bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective effect of Lactobacillus reuteri DSM 17938 against experimental necrotizing enterocolitis is mediated by Toll-like receptor 2
Authors: Hoang Thomas K. , He Baokun , Wang Ting , Tran Dat Q. , Rhoads J. Marc , Liu Yuying 
Published: April 2018

Lactobacillus reuteri DSM 17938 (LR 17938) has been shown to reduce the incidence and severity of necrotizing enterocolitis (NEC). It is unclear if preventing NEC by LR 17938 is mediated by Toll-like receptor 2 (TLR2), which is known to mediate proinflammatory responses to bacterial cell wall components. NEC was induced in newborn TLR2−/− or wild-type (WT) mice by the combination of gavage-feeding cow milk-based formula and exposure to hypoxia and cold stress. Treatment groups were administered formula supplemented with LR 17938 or placebo (deMan-Rogosa-Sharpe media). We observed that LR 17938 significantly reduced the incidence of NEC and reduced the percentage of activated effector CD4+T cells, while increasing Foxp3+ regulatory T cells in the intestinal mucosa of WT mice with NEC, but not in TLR2−/− mice. Dendritic cell (DC) activation by LR 17938 was mediated by TLR2. The percentage of tolerogenic DC in the intestine of WT mice was increased by LR 17938 treatment during NEC, a finding not observed in TLR2−/− mice. Furthermore, gut levels of proinflammatory cytokines IL-1β and IFN-γ were decreased after treatment with LR 17938 in WT mice but not in TLR2−/− mice. In conclusion, the combined in vivo and in vitro findings suggest that TLR2 receptors are involved in DC recognition and DC-priming of T cells to protect against NEC after oral administration of LR 17938. Our studies further clarify a major mechanism of probiotic LR 17938 action in preventing NEC by showing that neonatal immune modulation of LR 17938 is mediated by a mechanism requiring TLR2. NEW & NOTEWORTHY Lactobacillus reuteri DSM 17938 (LR 17938) has been shown to protect against necrotizing enterocolitis (NEC) in neonates and in neonatal animal models. The role of Toll-like receptor 2 (TLR2) as a sensor for gram-positive probiotics, activating downstream anti-inflammatory responses is unclear. Our current studies examined TLR2 −/− mice subjected to experimental NEC and demonstrated that the anti-inflammatory effects of LR 17938 are mediated via a mechanism requiring TLR2.
Impact of recurrent laryngeal nerve lesion on oropharyngeal muscle activity and sensorimotor integration in an infant pig model
Authors: DeLozier Katherine R. , Gould Francois D. H. , Ohlemacher Jocelyn , Thexton Allan J. , German Rebecca Z. 
Published: April 2018

The successful performance of a swallow requires dynamic integration between a wide range of sensory inputs and muscle activities to produce the coordinated kinematics of oropharyngeal structures. Damage to the recurrent laryngeal nerve (RLN) produces dysphagia in infants, with food or liquid entering the airway despite this nerve having minimal direct sensory or motor connections to the act of swallowing, apart from vocal fold closure. Previous results have demonstrated that a complete RLN lesion disrupts both performance and kinematics before initiation of the pharyngeal swallow in infants. We tested the hypothesis that a RLN lesion produces changes in the normal activity of oral floor, tongue, and infrahyoid muscles during a swallow. We recorded swallowing in our validated infant pig model, with synchronous high-speed imaging and fine-wire, chronic electromyography. We found changes in the timing, duration, and amplitude of the motor pattern in an array of muscles that are supplied by several different cranial and cervical nerves. Some of these changes in muscle activity are associated with the preparatory aspects of bolus aggregation or movement and so occur before the pharyngeal swallow. Taken with previous biomechanical results, these patterns suggest an intricate brain stem sensorimotor integration that occurs as part of a swallow. In particular, the execution of oral motor function is changed as a result of this simple lesion. NEW & NOTEWORTHY Damage to the recurrent laryngeal nerve compromises swallowing despite an absent or minimal contribution to either the motor or sensory aspects of this function. This study documents EMG changes, following RLN lesion, to non-RLN innervated muscles that are active during swallowing in an infant model. Some of these muscles fire before the pharyngeal swallow and are associated with the preparatory aspects of bolus aggregation and movement, suggesting important sensorimotor integration at a brain stem level.
BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti–PD-1 Antibody
Authors: Sanlorenzo Martina , Vujic Igor , Floris Arianna , Novelli Mauro , Gammaitoni Loretta , Giraudo Lidia , Macagno Marco , Leuci Valeria , Rotolo Ramona , Donini Chiara , Basiricò Marco , Quaglino Pietro , Fierro Maria Teresa , Giordano Silvia , Sibilia Maria , Carnevale-Schianca Fabrizio , Aglietta Massimo , Sangiolo Dario 
Published: April 2018

