bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simplified method to quantify valve back‐leak uncovers severe mesenteric lymphatic valve dysfunction in mice deficient in connexins 43 and 37
Authors: Castorena‐Gonzalez Jorge A. , Srinivasan R. Sathish , King Philip D. , Simon Alexander M. , Davis Michael J. 
Published: April 2020

Key points
Lymphatic valve defects are one of the major causes of lymph transport dysfunction; however, there are no accessible methods for quantitatively assessing valve function.
This report describes a novel technique for quantifying lymphatic valve back‐leak.
Postnatal endothelial‐specific deletion of connexin 43 (Cx43) in connexin 37 null (Cx37−/−) mice results in rapid regression of valve leaflets and severe valve dysfunction.
This method can also be used for assessing the function of venous and lymphatic valves from various species, including humans.
AbstractThe lymphatic system relies on robust, spontaneous contractions of collecting lymphatic vessels and one‐way secondary lymphatic valves to efficiently move lymph forward. Secondary valves prevent reflux and allow for the generation of propulsive pressure during each contraction cycle. Lymphatic valve defects are one of the major causes of lymph transport dysfunction. Genetic mutations in multiple genes have been associated with the development of primary lymphoedema in humans; and many of the same mutations in mice result in valve defects that subsequently lead to chylous ascites or chylothorax. At present the only experimental technique for the quantitative assessment of lymphatic valve function utilizes the servo‐null micropressure system, which is highly accurate and precise, but relatively inaccessible and difficult to use. We developed a novel, simplified alternative method for quantifying valve function and determining the degree of pressure back‐leak through an intact valve in pressurized, single‐valve segments of isolated lymphatic vessels. With this diameter‐based method, the competence of each lymphatic valve is challenged over a physiological range of pressures (e.g. 0.5–10cmH2O) and pressure back‐leak is extrapolated from calibrated, pressure‐driven changes in diameter upstream from the valve. Using mesenteric lymphatic vessels from C57BL/6J, Ub‐CreERT2;Rasa1fx/fx, Foxc2Cre/+, Lyve1‐Cre;Cx43fx/fx, and Prox1‐CreERT2;Cx43fx/fx;Cx37−/− mice, we tested our method on lymphatic valves displaying a wide range of dysfunction, from fully competent to completely incompetent. Our results were validated by simultaneous direct measurement of pressure back‐leak using a servo‐null micropressure system. Our diameter‐based technique can be used to quantify valve function in isolated lymphatic valves from a variety of species. This method also revealed that haplodeficiency in Foxc2 (Foxc2Cre/+) is not sufficient to cause significant valve dysfunction; however, postnatal endothelial‐specific deletion of Cx43 in Cx37−/− mice results in rapid regression of valve leaflets and severe valve dysfunction.
Toward Tradeoff Between Impact Force Reduction and Maximum Safe Speed: Dynamic Parameter Optimization of Variable Stiffness Robots
Authors: Song Siyang , She Yu , Wang Junmin , Su Hai-Jun 
Published: April 2020

Abstract
Variable stiffness robots may provide an effective way of trading-off between safety and speed during physical human–robot interaction. In such a compromise, the impact force reduction capability and maximum safe speed are two key performance measures. To quantitatively study how dynamic parameters such as mass, inertia, and stiffness affect these two performance measures, performance indices for impact force reduction capability and maximum speed of variable stiffness robots are proposed based on the impact ellipsoid in this paper. The proposed performance indices consider different impact directions and kinematic configurations in the large. Combining the two performance indices, the global performance of variable stiffness robots is defined. A two-step optimization method is designed to achieve this global performance. A two-link variable stiffness link robot example is provided to show the efficacy of the proposed method.
Fabrication of Microscale Polymeric Wavy and Coiling Structures via Side-Electrode-Assisted Near-Field Electrospinning: Modeling and Experiments
Authors: You Xiangyu , Yang Yang , Guo Ping 
Published: April 2020

