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Article ; Online: Protein phosphatases in TLR signaling

Clovis H. T. Seumen / Tanja M. Grimm / Christof R. Hauck

Cell Communication and Signaling, Vol 19, Iss 1, Pp 1-

2021 Volume 18

Abstract: Abstract Toll-like receptors (TLRs) are critical sensors for the detection of potentially harmful microbes. They are instrumental in initiating innate and adaptive immune responses against pathogenic organisms. However, exaggerated activation of TLR ... ...

Abstract	Abstract Toll-like receptors (TLRs) are critical sensors for the detection of potentially harmful microbes. They are instrumental in initiating innate and adaptive immune responses against pathogenic organisms. However, exaggerated activation of TLR receptor signaling can also be responsible for the onset of autoimmune and inflammatory diseases. While positive regulators of TLR signaling, such as protein serine/threonine kinases, have been studied intensively, only little is known about phosphatases, which counterbalance and limit TLR signaling. In this review, we summarize protein phosphorylation events and their roles in the TLR pathway and highlight the involvement of protein phosphatases as negative regulators at specific steps along the TLR-initiated signaling cascade. Then, we focus on individual phosphatase families, specify the function of individual enzymes in TLR signaling in more detail and give perspectives for future research. A better understanding of phosphatase-mediated regulation of TLR signaling could provide novel access points to mitigate excessive immune activation and to modulate innate immune signaling. Video Abstract
Keywords	Protein serine/threonine phosphatase ; Toll-like receptors ; Innate immunity ; Phosphorylation ; Inflammation ; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) ; Medicine ; R ; Cytology ; QH573-671
Subject code	572
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integrated model of primary and mental healthcare for the refugee population served by an academic medical centre

Claudia W Allen / Fern R Hauck / Katharine E Daniel / Sarah R Blackstone / Joseph S Tan / Richard L Merkel

Family Medicine and Community Health, Vol 11, Iss

2023 Volume 2

Abstract: Refugees are at increased risk for developing mental health concerns due to high rates of trauma exposure and postmigration stressors. Moreover, barriers to accessing mental health services result in ongoing suffering within this population. Integrated ... ...

Abstract	Refugees are at increased risk for developing mental health concerns due to high rates of trauma exposure and postmigration stressors. Moreover, barriers to accessing mental health services result in ongoing suffering within this population. Integrated care—which combines primary healthcare and mental healthcare into one cohesive, collaborative setting—may improve refugees’ access to comprehensive physical and mental health services to ultimately better support this uniquely vulnerable population. Although integrated care models can increase access to care by colocating multidisciplinary services, establishing an effective integrated care model brings unique logistic (eg, managing office space, delineating roles between multiple providers, establishing open communication practices between specialty roles) and financial (eg, coordinating across department-specific billing procedures) challenges. We therefore describe the model of integrated primary and mental healthcare used in the International Family Medicine Clinic at the University of Virginia, which includes family medicine providers, behavioural health specialists and psychiatrists. Further, based on our 20-year history of providing these integrated services to refugees within an academic medical centre, we offer potential solutions for addressing common challenges (eg, granting specialty providers necessary privileges to access visit notes entered by other specialty providers, creating a culture where communication between providers is the norm, establishing a standard that all providers ought to be CC’ed on most visit notes). We hope that our model and the lessons we have learned along the way can help other institutions that are interested in developing similar integrated care systems to support refugees’ mental and physical health.
Keywords	Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Elimination of negative feedback in TLR signalling allows rapid and hypersensitive detection of microbial contaminants

Clovis H. T. Seumen / Urte Tomasiunaite / Daniel F. Legler / Christof R. Hauck

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract The exquisite specificity of Toll-like receptors (TLRs) to sense microbial molecular signatures is used as a powerful tool to pinpoint microbial contaminants. Various cellular systems, from native human blood cells to transfected cell lines ... ...

