bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porcine signal regulatory protein alpha binds to human CD47 to inhibit phagocytosis: Implications for human hematopoietic stem cell transplantation into severe combined immunodeficient pigs
Authors: Boettcher Adeline N. , Cunnick Joan E. , Powell Ellis J. , Egner Timothy K. , Charley Sara E. , Loving Crystal L. , Tuggle Christopher K. 
Published: October 2018

AbstractBackgroundSevere combined immunodeficient (SCID) pigs are an emerging animal model being developed for biomedical and regenerative medicine research. SCID pigs can successfully engraft human‐induced pluripotent stem cells and cancer cell lines. The development of a humanized SCID pig through xenotransplantation of human hematopoietic stem cells (HSCs) would be a further demonstration of the value of such a large animal SCID model. Xenotransplantation success with HSCs into non‐obese diabetic (NOD)‐derived SCID mice is dependent on the ability of NOD mouse signal regulatory protein alpha (SIRPA) to bind human CD47, inducing higher phagocytic tolerance than other mouse strains. Therefore, we investigated whether porcine SIRPA binds human CD47 in the context of developing a humanized SCID pig.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from SCID and non‐SCID pigs. Flow cytometry was used to assess whether porcine monocytes could bind to human CD47. Porcine monocytes were isolated from PBMCs and were subjected to phagocytosis assays with pig, human, and mouse red blood cell (RBC) targets. Blocking phagocytosis assays were performed by incubating human RBCs with anti‐human CD47 blocking antibody B6H12, non‐blocking antibody 2D3, and nonspecific IgG1 antibody and exposing to human or porcine monocytes.ResultsWe found that porcine SIRPA binds to human CD47 in vitro by flow cytometric assays. Additionally, phagocytosis assays were performed, and we found that porcine monocytes phagocytose human and porcine RBCs at significantly lower levels than mouse RBCs. When human RBCs were preincubated with CD47 antibodies B6H12 or 2D3, phagocytosis was induced only after B6H12 incubation, indicating the lower phagocytic activity of porcine monocytes with human cells requires interaction between porcine SIRPA and human CD47.ConclusionsWe have shown the first evidence that porcine monocytes can bind to human CD47 and are phagocytically tolerant to human cells, suggesting that porcine SCID models have the potential to support engraftment of human HSCs.
Dynamic structural rearrangements and functional regulation of voltage‐sensing phosphatase
Authors: Sakata Souhei , Okamura Yasushi 
Published: October 2018

AbstractThe voltage‐sensing phosphatase (VSP) consists of a voltage sensor domain (VSD) and a cytoplasmic catalytic region. The latter contains a phosphatase domain and a C2 domain, showing remarkable similarity to the tumour suppressor enzyme PTEN. In VSP, membrane depolarization induces a conformational change in the VSD, which activates the phosphoinositide phosphatase. The final outcome in VSP is enzymatic activity in the cytoplasmic region, unlike in voltage‐gated ion channels where conformational change of the transmembrane pore is induced by the VSD. Therefore, it is crucial to detect structural change in the cytoplasmic catalytic region to gain insights into the operating mechanisms of VSP. This review summarizes a recent study in which a method of genetic incorporation of a non‐canonical amino acid, Anap, was used to detect dynamic membrane voltage‐controlled rearrangements of the structure of the catalytic region of sea squirt VSP (Ci‐VSP). Upon membrane depolarization, both the phosphatase domain and the C2 domain move in a similar time frame, suggesting that the two regions are coupled to each other. Measurement of Förster resonance energy transfer (FRET) between Anap introduced into the C2 domain of Ci‐VSP and dipicrylamine in the cell membrane suggested no large movement of the enzyme towards the membrane. Fluorescence changes in Anap induced by different membrane potentials indicate the presence of multiple conformations of the active enzyme.
Refractive error and visual impairment in Ireland schoolchildren
Authors: Harrington Siofra Christine , Stack Jim , Saunders Kathryn , O’Dwyer Veronica 
Published: October 2018

