bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tuning the Antigen Density Requirement for CAR T-cell Activity
Authors: Majzner Robbie G. , Rietberg Skyler P. , Sotillo Elena , Dong Rui , Vachharajani Vipul T. , Labanieh Louai , Myklebust June H. , Kadapakkam Meena , Weber Evan W. , Tousley Aidan M. , Richards Rebecca M. , Heitzeneder Sabine , Nguyen Sang M. , Wiebking Volker , Theruvath Johanna , Lynn Rachel C. , Xu Peng , Dunn Alexander R. , Vale Ronald D. , Mackall Crystal L. 
Published: March 2020

AbstractInsufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBζ CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBζ-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence.Significance:Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28ζ-CARs outperform 4-1BBζ-CARs when antigen density is low. However, 4-1BBζ-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.This article is highlighted in the In This Issue feature, p. 627
Accumulation of Pericardial Fat Is Associated With Alterations in Heart Rate Variability Patterns in Hypercholesterolemic Pigs
Authors: Uceda Domingo E. , Zhu Xiang-Yang , Woollard John R. , Ferguson Christopher M. , Patras Ioannis , Carlson Daniel F. , Asirvatham Samuel J. , Lerman Amir , Lerman Lilach O. 
Published: March 2020

Background:
Heart rate variability (HRV) and pulse rate variability are indices of autonomic cardiac modulation. Increased pericardial fat is associated with worse cardiovascular outcomes. We hypothesized that progressive increases in pericardial fat volume and inflammation prospectively dampen HRV in hypercholesterolemic pigs.

Methods:
WT (wild type) or PCSK9 (proprotein convertase subtilisin-like/kexin type-9) gain-of-function Ossabaw mini-pigs were studied in vivo before and after 3 and 6 months of a normal diet (WT-normal diet, n=4; PCSK9-normal diet, n=6) or high-fat diet (HFD; WT-HFD, n=3; PCSK9-HFD, n=6). The arterial pulse waveform was obtained from an arterial telemetry transmitter to analyze HRV indices, including SD (SD of all pulse-to-pulse intervals over a single 5-minute period), root mean square of successive differences, proportion >50 ms of normal-to-normal R-R intervals, and the calculated ratio of low-to-high frequency distributions (low-frequency power/high-frequency power). Pericardial fat volumes were evaluated using multidetector computed tomography and its inflammation by gene expression of TNF (tumor necrosis factor)-α. Plasma lipid panel and norepinephrine level were also measured.

Results:

At diet completion, hypercholesterolemic PCSK9-HFD had significantly (
P
<0.05 versus baseline) depressed HRV (SD of all pulse-to-pulse intervals over a single 5-minute period, root mean square of successive differences, proportion >50 ms, high-frequency power, low-frequency power), and both HFD groups had higher sympathovagal balance (SD of all pulse-to-pulse intervals over a single 5-minute period/root mean square of successive differences, low-frequency power/high-frequency power) compared with normal diet. Pericardial fat volumes and LDL (low-density lipoprotein) cholesterol concentrations correlated inversely with HRV and directly with sympathovagal balance, while sympathovagal balance correlated directly with plasma norepinephrine. Pericardial fat TNF-α expression was upregulated in PCSK9-HFD, colocalized with nerve fibers, and correlated inversely with root mean square of successive differences and proportion >50 ms.

Conclusions:
Progressive pericardial fat expansion and inflammation are associated with a fall in HRV in Ossabaw mini-pigs, implying aggravated autonomic imbalance. Hence, pericardial fat accumulation is associated with alterations in HRV and the autonomic nervous system.

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Relation of Fractionated Atrial Potentials With the Vagal Innervation Evaluated by Extracardiac Vagal Stimulation During Cardioneuroablation
Authors: Pachon-M Enrique I. , Pachon-Mateos Jose Carlos , Higuti Christian , Santillana-P Tomas G. , Lobo Tasso , Pachon Carlos , Pachon-Mateos Juan , Zerpa Juan , Ortencio Felipe , Amarante Ricardo Carneiro , Silva Ricardo Ferreira , Osório Thiago Guimarães 
Published: March 2020

Background:
Vagal hyperactivity is directly related to several clinical conditions as reflex/functional bradyarrhythmias and vagal atrial fibrillation (AF). Cardioneuroablation provides therapeutic vagal denervation through endocardial radiofrequency ablation for these cases. The main challenges are neuromyocardium interface identification and the denervation control and validation. The finding that the AF-Nest (AFN) ablation eliminates the atropine response and decreases RR variability suggests that they are related to the vagal innervation.