Abstract
It is challenging for the existing fabrication strategies to generate microscale wavy and coiling structures with low cost and high efficiency. In this work, we develop a novel and simple method that allows the fabrication of microscale wavy and coiling fiber arrays via near-field electrospinning (NFES). In addition to the main vertical electric potential for polymer jet generation, additional electrostatic signals are applied to the side-auxiliary electrodes to dynamically control the fiber deposition. Compared with traditional electrospinning based on the buckling instability or mechanical collector movement, the proposed method shows advantages in terms of the controllability, stability, accuracy, and minimal feature size. A theoretical model to describe the polymer jet behaviors has been proposed to simulate the fabrication process by considering the momentum balance of viscoelastic, charge repulsive, and electric forces. The model has been directly verified through the comparison with experimental results. The effects of different process parameters on the fiber deposition patterns are analyzed and discussed. The processing capability has been further demonstrated by fabricating two-dimensional wavy and coiling patterns as well as three-dimensional wavy structures with the radius of curvature less than 100 µm.
Cognate Stimulatory B-Cell–T-Cell Interactions Are Critical for T-Cell Help Recruited by Glycoconjugate Vaccines
Authors: Guttormsen Hilde-Kari , Sharpe Arlene H. , Chandraker Anil K. , Brigtsen Anne Karin , Sayegh Mohammed H. , Kasper Dennis L. 
Published: April 2020

ABSTRACTCovalent linkage of a bacterial polysaccharide to an immunogenic protein greatly enhances the carbohydrate's immunogenicity and induces polysaccharide-specific B-cell memory in vivo. These findings have spurred the development of glycoconjugate vaccines for serious bacterial infections. The specific B-cell–T-cell interactions responsible for recruitment of T-cell help by glycoconjugate vaccines are not well defined. We used mice deficient in molecules critical for stimulatory, cognate B-cell–T-cell interactions to study how T cells improve the immunogenicity of a glycoconjugate vaccine against group B streptococcal disease. Isotype switching to immunoglobulin G (IgG) was abrogated in mice deficient in major histocompatibility complex (MHC) class II antigen (Ag)–T-cell receptor (TCR), B7-CD28, or CD40-CD40L interactions. However, expression of either the B7-1 or the B7-2 molecule on antigen-presenting cells was sufficient for optimal T-cell costimulation. T cells activated by the vaccine also played a pivotal role in determining the magnitude of the IgM response to the polysaccharide. Comparable results were obtained with pathway antagonists. These data suggest that MHC class II Ag-TCR, B7-CD28, and CD40-CD40L interactions are critical for immune responses to glycoconjugate vaccines in vivo.
Targeting Improves the Efficacy of a DNA Vaccine againstCorynebacterium pseudotuberculosisin Sheep
Authors: Chaplin Paul J. , De Rose Robert , Boyle Jefferey S. , McWaters Peter , Kelly Julie , Tennent Jan M. , Lew Andrew M. , Scheerlinck Jean-Pierre Y. 
Published: April 2020

ABSTRACTA large-scale DNA vaccination trial was performed with sheep to investigate whether an antigen targeted by CTLA-4 enhanced and accelerated the humoral immune response. Vaccination with genetically detoxified phospholipase D (ΔPLD) has been shown to be effective, at least partially, againstCorynebacterium pseudotuberculosis, the causal agent of caseous lymphadenitis in sheep. CTLA-4 binds to B7 on antigen-presenting cells and thus was used to direct the fusion antigens to sites of immune induction. Here we demonstrated that targeting ΔPLD as a CTLA-4 fusion protein significantly enhanced the speed, magnitude, and longevity of the antibody response compared to that obtained with DNA encoding ΔPLD. While all groups of sheep vaccinated with DNA encoding ΔPLD were afforded better protection against an experimental challenge withC. pseudotuberculosisthan those immunized with an irrelevant plasmid or those left unimmunized, the best protection was provided by the targeted DNA vaccine. We propose that targeting antigens to antigen-presenting cells offers a generic strategy for enhancing the efficacy of DNA vaccines.
Acquisition of Plasmin Activity by
Fusobacterium nucleatum
subsp.
nucleatum
and Potential Contribution to Tissue Destruction during Periodontitis
Authors: Darenfed H. , Grenier D. , Mayrand D. 
Published: April 2020