AimTo report refractive error prevalence and visual impairment in Republic of Ireland (henceforth 'Ireland') schoolchildren.MethodsThe Ireland Eye Study examined 1626 participants (881 boys, 745 girls) in two age groups, 6–7 years (728) and 12–13 years (898), in Ireland between June 2016 and January 2018. Participating schools were selected by stratified random sampling, representing a mix of school type (primary/postprimary), location (urban/rural) and socioeconomic status (disadvantaged/advantaged). Examination included monocular logarithm of the minimum angle of resolution (logMAR) presenting visual acuity (with spectacles if worn) and cycloplegic autorefraction (1% Cyclopentolate Hydrochloride). Parents completed a questionnaire to ascertain participants’ lifestyle.ResultsThe prevalence of myopia (spherical equivalent refraction (SER): ≤−0.50 D), hyperopia (SER: ≥+2.00 D) and astigmatism (≤−1.00 DC) among participants aged 6–7 years old was 3.3%, 25% and 19.2%, respectively, and among participants aged 12–13 years old was 19.9%, 8.9% and 15.9%, respectively. Astigmatic axes were predominately with-the-rule. The prevalence of ‘better eye’ presenting visual impairment (≥0.3 logMAR, with spectacles, if worn) was 3.7% among younger and 3.4% among older participants. Participants in minority groups (Traveller and non-white) were significantly more likely to present with presenting visual impairment in the ‘better eye’.ConclusionsThe Ireland Eye Study is the first population-based study to report on refractive error prevalence and visual impairment in Ireland. Myopia prevalence is similar to comparable studies of white European children, but the levels of presenting visual impairment are markedly higher than those reported for children living in Northern Ireland, suggesting barriers exist in accessing eye care.
Utility of broad-range 16S rRNA PCR assay versus conventional methods for laboratory diagnosis of bacterial endophthalmitis in a tertiary care hospital
Authors: Mishra Deepanshi , Satpathy Gita , Chawla Rohan , Venkatesh Pradeep , Ahmed Nishat Hussain , Panda Subrat Kumar 
Published: October 2018

BackgroundEndophthalmitis, a sight-threatening intraocular infection, can be of postsurgical, post-traumatic or endogenous origin. Laboratory diagnosis-based appropriate therapy can be vision-saving. Conventional culture-based laboratory diagnosis takes time and lacks sensitivity. In this study a broad-range PCR assay was assessed against conventional and automated culture methods in vitreous specimens for accurate microbiological diagnosis.AimsTo use broad-range PCR assay targeting 16S ribosomal RNA (rRNA) region of bacteria and to assess its performance vis-à-vis conventional and automated culture methods in the laboratory diagnosis of endophthalmitis.MethodsVitreous specimens from 195 patients with clinically diagnosed endophthalmitis were processed for classical and automated culture methods, antimicrobial sensitivity and broad-range PCR assay targeting 762 bp region of 16S rRNA followed by nucleotide sequencing by Sanger’s method. Causative agents were identified from the nucleotide sequences analysed against the GenBank database, and organisms were identified using the Clinical and Laboratory Standards Institute (CLSI) MM18A guidelines.ResultsBacteria could be detected from 127 (65.13%) of the 195 vitreous specimens by broad-range PCR assay; bacterial isolation was possible from 17 (8.7%) and 60 (30.76%) of these specimens by conventional and automated culture methods, respectively (p<0.0001). PCR assay could detect two uncultured bacterium, and in five cases the bacterial identity could not be determined from NCBI database matching.ConclusionBroad-range PCR assay could provide definitive microbial diagnosis within 24 hours in significantly more patients (p<0.0001). Some rare organisms could be detected, useful in treatment modalities. Automated culture was significantly more sensitive than conventional culture.
Conceptual review of measuring functional impairment: findings from the Weiss Functional Impairment Rating Scale
Authors: Weiss Margaret D. , McBride Nicole Michelle , Craig Stephanie , Jensen Peter 
Published: October 2018

ObjectiveThis is a narrative review of validation and outcome studies using the Weiss Functional Impairment Rating Scale (WFIRS). The objective of the review is to establish a framework for understanding functional impairment and create a definition for functional response and remission.MethodsWe conducted a literature search via MEDLINE, EBSCO and Google Scholar with no date restrictions and reviewed bibliographies of selected publications. Publications found in languages other than English were translated and clarification obtained from the author(s) if needed. Inclusion criteria were any manuscript that was either a WFIRS psychometric validation study or a clinical trial using the WFIRS as an outcome. There were no exclusion criteria.ResultsThe WFIRS has been validated in multiple cultures, and in clinical, research and control populations. The WFIRS has robust psychometric properties across ages, psychiatric status and informants. Outcome studies show variable improvement, with different response patterns between domains and among different interventions.ConclusionSymptom improvement and remission needs to be complemented with evaluation of functional improvement and remission to obtain a full picture of clinical status over the course of treatment.
Clinicopathological features and outcome of antibody-negative anti-glomerular basement membrane disease
Authors: Liang Dandan , Liang Shaoshan , Xu Feng , Zhang Mingchao , Li Xiaomei , Tu Yiyao , Liu Zhihong , Zeng Caihong 
Published: October 2018