Abstract	Abstract The exquisite specificity of Toll-like receptors (TLRs) to sense microbial molecular signatures is used as a powerful tool to pinpoint microbial contaminants. Various cellular systems, from native human blood cells to transfected cell lines exploit TLRs as pyrogen detectors in biological preparations. However, slow cellular responses and limited sensitivity have hampered the replacement of animal-based tests such as the rabbit pyrogen test or lipopolysaccharide detection by Limulus amoebocyte lysate. Here, we report a novel human cell-based approach to boost detection of microbial contaminants by TLR-expressing cells. By genetic and pharmacologic elimination of negative control circuits, TLR-initiated cellular responses to bacterial molecular patterns were accelerated and significantly elevated. Combining depletion of protein phosphatase PP2ACA and pharmacological inhibition of PP1 in the optimized reporter cells further enhanced the sensitivity to allow detection of bacterial lipoprotein at 30 picogram/ml. Such next-generation cellular monitoring is poised to replace animal-based testing for microbial contaminants.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Clustering of integrin β cytoplasmic domains triggers nascent adhesion formation and reveals a protozoan origin of the integrin-talin interaction

Timo Baade / Christoph Paone / Adrian Baldrich / Christof R. Hauck

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 13

Abstract: Abstract Integrins and integrin-dependent cell-matrix adhesions are essential for a number of physiological processes. Integrin function is tightly regulated via binding of cytoplasmic proteins to integrin intracellular domains. Yet, the complexity of ... ...

Abstract	Abstract Integrins and integrin-dependent cell-matrix adhesions are essential for a number of physiological processes. Integrin function is tightly regulated via binding of cytoplasmic proteins to integrin intracellular domains. Yet, the complexity of cell-matrix adhesions in mammals, with more than 150 core adhesome proteins, complicates the analysis of integrin-associated protein complexes. Interestingly, the evolutionary origin of integrins dates back before the transition from unicellular life to complex multicellular animals. Though unicellular relatives of metazoa have a less complex adhesome, nothing is known about the initial steps of integrin activation and adhesion complex assembly in protozoa. Therefore, we developed a minimal, microscope-based system using chimeric integrins to investigate receptor-proximal events during focal adhesion assembly. Clustering of the human integrin β1 tail led to recruitment of talin, kindlin, and paxillin and mutation of the known talin binding site abolished recruitment of this protein. Proteins indirectly linked to integrins, such as vinculin, migfilin, p130CAS, or zyxin were not enriched around the integrin β1 tail. With the exception of integrin β4 and integrin β8, the cytoplasmic domains of all human integrin β subunits supported talin binding. Likewise, the cytoplasmic domains of integrin β subunits expressed by the protozoan Capsaspora owczarzaki readily recruited talin and this interaction was based on an evolutionary conserved NPXY/F amino acid motif. The results we present here validate the use of our novel microscopic assay to uncover details of integrin-based protein-protein interactions in a cellular context and suggest that talin binding to integrin β cytoplasmic tails is an ancient feature of integrin regulation.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural failure in bridging stentgrafts for branched endovascular aneurysm repair

Sven R. Hauck / Alexander Kupferthaler / Martin C. Freund / Peter Pichler / Marie-Elisabeth Stelzmüller / Christopher Burghuber / Marek Ehrlich / Harald Teufelsbauer / Christian Loewe / Martin A. Funovics

Insights into Imaging, Vol 13, Iss 1, Pp 1-

a case–control study

2022 Volume 13

Abstract: Abstract Objective To present a case series of spontaneous structural failure of bridging stentgrafts (BSGs) after branched endovascular aortic repair (bEVAR), as well as their failure types and their detection. While bEVAR is a safe and effective ... ...