ABSTRACT

Fusobacterium nucleatum
subsp.
nucleatum
has been associated with a variety of oral and nonoral infections such as periodontitis, pericarditis, bone infections, and brain abscesses. Several studies have shown the role of plasmin, a plasma serine protease, in increasing the invasive capacity of microorganisms. In this study, we investigated the binding of human plasminogen to
F. nucleatum
subsp.
nucleatum
, and its subsequent activation into plasmin. Plasminogen-binding activity of bacterial cells was demonstrated by a solid-phase dot blot assay using an anti-plasminogen antibody. The binding activity was heat resistant and involved cell-surface lysine residues since it was abolished in the presence of the lysine analog ɛ-aminocaproic acid. Activation of plasminogen-coated bacteria occurred following incubation with either streptokinase, urokinase-type plasminogen activator (u-PA), or a
Porphyromonas gingivalis
culture supernatant. In the case of the
P. gingivalis
culture supernatant, a cysteine protease was likely involved in the activation. The plasmin activity generated on the cell surface of
F. nucleatum
subsp.
nucleatum
could be inhibited by aprotinin. Activation of plasminogen by u-PA was greatly enhanced when plasminogen was bound to bacteria rather than in a free soluble form. u-PA-activated plasminogen-coated
F. nucleatum
subsp.
nucleatum
was found to degrade fibronectin, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Tissue inhibitor of metalloproteinase-1 was also degraded by the plasmin activity generated on the bacterial cells. This study suggests a possible role for plasminogen, which is present in affected periodontal sites, in promoting tissue destruction and invasion by nonproteolytic bacteria such as
F. nucleatum
subsp.
nucleatum
.
Shiga Toxins 1 and 2 Translocate Differently across Polarized Intestinal Epithelial Cells
Authors: Hurley Bryan P. , Jacewicz Mary , Thorpe C. M. , Lincicome Lisa L. , King Andrew J. , Keusch Gerald T. , Acheson David W. K. 
Published: April 2020

ABSTRACT

Shiga toxin-producing
Escherichia coli
(STEC) is an important food-borne pathogen that causes hemolytic-uremic syndrome. Following ingestion, STEC cells colonize the intestine and produce Shiga toxins (Stx), which appear to translocate across the intestinal epithelium and subsequently reach sensitive endothelial cell beds. STEC cells produce one or both of two major toxins, Stx1 and Stx2. Stx2-producing STEC is more often associated with disease for reasons as yet undetermined. In this study, we used polarized intestinal epithelial cells grown on permeable filters as a model to compare Stx1 and Stx2 movement across the intestinal epithelium. We have previously shown that biologically active Stx1 is able to translocate across cell monolayers in an energy-dependent, saturable manner. This study demonstrates that biologically active Stx2 is also capable of movement across the epithelium without affecting barrier function, but significantly less Stx2 crossed monolayers than Stx1. Chilling the monolayers to 4°C reduced the amount of Stx1 and Stx2 movement by 200-fold and 20-fold respectively. Stx1 movement was clearly directional, favoring an apical-to-basolateral translocation, whereas Stx2 movement was not. Colchicine reduced Stx1, but not Stx2, translocation. Monensin reduced the translocation of both toxins, but the effect was more pronounced with Stx1. Brefeldin A had no effect on either toxin. Excess unlabeled Stx1 blocks the movement of
125
I-Stx1. Excess Stx2 failed to have any effect on Stx1 movement. Our data suggests that, despite the many common physical and biochemical properties of the two toxins, they appear to be crossing the epithelial cell barrier by different pathways.
Serum Immunoglobulin Response and Protection from Homologous Challenge by
Proteus mirabilis
in a Mouse Model of Ascending Urinary Tract Infection
Authors: Johnson David E. , Bahrani Farah K. , Lockatell C. Virginia , Drachenberg Cinthia B. , Hebel J. Richard , Belas Robert , Warren John W. , Mobley Harry L. T. 
Published: April 2020