AimTo explore the clinicopathological characteristics of patients with anti-GBM antibody-negative anti-GBM disease.MethodsThe clinical and renal pathological findings were retrospectively studied in 19 patients. All patients met the following inclusion criteria: linear GBM IgG deposition on immunofluorescence(IF); and lack of serum anti-GBM antibodies by ELISA and indirect immunofluorescence assay.ResultsThere were 17 male and two female patients, with a median age of 36 years (range 15–61 years). Hypertension was present in 68% of cases, nephrotic-range proteinuria (> 3.5 g/24 hours) in 42%, nephrotic syndrome in 37%, microhaematuria in 95%, renal insufficiency in 63% and lung involvement in 16%. On biopsy all patients had linear GBM staining for polyclonal IgG by IF. The dominant IgG subtype was IgG4 or IgG1. By light microscopy, mesangial proliferative GN without crescents was seen in four patients; proliferative GN (mesangial proliferative GN in eight; endocapillary proliferative GN in two; and membranoproliferative GN in two) with crescents (focal in 11; diffuse in one) in 12 patients; and crescentic GN without mesangial or endocapillary proliferative or membranoproliferative changes in three patients. By electron microscopy, six patients showed scarce electron dense deposits in glomeruli and 11 patients had global podocyte effacement. Totally, 10 (53%) patients received immunosuppressive therapy. The median follow-up was 15 months and six (32%) patients progressed to end-stage renal disease.ConclusionsAnti-GBM antibody-negative anti-GBM disease was different from classic anti-GBM disease clinically and pathologically. The pathogenesis of the renal injury in these patients has not been elucidated until now and it should be studied and identified further.
Digital trichoblastoma treated with electrochemotherapy in a dog
Authors: Dos Anjos Denner Santos , Rossi Ygor Amaral , Magalhães Larissa Fernandes , Calazans Sabryna Gouveia , Fonseca‐Alves Carlos Eduardo 
Published: October 2018

Canine trichoblastoma is a benign tumour derived from the trichoblastic epithelium, commonly affecting the head and neck and, less commonly, the limbs and trunk. Herein, the authors report a case of a dog with digital trichoblastoma successfully treated with electrochemotherapy (ECT). The dog received three sessions of ECT with systemic bleomycin. The tumour volume decreased throughout the ECT sessions, with a complete response after 81 days. The patient presented a disease‐free survival of 700 days. ECT may be a better approach than surgery for digital trichoblastomas because it avoids amputating the digit and provides a good cosmetic result.
M. Forster Heddle: an intimate friendship
Authors: Johnston Hamish H. 
Published: October 2018

Abstract
A lifelong friendship began in 1852 between Archibald Geikie (1835–1924) and Matthew Forster Heddle (1828–97), the most eminent Scottish mineralogist of his day. This paper follows the two men from their birth, through their education and early employment, to their first meeting in Edinburgh. It then traces the progress of their complementary, but different, careers and recounts shared events in their professional and personal lives. It describes how the astute Geikie supported the clever but unworldly Heddle through his difficulties at the University of St Andrews and helped him achieve scientific recognition. It concludes by comparing and contrasting their personalities and approach to science and defining the nature of their enduring friendship.
Paradoxical arteriole constriction compromises cytosolic and mitochondrial oxygen delivery in the isolated saline-perfused heart
Authors: Giles Abigail V. , Sun Junhui , Femnou Armel N. , Kuzmiak-Glancy Sarah , Taylor Joni L. , Covian Raul , Murphy Elizabeth , Balaban Robert S. 
Published: October 2018

The isolated saline-perfused heart is used extensively to study cardiac physiology. Previous isolated heart studies have demonstrated lower tissue oxygenation compared with in vivo hearts based on myoglobin oxygenation and the mitochondrial redox state. These data, consistent with small anoxic regions, suggest that the homeostatic balance between work and oxygen delivery is impaired. We hypothesized that these anoxic regions are caused by inadequate local perfusion due to a paradoxical arteriole constriction generated by a disrupted vasoregulatory network. We tested this hypothesis by applying two exogenous vasodilatory agents, adenosine and cromakalim, to relax vascular tone in an isolated, saline-perfused, working rabbit heart. Oxygenation was monitored using differential optical transmission spectroscopy and full spectral fitting. Increases in coronary flow over control with adenosine (27 ± 4 ml/min) or cromakalim (44 ± 4 ml/min) were associated with proportional spectral changes indicative of myoglobin oxygenation and cytochrome oxidase (COX) oxidation, consistent with a decrease in tissue anoxia. Quantitatively, adenosine decreased deoxymyoglobin optical density (OD) across the wall by 0.053 ± 0.008 OD, whereas the reduced form of COX was decreased by 0.039 ± 0.005 OD. Cromakalim was more potent, decreasing deoxymyoglobin and reducing the level of COX by 0.070 ± 0.019 OD and 0.062 ± 0.019 OD, respectively. These effects were not species specific, as Langendorff-perfused mouse hearts treated with adenosine demonstrated similar changes. These data are consistent with paradoxical arteriole constriction as a major source of regional anoxia during saline heart perfusion. We suggest that the vasoregulatory network is disrupted by the washout of interstitial vasoactive metabolites in vitro.NEW & NOTEWORTHY Regional tissue anoxia is a common finding in the ubiquitous saline-perfused heart but is not found in vivo. Noninvasive optical techniques confirmed the presence of regional anoxia under control conditions and demonstrated that anoxia is diminished using exogenous vasodilators. These data are consistent with active arteriole constriction, occurring despite regional anoxia, generated by a disrupted vasoregulatory network. Washout of interstitial vasoactive metabolites may contribute to the disruption of normal vasoregulatory processes in vitro.
Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma
Authors: Torok Jordan A. , Oh Patrick , Castle Katherine D. , Reinsvold Michael , Ma Yan , Luo Lixia , Lee Chang-Lung , Kirsch David G. 
Published: October 2018

