future studies are warranted to evaluate the functional changes associated with intestinal dysbiosis in dogs and cats.

关键词： Microbiome 16S rRNA Inflammatory bowel disease Probiotic Dog Cat

pH-dependent leaching behaviour and other performance properties of cement-treated mixed contaminated soil

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Journal of Environmental Sciences 2012年第9期24卷 1630-1638页

作者： Reginald b. Kogbara Abir Al-Tabbaa Yaolin Yi julia A. Stegemann Geotechnical and Environmental Group Cambridge University Engineering Department Trumpington Street Cambridge CB2 1PZ UK. Center of ExceUence in Environmental Studies King Abdulaziz University Jeddah 21589 Saudi Arabia Institute of Geotechnical Engineering Southeast University 2# Sipailou Nanjing 210096 China Department of Civil Environmental and Geomatic Engineering Chadwick Building University College London WCIE 6BT UK

Portland cement has been widely used for stabilisation/solidification （S/S） treatment of contaminated soils. However, there is a dearth of literature on pH-dependent leaching of contaminants from cement-treated soils. This study investigates the leachability of Cu, Pb, Ni, Zn and total petroleum hydrocarbons （TPH） from a mixed contaminated soil. A sandy soil was spiked with 3000 mg/kg each of Cd, Cu, Pb, Ni and Zn, and 10,000 mg/kg of diesel, and treated with ordinary Portland cement （CEM I）. Four different binder dosages, 5%, 10%, 15% and 20% （m/m） and different water contents ranging from 13%-19% dry weight were used in order to find a safe operating envelope for the treatment process. The pH-dependent leaching behaviour of the treated soil was monitored over an 84-day period using a 3-point acid neutralisation capacity （ANC） test. The monolithic leaching test was also conducted. Geotechnical properties such as unconfined compressive strength （UCS）, hydraulic conductivity and porosity were assessed over time. The treated soils recorded lower leachate concentrations of Ni and Zn compared to the untreated soil at the same pH depending on binder dosage. The binder had problems with Pb stabilisation and TPH leachability was independent of pH and binder dosage. The hydraulic conductivity of the mixes was generally of the order, 10-8 m/sec, while the porosity ranged from 26%--44%. The results of selected performance properties are compared with regulatory limits and the range of operating variables that lead to acceptable performance described.

关键词： diesel heavy metals hydraulic conductivity porosity Portland cement stabilisation/solidification

RbP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes

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Protein & Cell 2016年第3期7卷 201-209页

作者： julia Foldi Yingli Shang baohong Zhao Lionel b. Ivashkiv Xiaoyu Hu Graduate Program in Immunology and Microbial Pathogenesis Weill Cornell Graduate School of Medical Sciences New York NY 10021 USA School of Medicine and Institute for Immunology Tsinghua University Beijing 100084 China Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York NY 10021 USA

Development of alternatively activated （M2） macrophage phenotypes is a complex process that is coordinately regulated by a plethora of pathways and factors. Here, we report that RbP-J, a DNA-binding protein that integrates signals from multiple pathways including the Notch pathway, is critically involved in polarization of M2 macrophages. Mice deficient in RbP-J in the myeloid compartment exhibited impaired M2 phenotypes in vivo in a chitin-induced model of M2 polarization. Consistent with the in vivo findings, M2 polarization was partially compromised in vitro in Rbpj-deficient macrophages as demonstrated by reduced expression of a subset of M2 effector molecules including arginase 1. Functionally, myeloid Rbpj deficiency impaired M2 effector functions including recruitment of eosinophils and suppression of T cell proliferation. Collectively, we have identified RbP- Jas an essential regulator of differentiation and function of alternatively activated macrophages.