ABSTRACT

We tested the hypothesis that experimental
Proteus mirabilis
urinary tract infection in mice would protect against homologous bladder rechallenge. Despite production of serum immunoglobulin G (IgG) and IgM (median titers of 1:320 and 1:80, respectively), vaccinated (infected and antibiotic-cured) mice did not show a decrease in mortality upon rechallenge; the survivors experienced only modest protection from infection (mean log
10
number of CFU of
P. mirabilis
Nal
r
HI4320 per milliliter or gram in vaccinated mice versus sham-vaccinated mice: urine, 100-fold less [3.5 versus 5.5;
P
= 0.13]; bladder, 100-fold less [3.1 versus 5.1;
P
= 0.066]; kidneys, 40-fold less [2.7 versus 4.3;
P
= 0.016]). Western blots using protein from the wild-type strain and isogenic mutants demonstrated antibody responses to MR/P and PMF fimbriae and flagella. There was no correlation between serum IgG or IgM levels and protection from mortality or infection. There was a trend toward elevated serum IgA titers and protection from subsequent challenge (
P
≥ 0.09), although only a few mice developed significant serum IgA levels. We conclude that prior infection with
P. mirabilis
does not protect significantly against homologous challenge.
A Lithium Chloride-Extracted, Broad-Spectrum-Adhesive 42-Kilodalton Protein of
Staphylococcus epidermidis
Is Ornithine Carbamoyltransferase
Authors: Hussain Muzaffar , Peters Georg , Chhatwal Gursharan S. , Herrmann Mathias 
Published: April 2020

ABSTRACT

To identify novel putative staphylococcal adhesins, lithium chloride extraction (an established method for selective surface molecule solubilization) was employed. N-terminal sequencing and functional assays identified a 42-kDa fibronectin-binding protein from
Staphylococcus epidermidis
as ornithine carbamoyltransferase (OCTase). However, OCTase was not recognizable extracellularly, and this fact together with the fact that LiCl induced DNA release and a decrease in viability suggests that LiCl extraction may not be the method of choice for selective surface molecule extraction from staphylococci.
Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy
Authors: Schroeder Brett A , Black Ralph Graeme , Spadinger Sydney , Zhang Shihong , Kohli Karan , Cao Jianhong , Mantilla Jose G , Conrad Ernest U , Riddell Stanley R , Jones Robin L , Yee Cassian , Pollack Seth M 
Published: April 2020

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.
Efficacy and safety of avelumab treatment in patients with metastatic Merkel cell carcinoma: experience from a global expanded access program
Authors: Walker John W , Lebbé Celeste , Grignani Giovanni , Nathan Paul , Dirix Luc , Fenig Eyal , Ascierto Paolo Antonio , Sandhu Shahneen , Munhoz Rodrigo , Benincasa Elena , Flaskett Sarah , Reed Josh , Engelsberg Arne , Hariharan Subramanian , Kasturi Vijay 
Published: April 2020

BackgroundAvelumab, a human anti–programmed death-ligand 1 immunoglobulin G1 monoclonal antibody, showed favorable efficacy and safety in patients with metastatic Merkel cell carcinoma (mMCC) in the phase II JAVELIN Merkel 200 trial, leading to approval in multiple countries. We describe real-world experience with avelumab in patients with mMCC from an expanded access program.MethodsEligible patients had mMCC and progressive disease during or after chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received an initial 3-month supply of avelumab (administered as 10 mg/kg intravenously every 2 weeks until progressive disease or unacceptable toxicity); resupply was allowed following complete response, partial response, stable disease, or clinical benefit per physician assessment.ResultsBetween December 15, 2015, and March 4, 2019, 558 of 620 requests from 38 countries were medically approved, and 494 patients received avelumab. Among 240 evaluable patients, the objective response rate was 46.7% (complete response in 22.9%, including 3 of 16 potentially immunocompromised patients), and the disease control rate was 71.2%. The median duration of treatment in evaluable patients with response was 7.9 months (range, 1.0–41.7) overall and 5.2 months (range, 3.0–13.9) in immunocompromised patients. No new safety signals were identified. The expanded access program closed for new requests on December 31, 2018, as required after regulatory approval; benefitting patients continued to receive avelumab.ConclusionsThe avelumab expanded access program for patients with mMCC demonstrated efficacy and safety in a real-world setting, consistent with the results from JAVELIN Merkel 200, and provided a treatment for patients with limited options.
The studies on $$Z \rightarrow \Upsilon (1S)+g+g$$ at the next-to-leading-order QCD accuracy
Authors: Sun Zhan 
Published: April 2020