Method:
Prospective, controlled, longitudinal, nonrandomized study enrolling 62 patients in 2 groups: AFN group (AFN group 32 patients) with functional or reflex bradyarrhythmias or vagal AF treated with AFN ablation and a control group (30 patients) with anomalous bundles, ventricular premature beats, atrial flutter, atrioventricular nodal reentry, and atrial tachycardia, treated with conventional ablation (non-AFN ablation). In AFN group, ablation delivered at AFN detected by fragmentation/fractionation of the endocardial electrograms and by 3-dimensional anatomic location of the ganglionated plexus. Vagal response was evaluated before, during, and postablation by 5 s noncontact vagal stimulation at the jugular foramen, through the internal jugular veins (extracardiac vagal stimulation [ECVS]), analyzing 15 s mean heart rate, longest RR, pauses, and atrioventricular block. All patients had current guidelines arrhythmia ablation indication.

Results:

Preablation ECVS induced sinus pauses, asystole, and transient atrioventricular block in both groups showing a strong vagal response (
P
=0.96). Postablation ECVS in the AFN group showed complete abolishment of the cardiac vagal response in all cases (pre/postablation ECVS=
P
<0.0001), demonstrating robust vagal denervation. However, in the control group, vagal response remained practically unchanged postablation (
P
=0.35), showing that non-AFN ablation promotes no significant denervation.

Conclusions:
AFN ablation causes significant vagal denervation. Non-AFN ablation causes no significant vagal denervation. These results suggest that AFNs are intrinsically related to vagal innervation. ECVS was fundamental to stepwise vagal denervation validation during cardioneuroablation.

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Short term effects of limb autotomy on immune function and disease resistance of Portunus trituberculatus (Brachyura, Portunidae)
Authors: Wang Xujie , Peng Yingying , Yu Huaihua , Xu Wenjun , Shi Hui , He Jie 
Published: March 2020

Abstract
Crustaceans usually autotomize their limbs in response to physical or physiological threats. In this study, the short term effects of different degrees of autotomy on immune function and disease resistance of Portunus trituberculatus were studied by autotomizing one limb (mild autotomy) or four limbs (severe autotomy). The results indicate that the total haemocyte count (THC) of these crabs showed a tendency to decrease rapidly at first, then increase, and then decrease after mild autotomy and severe autotomy, but the THC changes for individuals with mild autotomy lagged relatively behind. The haemocyte compositions of the crabs also changed greatly after limb autotomy; especially in the severe autotomy group, the proportion of large granular cells and non-granular cells increased significantly within 0.5 h and 2 h after treatment, and the proportion of small particle cells clearly decreased. From the changes in related immune enzyme activities, the effect of autotomy on the activity of haemolymph superoxide dismutase (SOD) in P. trituberculatus was notably low, but had a greater influence on the activities of phenoloxidase (PO), lysozyme (LZM), acid phosphatase (ACP) and alkaline phosphatase (AKP). Among these activities, PO activity decreased significantly within 1 h after treatment and then gradually recovered, LZM activity began to rise continuously within 4 h of autotomy, and both ACP and AKP activity increased immediately after treatment and then gradually decreased. Compared with the individuals with severe autotomy, the haemolymph immunoenzymatic activity of the mild autotomy crabs was slight and slower. In addition, limb autotomy directly affects the disease resistance of P. trituberculatus, especially for the case of severe autotomy, i.e., the resistance of P. trituberculatus to disease is significantly weakened, and the probability of death greatly increases. On the whole, P. trituberculatus could respond to the short term negative effects of limb autotomy by corresponding physiological regulation mechanisms, but the disease resistance was still reduced. This study showed that the self-regulation ability of P. trituberculatus in response to limb autotomy was limited, especially in the case of severe autotomy.
Breaking of Internal Waves and Turbulent Dissipation in an Anticyclonic Mode Water Eddy
Authors: Fernández-Castro Bieito , Evans Dafydd Gwyn , Frajka-Williams Eleanor , Vic Clément , Naveira-Garabato Alberto C. 
Published: March 2020