Abstract	Abstract Objective To present a case series of spontaneous structural failure of bridging stentgrafts (BSGs) after branched endovascular aortic repair (bEVAR), as well as their failure types and their detection. While bEVAR is a safe and effective procedure, one main limitation is the reintervention rate associated with the BSGs. Structural failure of BSGs, defined as fabric disruption, stent fracture with leak or complete separation is a major cause for reinterventions and difficult to detect in computed tomography angiography (CTA). Methods From a multicenter bEVAR complication database, structural BSG failures were identified. Patient and BSG characteristics, detection mode, failure type, treatment and outcome were recorded and compared with bEVAR patients with intact BSGs. Results Twenty-three BSG failures were detected in 12 patients with only 43% directly identified in CTA, after a mean of 21.4 months after implantation. The BSGs were Advanta (n = 4), E-Ventus (n = 16) and BeGraft (n = 3) in 10 renal, 9 superior mesenteric, and 4 celiac branches. Religning with another BSG was successful in 20/22 cases, one BSG failure necessitated renal branch embolization (organ loss), and one mesenteric bypass surgery. Two reintervention-related mortalities occurred. Conclusion Structural failure of BSGs is a serious limitation for bEVAR, which can result in high reintervention rates and serious complications. BSG failure typically occurs in single-layer types and events are clustered in patients. The necessary reinterventions carry serious morbidity and mortality. Since the use as BSG in bEVAR is off-label with all current BSG manufacturers, caution is advised regarding patient-informed consent.
Keywords	Bridging stentgraft ; Structural failure ; Branched EVAR ; Type 3 endoleak ; bEVAR complication ; Medical physics. Medical radiology. Nuclear medicine ; R895-920
Subject code	616
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	SpringerOpen
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Barriers to the use of trained interpreters in consultations with refugees in four resettlement countries

Anne MacFarlane / Susann Huschke / Kevin Pottie / Fern R. Hauck / Kim Griswold / Mark F. Harris

BMC Family Practice, Vol 21, Iss 1, Pp 1-

a qualitative analysis using normalisation process theory

2020 Volume 8

Abstract: Abstract Background Increasing numbers of primary care practitioners in refugee resettlement countries are providing care to refugees. Access to trained interpreters is a priority for these practitioners, but there are many barriers to the implementation ...

Abstract	Abstract Background Increasing numbers of primary care practitioners in refugee resettlement countries are providing care to refugees. Access to trained interpreters is a priority for these practitioners, but there are many barriers to the implementation of interpreted consultations in routine care. There is a lack of international, theoretically informed research. The purpose of this paper is to understand barriers to interpreter use in primary care consultations in four resettlement countries using Normalisation Process Theory. Method We conducted a cross-sectional online survey with networks of primary care practitioners (PCPs) who care for refugees in Australia, Canada, Ireland and the US (n = 314). We analysed qualitative data from the survey about barriers to interpreter use (n = 178). We completed an inductive thematic analysis, iteratively developed a Normalisation Process Theory (NPT)-informed coding frame and then mapped the emergent findings onto the theory’s construct about enacting interpreted consultations. Results In all four countries, the use of an interpreter presented communication and interaction challenges between providers and patients, which can impede the goals of primary care consultations. Primary care practitioners did not always have confidence in interpreted consultations and described poor professional practice by some interpreters. There was variation across countries, and inconsistency within countries, in the availability of trained interpreters and funding sources. Conclusion There are shared and differential barriers to implementation of interpreted consultations in a consistent and sustained way in the four countries studied. These findings can be used to inform country-specific and international level policies and interventions focusing on improving skills and resources for interpreted consultations to improve implementation of interpreted primary care consultations.
Keywords	Refugees ; Communication ; Primary health care ; Health equity ; Health resources ; Surveys and questionnaires ; Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Biosecurity Assessment and Seroprevalence of Respiratory Diseases in Backyard Poultry Flocks Located Close to and Far from Commercial Premises

Derksen, T / M. Pitesky / R. A. Gallardo / R. Hauck / R. Lampron

Avian diseases. 2018 Mar., v. 62, no. 1

2018

Abstract: Raising backyard chickens is an ever-growing hobby in the United States. These flocks can be a substrate for respiratory disease amplification and transmission to commercial facilities. Five hundred fifty-four chickens from 41 backyard flocks were ... ...