关键词： macrophages RbP-J M2 arginase chitin

Photonic curing of solution-deposited ZrO_(2) dielectric on PEN:a path towards high-throughput processing of oxide electronics

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npj Flexible Electronics 2020年第1期4卷 66-72页

作者： Trey b.Daunis Kurt A.Schroder julia W.P.Hsu Department of Materials Science&Engineering University of Texas at DallasRichardsonTXUSA NovaCentrix AustinTXUSA

High-throughput manufacturing of oxide electronics will enable new applications ranging from large-area displays to flexible medical devices and low-cost solar ***,high-quality oxide films from solution-based precursors typically require 20 min or more of thermal annealing at high temperature(>250℃)for each layer,severely limiting both the throughput and substrate ***,we report high-speed photonic curing of ZrO_(2) dielectric thin films on flexible plastic *** curing and patterning processes can be achieved simultaneously by using shadow mask patterning or adjusting conditions to convert oxide only on top of underlying metal contacts,***-aligned ***-insulator-metal capacitors using two layers of ZrO_(2) films photonically cured in just 100 s per layer show non-dispersive capacitance-frequency behaviour from 10^(2) to 10^(6) Hz,high areal capacitance of 200 nF/cm^(2) and low dissipation factor of 0.03 at 10^(5) Hz,leakage current density of~10^(−7) A/cm^(2) at an applied field of 2 MV/cm,and a breakdown field of nearly 8 MV/*** an upgraded tool,similar dielectric properties are achieved in as short as 100 ms using a single pulse of light,revealing a pathway to oxide film processing beyond 30 m/min.

关键词： dielectric capacitance curing

Macromolecules Mimicking backbones of Nucleic and Teichoic ***,Some Properties and Applications

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复旦学报（自然科学版） 2007年第5期46卷 557-558页

作者： Stanislaw Penczek julia b.Pretula Krzysztof Kaluzynski Centre of Molecular and Macromolecular Studies Polish Academy of Sciences 90-363 Lodz Poland

1 Results Several methods have been elaborated in this laboratory allowing preparation of macromolecules with phosphodiester bonds,and having sequence of atoms similar as in the chains of biomacromolecules - nucleic or teichoic acids (TA),namely:-(C)n-O-PO-,where n=2 (for teichoic acids) or *** methods,to be discussed in the lecture,are based on the ring-opening polymerization,transesterification,and recently elaborated direct addition of phosphoric acid to *** the first time an attempt h...

关键词： macromolecules teichoic acid mimicking backbones

Selecting the best:Interspecific and age-related diet differences among sympatric steppe passerines

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Avian Research 2023年第4期14卷 611-622页

作者： julia Zurdo Paula Gomez-Lopez Adrian barrero Daniel bustillo-de la Rosa julia Gomez-Catasús Margarita Reverter Cristian Perez-Granados Manuel b.Morales Juan Traba Terrestrial Ecology Group Department of EcologyUniversidad Autonoma de Madrid(TEG-UAM)MadridSpain Centro de Investigacion en biodiversidady Cambio Global Universidad Autonoma de Madrid(CIBC-UAM)MadridSpain Ecology Department/IMEM“Ramon Margalef” Universidad de AlicanteAlicanteSpain

Parental food provisioning is crucial for the growth and survival of *** rate depends on food quality and food supplied to offspring may differ from what adults use for their *** the case of steppe passerine birds,detailed characterization on nestling dietary composition,as well as prey choice and resource partitioning among species,is a pending *** differences between nestlings and adults remain also largely *** using faecal DNA metabarcoding,we described the diet of nestlings and adults of five shrub-steppe passerine species over the 2017–2019 breeding seasons in central *** also monitored arthropod availability in the field to assess dietary *** expected interspecific dietary differences to limit competition for food resources among sympatric species,as well as parental selection of high quality prey for *** also predicted age-related differences,with nestlings being fed nutrient-rich prey more frequently than *** main arthropod orders provisioned to nestlings were Orthoptera,Julida,Araneae and *** of the different species showed high interspecific diet overlap,indicating both a coincidence in growth needs among bird species and no or little limitation of the most profitable resources during the breeding *** of all species showed higher diet richness than nestlings,and age-related differences in prey composition were mainly driven by the selection of the most easily digestible,larger protein-and calcium-rich prey for nestlings,which may favour their rapid growth,and avoiding highly sclerotized and less nutritional prey such as *** study sheds light on the basic ecology and conservation of these declining steppe birds,indicating that interspecific competition may not be a major factor during the breeding *** the current global decline of arthropods,further long-term research would be necessary,along with the implementation of effective conservation measure

关键词： 18S Faecal material Nestling diet Prey choice Resource partitioning