Abstract

Stereotactic body radiotherapy is utilized to treat lung cancer. The mechanism of tumor response to high-dose radiotherapy (HDRT) is controversial, with competing hypotheses of increased direct tumor cell killing versus indirect effects on stroma including endothelial cells. Here we used dual recombinase technology in a primary murine lung cancer model to test whether tumor cells or endothelial cells are critical HDRT targets. Lenti-Cre deleted one or two copies of ataxia-telangiectasia mutated gene (Atm; KPAFL/+ or KPAFL/FL), whereas adeno-FlpO–infected mice expressed Cre in endothelial cells to delete one or both copies of Atm (KPVAFL/+ or KPVAFL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively. Deletion of Atm in either tumor cells or endothelial cells had no impact on tumor growth in the absence of radiation. Despite increased endothelial cell death in KPVAFL/FL mice following irradiation, tumor growth delay was not significantly increased. In contrast, a prolonged tumor growth delay was apparent in KPAFL/FL mice. Primary tumor cell lines lacking Atm expression also demonstrated enhanced radiosensitivity as determined via a clonogenic survival assay. These findings indicate that tumor cells, rather than endothelial cells, are critical targets of HDRT in primary murine lung cancer.

Significance:
These findings establish radiosensitizing tumor cells rather than endothelial cells as the primary mechanism of tumor response to high-dose radiotherapy, supporting efforts to maximize local control by radiosensitizing tumors cells.
See related commentary by Hallahan, p. 704
Pomalidomide Inhibits PD-L1 Induction to Promote Antitumor Immunity
Authors: Fujiwara Yuki , Sun Yi , Torphy Robert J. , He Jiadai , Yanaga Katsuhiko , Edil Barish H. , Schulick Richard D. , Zhu Yuwen 
Published: October 2018

Abstract

Thalidomide-like drugs have been approved for the treatment of human multiple myeloma, with their direct antitumor effects and immunomodulatory functions well documented. However, the exact molecular mechanisms that govern these effects remain unclear. Here we demonstrate that pomalidomide promotes immune response by inhibiting expression of PD-L1. Pomalidomide inhibited PD-L1 expression on tumor cells to promote CTL activity in vitro and suppressed PD-L1 upregulation on antigen-presenting cells to prevent peptide-induced T-cell tolerance. Knockout of PD-L1 on tumor cells or in mice completely eliminated the immunomodulatory effect of pomalidomide. Furthermore, pomalidomide synergized with other immunotherapies to improve anticancer therapy. Taken together, this study identifies a new mechanism for the immunomodulatory functions of pomalidomide in cancer therapy. These results also offer a clinical approach for blocking PD-L1 induction and potentially promoting antitumor immunity.

Significance:
These findings report that the immunomodulatory drug pomalidomide, widely used to treat myeloma and other cancers, enhances antitumor immunity by inhibiting PD-1/PD-L1 expression.
Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α
Authors: Orsini Franca , Fumagalli Stefano , Császár Eszter , Tóth Krisztina , De Blasio Daiana , Zangari Rosalia , Lénárt Nikolett , Dénes Ádám , De Simoni Maria-Grazia 
Published: October 2018

Objective—
Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet.

Approach and Results—

Here we show that MBL-deficient (MBL
−/−
) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL
−/−
mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL
−/−
mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage.

Conclusions—
We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.
Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation
Authors: Rinne Petteri , Guillamat-Prats Raquel , Rami Martina , Bindila Laura , Ring Larisa , Lyytikäinen Leo-Pekka , Raitoharju Emma , Oksala Niku , Lehtimäki Terho , Weber Christian , van der Vorst Emiel P.C. , Steffens Sabine 
Published: October 2018

Objective—

Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by
N
-acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored.

Approach and Results—

First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce
N
-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability.
N
-acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE
−/−
) mice during atherogenesis.
N
-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE
−
/−
mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties.

Conclusions—
The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.