Abstract	Raising backyard chickens is an ever-growing hobby in the United States. These flocks can be a substrate for respiratory disease amplification and transmission to commercial facilities. Five hundred fifty-four chickens from 41 backyard flocks were sampled in this study. ELISA kits were used to detect antibodies against avian influenza (AI), infectious laryngotracheitis (ILT), Newcastle disease (ND), infectious bronchitis (IB), Ornithobacterium rhinotracheale (ORT), Mycoplasma gallisepticum (MG), and Mycoplasma synoviae (MS). All visited flock owners answered a biosecurity questionnaire that assessed biosecurity measures. The questionnaire revealed that backyard poultry owners lack simple biosecurity measures such as use of dedicated shoes, their chicken sources are unreliable, and few of them benefit from veterinary oversight. Only one flock had a clear vaccination history against ND and IB. ORT, ND, IB, MS, MG, and ILT were the most seroprevalent in backyard poultry flocks with 97% (41/42), 77.5% (31/40), 75% (30/40), 73% (31/42), 69% (29/42), and 45% (19/42), respectively. The vaccinated flock was not considered in these calculations. When examining the distance between backyard flocks and the nearest commercial poultry facility, ND and MG were significantly more likely to be found in backyard flocks close to (<4 miles) whereas ORT was significantly more likely in backyard chickens located far from (>4 miles) commercial poultry. Birds purchased directly from National Poultry Improvement Plan hatcheries showed a reduced ND, MG, and MS antibody prevalence. Wearing dedicated shoes decreased MS antibody-positive birds. Finally, history of wild bird contact had a clear effect on an increased seroprevalence of NDV and MG. Serological results suggest that backyard poultry flocks have the potential to serve as a reservoir or amplifier for poultry respiratory diseases. The information generated in this project should direct extension efforts toward emphasizing the importance of small flock biosecurity and chick acquisition sources.
Keywords	avian influenza ; biosecurity ; chickens ; chicks ; enzyme-linked immunosorbent assay ; flocks ; hatcheries ; infectious bronchitis ; Mycoplasma gallisepticum ; Mycoplasma synoviae ; Newcastle disease ; Ornithobacterium rhinotracheale ; questionnaires ; seroprevalence ; vaccination ; wild birds ; United States
Language	English
Dates of publication	2018-03
Size	p. 1-5.
Publishing place	American Association of Avian Pathologists
Document type	Article
ZDB-ID	40871-2
ISSN	1938-4351 ; 0005-2086
ISSN (online)	1938-4351
ISSN	0005-2086
DOI	10.1637/11672-050917-Reg.1
Database	NAL-Catalogue (AGRICOLA)

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Article: Understanding Immune Resistance to Infectious Bronchitis Using Major Histocompatibility Complex Chicken Lines

da Silva, A. P / H. Zhou / R. A. Gallardo / R. Hauck

Avian diseases. 2017 Sept., v. 61, no. 3

2017

Abstract: Genetic resistance or susceptibility to infectious diseases has been largely associated with the avian major histocompatibility complex (MHC) genes. Our goal was to determine resistance and susceptibility of MHC B haplotype in congenic and inbred chicken ...

Abstract	Genetic resistance or susceptibility to infectious diseases has been largely associated with the avian major histocompatibility complex (MHC) genes. Our goal was to determine resistance and susceptibility of MHC B haplotype in congenic and inbred chicken lines in order to establish a resistant–susceptible model. Eight congenic lines (253/B18, 254/B15, 330/B21, 312/B24, 331/B2, 335/B19, 336/B21, and 342/BO), two inbred lines (003/B17 and 077/B19), and three commercial lines (white leghorn, brown layers, and broilers) were used in two experiments. We analyzed and compared immunologic responses and the effect of challenge by measuring viral load, IgG and IgA humoral responses, histopathology and histomorphometry, clinical signs, and immune cell populations in the different MHC B haplotype lines. We found that respiratory signs, tracheal deciliation and inflammation, airsacculitis, viral shedding in tears, and local humoral responses were good parameters to determine resistance or susceptibility. Based on these results, we identified 331/B2 as the most resistant and 335/B19 as the most susceptible congenic chicken lines. These two lines will be used as an animal model in subsequent experiments to understand the mechanisms by which the immune system in chickens generates resistance to infectious bronchitis virus.
Keywords	animal models ; chickens ; genetic resistance ; haplotypes ; histopathology ; humoral immunity ; immune system ; immunoglobulin A ; immunoglobulin G ; inbred lines ; infectious bronchitis ; Infectious bronchitis virus ; inflammation ; major histocompatibility complex ; signs and symptoms (animals and humans) ; tears ; viral load ; viral shedding ; White Leghorn ; covid19
Language	English
Dates of publication	2017-09
Size	p. 358-365.
Publishing place	American Association of Avian Pathologists
Document type	Article
ZDB-ID	40871-2
ISSN	1938-4351 ; 0005-2086
ISSN (online)	1938-4351
ISSN	0005-2086
DOI	10.1637/11666-050117-RegR
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Detection of SARS-CoV-2 from raw patient samples by coupled high temperature reverse transcription and amplification.