AbstractA 4-month glider mission was analyzed to assess turbulent dissipation in an anticyclonic eddy at the western boundary of the subtropical North Atlantic. The eddy (radius ≈ 60 km) had a core of low potential vorticity between 100 and 450 m, with maximum radial velocities of 0.5 m s−1 and Rossby number ≈ −0.1. Turbulent dissipation was inferred from vertical water velocities derived from the glider flight model. Dissipation was suppressed in the eddy core (ε ≈ 5 × 10−10 W kg−1) and enhanced below it (>10−9 W kg−1). Elevated dissipation was coincident with quasiperiodic structures in the vertical velocity and pressure perturbations, suggesting internal waves as the drivers of dissipation. A heuristic ray-tracing approximation was used to investigate the wave–eddy interactions leading to turbulent dissipation. Ray-tracing simulations were consistent with two types of wave–eddy interactions that may induce dissipation: the trapping of near-inertial wave energy by the eddy’s relative vorticity, or the entry of an internal tide (generated at the nearby continental slope) to a critical layer in the eddy shear. The latter scenario suggests that the intense mesoscale field characterizing the western boundaries of ocean basins might act as a “leaky wall” controlling the propagation of internal tides into the basin’s interior.
Contribution of Leisure Activities to Health Perception, Life Satisfaction, and Self-Esteem among Korean Individuals with Visual Impairments
Authors: Kim Junhyoung , Han Areum , Hodges Jan S. , Kim May 
Published: March 2020

Introduction: We determined the types of leisure activities that affect health perception, life satisfaction, and self-esteem among Korean individuals with mild and severe visual impairments (i.e., those who have low vision or are blind). Methods: Using the 2015 Korean national census data, 429 individuals were selected and classified into two groups based on visual impairment level: severe and mild. A one-way multivariate analysis of variance was used to compare each group difference, followed by univariate analyses. Results: Participants with mild visual impairment reported social activity was the highest mean scores on health perception ( M = 2.70, SD = 0.56) and life satisfaction ( M = 3.54, SD = 0.37), and religious activity was the highest mean score on self-esteem ( M = 2.79, SD = 0.52). Computer or Internet use was the second-highest score on health perception ( M = 2.59, SD = 0.51), religious activity was the second-highest on life satisfaction ( M = 3.33, SD = 0.46), and social activity was the second-highest on self-esteem ( M = 2.77, SD = 0.61). Among participants with severe visual impairment, computer or Internet use showed the highest mean scores on health perception ( M = 2.86, SD = 0.38) and self-esteem ( M = 2.64, SD = 0.50), while social activity had the highest mean score on life satisfaction ( M = 3.37, SD = 0.42). Discussion: Social and religious activity promoted health perception, life satisfaction, and self-esteem among participants with mild visual impairments. Social activity and computer or Internet use contributed to health perception, life satisfaction, and self-esteem among participants with severe visual impairments. Implications for practitioners: Leisure service providers and recreational therapists can support socialization and the building of friendships by individuals with visual impairments by designing and implementing social activities. Marketing and information dissemination using the Internet could aid access to necessary information among such individuals. Employing online social communities for social networking, information access, and education will contribute to their health and life satisfaction.
Early-onset androgenetic alopecia in China: a descriptive study of a large outpatient cohort
Authors: Ding Qi , Xu Yu-Xuan , Sun Wei-Ling , Liu Jing-Jing , Deng Yu-Yu , Wu Qiao-Fang , Cao Chun-Yu , Zhou Lan-Bo , Lu Yan , Fan Wei-Xin 
Published: March 2020