Abstract
Purpose: BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti–PD-1 antibody. A portion of melanoma cells may express PD-1, and anti–PD-1 antibody could have a direct antitumor effect. Here, we explore whether BRAF/MEKi modulate rates of PD-1+ melanoma cells, supporting an additional—lymphocyte-independent—basis for their therapeutic combination with anti–PD-1 antibody.
Experimental Design: With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, N = 61; validation cell lines, N = 7) and melanoma tumors (TCGA, N = 214). We explored in vitro how BRAF/MEKi affect rates of PD-1+, PD-L1/2+ melanoma cells, and characterized the proliferative and putative stemness features of PD-1+ melanoma cells. We tested the functional lymphocyte-independent effect of anti–PD-1 antibody alone and in combination with BRAF/MEKi in vitro and in an in vivo immunodeficient murine model.
Results: PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1+ cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), P = 0.0156; N = 7], together with PD-L2+ melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), P = 0.0312; N = 7]. PD-1+ cells proliferate less than PD-1− cells (avg. 65% less; t = 7 days) and are preferentially endowed with stemness features. In vivo, the direct anti-melanoma activity of PD-1 blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse.
Conclusions: BRAF/MEKi increase the rates of PD-1+ melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody. Clin Cancer Res; 24(14); 3377–85. ©2018 AACR.
Body Mass Index and Cardiovascular Risk Factors in Children and Adolescents with High Birth Weight
Authors: Ledo Daniel L. , Suano-Souza Fabíola Isabel , Franco Maria do Carmo P. , Strufaldi Maria Wany L. 
Published: April 2018

<b><i>Background/Aims:</i></b> This study aimed to identify a possible association among high birth weight with overweight/obesity, high arterial blood pressure, dyslipidemia, and insulin resistance in children and adolescents. <b><i>Methods:</i></b> This is a cross-sectional study with 719 children and adolescents (6–12 years) stratified according to birth weight (low birth weight [LBW] &#x3c;2,500 g, adequate birth weight [ABW] 2,500–3,999 g, and high birth weight [HBW] ≥4,000 g). Data collected were anthropometric data, arterial blood pressure levels, lipid profile, and insulin resistance (fasting glucose and insulin, used to calculate homeostatic model assessment-IR). <b><i>Results:</i></b> The mean age of schoolchildren was 9.5 ± 2.0 years and 371 (51.6%) were male. LBW and HBW were observed in 79 of 719 (10.9%) and 40 of 719 (55.6%) children/adolescents, respectively. There was no increased risk of overweight (OR 0.9; 95% CI 0.4–2.1; <i>p</i> = 0.964) and obesity (OR 1.4; 95% CI 0.6–3.5; <i>p</i> = 0.588) in HBW group compared to LBW and ABW groups. HBW was not associated with high blood pressure, dyslipidemia, and insulin resistance. The LBW group was independently associated with higher values of systolic (OR 1.07; 95% CI 1.05–1.10; <i>p</i> &#x3c; 0.01) and diastolic blood pressure (OR 1.04; 95% CI 1.00–1.07; <i>p</i> = 0.044). <b><i>Conclusion:</i></b> There was no association between HBW with overweight/obesity and classic cardiovascular risk factors in this group of children/adolescents. Only LBW was related to higher blood pressure levels.
MicroRNA-Mediated Therapy Modulating Blood–Brain Barrier Disruption Improves Vascular Cognitive Impairment
Authors: Toyama Kensuke , Spin Joshua M. , Deng Alicia C. , Huang Ting-Ting , Wei Ke , Wagenhäuser Markus U. , Yoshino Takuya , Nguyen Huy , Mulorz Joscha , Kundu Soumajit , Raaz Uwe , Adam Matti , Schellinger Isabel N. , Jagger Ann , Tsao Philip S. 
Published: April 2018

Objective—
There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood–brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood–brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment.