AbstractIn this paper, we carry out the next-to-leading-order (NLO) studies on $$Z \rightarrow \Upsilon (1S)+g+g$$Z→Υ(1S)+g+g via the color-singlet (CS) $$b{\bar{b}}$$bb¯ state. We find the newly calculated NLO QCD corrections to this process can significantly influence its leading-order (LO) results and greatly improve the dependence on the renormalization scale. By including the considerable feeddown contributions, the branching ratio $${\mathcal {B}}_{Z \rightarrow \Upsilon (1S)+g+g}$$BZ→Υ(1S)+g+g is predicted to be (0.56–0.95) $$\times 10^{-6}$$×10-6, which can reach up to 19–31$$\%$$% of the LO predictions given by the CS dominant process $$Z \rightarrow \Upsilon (1S)+b+{\bar{b}}$$Z→Υ(1S)+b+b¯. Moreover, $$Z \rightarrow \Upsilon (1S)+g+g$$Z→Υ(1S)+g+g also seriously affects the CS predictions on the $$\Upsilon (1S)$$Υ(1S) energy distributions, especially when z is relatively small. In summary, for the inclusive $$\Upsilon (1S)$$Υ(1S) productions in Z decay, besides $$Z \rightarrow \Upsilon (1S)+b+{\bar{b}}$$Z→Υ(1S)+b+b¯, the gluon radiation process $$Z \rightarrow \Upsilon (1S)+g+g$$Z→Υ(1S)+g+g can provide indispensable contributions as well.
Fold and thrust belts: structural style, evolution and exploration – an introduction
Authors: Hammerstein James A. , Di Cuia Raffaele , Cottam Michael A. , Zamora Gonzalo , Butler Robert W. H. 
Published: April 2020

Abstract
The outer parts of collision mountain belts are commonly represented by fold and thrust belts. Many of the key concepts in the structural geology of fold and thrust belts have origins in ancient orogens such as the Appalachians and Caledonian chains of Europe, together with the Alps. Impetus in thrust belt research then came from the desire to exploit geological resources that reside in the subsurface, especially arising from hydrocarbon exploration in the foothills of the Canadian Cordillera in the 1960s and 1970s. Notwithstanding decades of exploitation, continental fold and thrust belts are still estimated to hold reserves of 700 billion barrels of oil equivalent. But exploration will focus increasingly on small, hard-to-resolve structures. Basic geological understanding remains as important today as it did for the pioneering explorers in the Canadian foothills. It is a theme that runs throughout this Special Publication.
Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases
Authors: Jochems Angela C.C. , Blair Gordon W. , Stringer Michael S. , Thrippleton Michael J. , Clancy Una , Chappell Francesca M. , Brown Rosalind , Jaime Garcia Daniela , Hamilton Olivia K.L. , Morgan Alasdair G. , Marshall Ian , Hetherington Kirstie , Wiseman Stewart , MacGillivray Tom , Valdés-Hernández Maria C. , Doubal Fergus N. , Wardlaw Joanna M. 
Published: April 2020

Background and Purpose—
Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging.

Methods—
We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility.

Results—
Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%–18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (β=0.468 [95% CI, 0.187–0.750]) and transverse sinus pulsatility (β=0.547 [95% CI, 0.309–0.786]) and adjusting for age, sex, and systolic blood pressure.

Conclusions—
Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.