Objective To describe the clinical features of early-onset androgenetic alopecia (AGA) in a large cohort of Chinese patients. Methods This descriptive study recruited consecutive patients seeking medical treatment for AGA between 1 January 2013 and 30 November 2018. Patients were included in the study if they reported being ≤35 years old at AGA onset and if their pattern of hair loss was documented with photographs. The age of onset, sex, body mass index (BMI), BAsic and SPecific classification of hair loss and family history of alopecia were collected in an electronic database. Results A total of 3897 patients with early-onset AGA were recruited to the study. The majority of patients (70.6%; 2751 of 3897) were 21–30 years old and male (72.7%; 2834 of 3897). No association was found between high BMI (≥25 kg/m2) and early-onset AGA. There were significantly more overweight male AGA patients than overweight female patients (86.8% [632 of 728] versus 13.2% [96 of 728], respectively). The overall prevalence of familial AGA was 72.8% (2837 of 3897) and the condition was inherited more often from the father (52.8%; 1498 of 2837) than from the mother (24.3%; 688 of 2837). Conclusions Early-onset AGA primarily affects male patients between 21–30 years of age. Males with early-onset AGA are likely to have inherited AGA from their fathers.
Construction and characterization of an adenoviral vector encoding human bone morphogenetic protein-2
Authors: Peng Liangquan , Chen Kang , Zhu Weimin , Lu Wei , Xu Jian , Huang Yong , Kuai Shengzheng , Deng Zhenhan , Wang Daping 
Published: March 2020

Objectives Construction of adenoviral vectors can be complicated and time-consuming. The aim of this study was to construct an adenoviral vector expressing human bone morphogenetic protein 2 (BMP-2). Methods An adenoviral vector expressing human BMP-2 was constructed using the Gateway™ technique based on site-specific recombination. Briefly, BMP-2 cDNA was obtained by polymerase chain reaction, inserted into the pMD19-T cloning vector, and subcloned into a shuttle vector. The DNA sequence encoding BMP-2 was then subcloned from pEC3.1-BMP2 into the pAd/BLOCK-iT™-DEST adenoviral vector genome, which was then linearized and used to transfect 293 cells for adenovirus packaging. Adenovirus particles were generated with a titer of 1 × 1010 infectious units/mL. Results Potent expression of BMP-2 mRNA and protein was detected in adenovirus-infected 293 cells, confirming that the adenoviral vector encoding BMP-2 was successfully constructed. Conclusions This recombinant adenoviral vector encoding BMP-2 can be applied in future studies to explore the roles of BMP-2 in various cell types and tissues.
Repair of Osteochondral Defects With Predifferentiated Mesenchymal Stem Cells of Distinct Phenotypic Character Derived From a Nanotopographic Platform
Authors: Wu Yingnan , Yang Zheng , Denslin Vinitha , Ren XiaFei , Lee Chang Sheng , Yap Fung Ling , Lee Eng Hin 
Published: March 2020

Background: Articular cartilage has a zonal architecture and biphasic mechanical properties. The recapitulation of surface lubrication properties with high compressibility of the deeper layers of articular cartilage during regeneration is essential in achieving long-term cartilage integrity. Current clinical approaches for cartilage repair, especially with the use of mesenchymal stem cells (MSCs), have yet to restore the hierarchically organized architecture of articular cartilage. Hypothesis: MSCs predifferentiated on surfaces with specific nanotopographic patterns can provide phenotypically stable and defined chondrogenic cells and, when delivered as a bilayered stratified construct at the cartilage defect site, will facilitate the formation of functionally superior cartilage tissue in vivo. Study Design: Controlled laboratory study. Methods: MSCs were subjected to chondrogenic differentiation on specific nanopatterned surfaces. The phenotype of the differentiated cells was assessed by the expression of cartilage markers. The ability of the 2-dimensional nanopattern-generated chondrogenic cells to retain their phenotypic characteristics after removal from the patterned surface was tested by subjecting the enzymatically harvested cells to 3-dimensional fibrin hydrogel culture. The in vivo efficacy in cartilage repair was demonstrated in an osteochondral rabbit defect model. Repair by bilayered construct with specific nanopattern predifferentiated cells was compared with implantation with cell-free fibrin hydrogel, undifferentiated MSCs, and mixed-phenotype nanopattern predifferentiated MSCs. Cartilage repair was evaluated at 12 weeks after implantation. Results: Three weeks of predifferentiation on 2-dimensional nanotopographic patterns was able to generate phenotypically stable chondrogenic cells. Implantation of nanopatterned differentiated MSCs as stratified bilayered hydrogel constructs improved the repair quality of cartilage defects, as indicated by histological scoring, mechanical properties, and polarized microscopy analysis. Conclusion: Our results indicate that with an appropriate period of differentiation, 2-dimensional nanotopographic patterns can be employed to generate phenotypically stable chondrogenic cells, which, when implanted as stratified bilayered hydrogel constructs, were able to form functionally superior cartilage tissue. Clinical Relevance: Our approach provides a relatively straightforward method of obtaining large quantities of zone-specific chondrocytes from MSCs to engineer a stratified cartilage construct that could recapitulate the zonal architecture of hyaline cartilage, and it represents a significant improvement in current MSC-based cartilage regeneration.
Effects of perfluorocarbon liquids in macular hole retinal detachment treatment
Authors: Chen Zhen , Zhang Yu , Nie Yu-Hong , Yang Hong-Xia , Xing Yi-Qiao 
Published: March 2020