Johannes W P Kuiper / Timo Baade / Marcel Kremer / Ramon Kranaster / Linda Irmisch / Marcus Schuchmann / Johannes Zander / Andreas Marx / Christof R Hauck

PLoS ONE, Vol 15, Iss 11, p e

2020 Volume 0241740

Abstract: SARS-CoV-2 is spreading globally with unprecedented consequences for modern societies. The early detection of infected individuals is a pre-requisite to contain the virus. Currently, purification of RNA from patient samples followed by RT-PCR is the gold ...

Abstract	SARS-CoV-2 is spreading globally with unprecedented consequences for modern societies. The early detection of infected individuals is a pre-requisite to contain the virus. Currently, purification of RNA from patient samples followed by RT-PCR is the gold standard to assess the presence of this single-strand RNA virus. However, these procedures are time consuming, require continuous supply of specialized reagents, and are prohibitively expensive in resource-poor settings. Here, we report an improved nucleic-acid-based approach to detect SARS-CoV-2 with the ability to detect as little as five viral genome equivalents. The approach delivers results without the need to purify RNA, reduces handling steps, minimizes costs, and allows evaluation by non-specialized equipment. The use of unprocessed swap samples is enabled by employing a heat-stable RNA- and DNA-dependent DNA polymerase, which performs the double task of stringent reverse transcription of RNA at elevated temperatures as well as PCR amplification of a SARS-CoV-2 specific target gene. As results are obtained within 2 hours and can be read-out by a hand-held LED-screen, this novel protocol will be of particular importance for large-scale virus surveillance in economically constrained settings.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neisseria meningitidis has two independent modes of recognizing its human receptor CEACAM1.

Katharina Kuespert / Alexandra Roth / Christof R Hauck

PLoS ONE, Vol 6, Iss 1, p e

2011 Volume 14609

Abstract: BACKGROUND: Several human-restricted gram-negative bacteria exploit carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for host colonization. For example, Neisseria meningitidis engages these human receptors via outer membrane proteins of ...

Abstract	BACKGROUND: Several human-restricted gram-negative bacteria exploit carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for host colonization. For example, Neisseria meningitidis engages these human receptors via outer membrane proteins of the colony opacity-associated (Opa) protein family triggering internalization into non-phagocytic cells. PRINCIPAL FINDINGS: We report that a non-opaque strain of N. meningitidis selectively interacts with CEACAM1, but not other CEACAM family members. Using functional assays of bacterial adhesion and internalisation, microscopic analysis, and a panel of CEACAM1 deletion mutants we demonstrate that the engagement of CEACAM1 by non-opaque meningococci occurs in a manner distinct from Opa protein-mediated association. In particular, the amino-terminal domain of CEACAM1 is necessary, but not sufficient for Opa protein-independent binding, which requires multiple extracellular domains of the human receptor in a cellular context. Knock-down of CEACAM1 interferes with binding to lung epithelial cells, whereas chemical or pharmacological disruption of host protein glycosylation does not abrogate CEACAM1 recognition by non-opaque meningococci. The previously characterized meningococcal invasins NadA or Opc do not operate in a CEACAM1-dependent manner. CONCLUSIONS: The results demonstrate a mechanistically distinct, Opa protein-independent interaction between N. meningitidis and human CEACAM1. Our functional investigations suggest the presence of a second CEACAM1-binding invasin on the meningococcal surface that associates with the protein backbone and not the carbohydrate structures of CEACAM1. The redundancy in meningococcal CEACAM1-binding factors further highlights the important role of CEACAM recognition in the biology of this human-adapted pathogen.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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