Objective: This study aims to evaluate the clinical efficacy and visual function prognosis of macular hole retinal detachment treatment for high myopia by inverting the internal limiting membrane to overlay the macular hole with the assistance of perfluorocarbon liquids. Methods: A total of 55 high myopia patients, who received macular hole retinal detachment treatment from 2013 to 2016, were included in this study. Among these patients, 38 patients were assigned to the first group and 17 patients (perfluorocarbon liquids) were assigned to the second group. The second group was further divided into two subgroups, according to the overlaying layer number of the internal limiting membrane valve: A group (multiple layers) and B group (single layer). Results: The success rate of the internal limiting membrane inversion and overlaying on the macular hole was 23.68% and 100% in the first and second group, respectively. The differences in macular hole closing rate and postoperative best-corrected visual acuity between these two groups were statistically significant ( p < 0.05). Furthermore, the differences in macular morphology recovery between the A and B groups were also statistically significant ( p = 0.004 < 0.05). Conclusion: Perfluorocarbon liquids play a positive role in the operation process of the internal limiting membrane.
Erythrocyte membrane polyunsaturated fatty acid profiles are associated with systemic inflammation and fish consumption in systemic lupus erythematosus: a cross-sectional study
Authors: Vordenbäumen Stefan , Sokolowski Alexander , Kutzner Laura , Rund Katharina M , Düsing Christina , Chehab Gamal , Richter Jutta G , Brinks Ralph , Schneider Matthias , Schebb Nils H 
Published: March 2020

Objective This study aimed to assess polyunsaturated fatty acid (PUFA) status and association with systemic inflammation and fish consumption in systemic lupus erythematosus (SLE). Methods Parameters of PUFA status including the proportion of omega-6 and -3 fatty acids in highly unsaturated fatty acids (omega-6%, omega-3%), essential fatty acids linoleic acid (LA) and alpha-linolenic acid (ALA), the omega-6 PUFA arachidonic acid (ARA) and the sum of key omega-3 PUFA eicosapentaenoic acid+docosahexaenoic acid (omega-3 status) were measured by gas chromatography in 68 SLE patients (88.2% female, aged 45.7±12.5 years). Associations with serum CRP, disease activity, damage and fish consumption were assessed by linear regression modelling adjusted for age, sex and body mass index. Associations are reported in terms of regression coefficients (β). Results Omega-6 PUFA were associated with higher CRP: omega-6% (β = 0.052, p = 0.02), the ratio of LA/ALA (β = 0.007, p = 0.02) and ARA (β = 0.308, p = 0.001). Conversely, omega-3% was associated with lower CRP (β = −0.051, p = 0.02). Increased dietary PUFA consumption from fish (g/day) was linked to a higher omega-3 status (β = 2.21, p = 0.02) and lower self-reported damage (Brief Index of Lupus Damage; β = −3.22, p = 0.02). Conclusions Omega-3 and omega-6 fatty acid status differentially reflect systemic inflammation in SLE and are linked to fish consumption.