Approach and Results—
Using a mouse model of vascular cognitive impairment, chronic cerebral hypoperfusion within the white matter was induced with bilateral common carotid artery stenosis (BCAS) surgery. TNFα gene expression was increased in white matter post-BCAS surgery, and TNFα stimulation decreased claudin-5, ZO-1 (tight-junction protein 1), and occludin gene expression in murine brain endothelial cells. In silico analysis predicted 8 candidate microRNAs as regulators of claudin-5, ZO-1, and occludin gene expression. Of these, only miR-501-3p was upregulated by TNFα in vitro and was upregulated in the white matter after BCAS surgery. Further, miR-501-3p directly bound to the 3′-untranslated region of human ZO-1 and downregulated transendothelial electric resistance. In vivo administration of a locked nucleic acid –modified antisense oligonucleotide versus miR-501-3p suppressed BCAS-induced reduction of ZO-1 gene expression and blood–brain barrier disruption within the white matter and significantly ameliorated working memory deficits after BCAS surgery.

Conclusions—
We here provide the first evidence that the TNFα–miR-501-3p–ZO-1 axis plays an important role in the pathogenesis of cerebral hypoperfusion–induced working memory deficits and white matter lesions, as a result of blood–brain barrier breakdown via tight junction disruption. Therapeutic manipulation of miR-501-3p holds promise for limiting vascular cognitive impairment progression.
High-Mobility Group Box 1 From Hypoxic Trophoblasts Promotes Endothelial Microparticle Production and Thrombophilia in Preeclampsia
Authors: Hu Yae , Yan Ruhong , Zhang Ce , Zhou Zhichao , Liu Meng , Wang Can , Zhang Hong , Dong Liang , Zhou Tiantian , Wu Yi , Dong Ningzheng , Wu Qingyu 
Published: April 2018

Objective—
Thrombophilia is a major complication in preeclampsia, a disease associated with placental hypoxia and trophoblast inflammation. Preeclampsia women are known to have increased circulating microparticles that are procoagulant, but the underlying mechanisms remain unclear. In this study, we sought to understand the mechanism connecting placental hypoxia, circulating microparticles, and thrombophilia.

Approach and Results—
We analyzed protein markers on plasma microparticles from preeclampsia women and found that the increased circulating microparticles were mostly from endothelial cells. In proteomic studies, we identified HMGB1 (high-mobility group box 1), a proinflammatory protein, as a key factor from hypoxic trophoblasts in stimulating microparticle production in human umbilical vein endothelial cells. Immunodepletion or inhibition of HMGB1 in the conditioned medium from hypoxic human trophoblasts abolished the endothelial microparticle-stimulating activity. Conversely, recombinant HMGB1 stimulated microparticle production in cultured human umbilical vein endothelial cells. The microparticles from recombinant HMGB1–stimulated human umbilical vein endothelial cells promoted blood coagulation and neutrophil activation in vitro. Injection of recombinant HMGB1 in pregnant mice increased plasma endothelial microparticles and promoted blood coagulation. In preeclampsia women, elevated placental HMGB1 expression was detected and high levels of plasma HMGB1 correlated with increased plasma endothelial microparticles.

Conclusions—
Our results indicate that placental hypoxia-induced HMGB1 expression and release from trophoblasts are important mechanism underlying increased circulating endothelial microparticles and thrombophilia in preeclampsia.
Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association
Authors: Konstam Marvin A. , Kiernan Michael S. , Bernstein Daniel , Bozkurt Biykem , Jacob Miriam , Kapur Navin K. , Kociol Robb D. , Lewis Eldrin F. , Mehra Mandeep R. , Pagani Francis D. , Raval Amish N. , Ward Carey 
Published: April 2018

Background and Purpose:
The diverse causes of right-sided heart failure (RHF) include, among others, primary cardiomyopathies with right ventricular (RV) involvement, RV ischemia and infarction, volume loading caused by cardiac lesions associated with congenital heart disease and valvular pathologies, and pressure loading resulting from pulmonic stenosis or pulmonary hypertension from a variety of causes, including left-sided heart disease. Progressive RV dysfunction in these disease states is associated with increased morbidity and mortality. The purpose of this scientific statement is to provide guidance on the assessment and management of RHF.

Methods:
The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through September 2017. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or reference to contemporary clinical practice recommendations.

Results:
Chronic RHF is associated with decreased exercise tolerance, poor functional capacity, decreased cardiac output and progressive end-organ damage (caused by a combination of end-organ venous congestion and underperfusion), and cachexia resulting from poor absorption of nutrients, as well as a systemic proinflammatory state. It is the principal cause of death in patients with pulmonary arterial hypertension. Similarly, acute RHF is associated with hemodynamic instability and is the primary cause of death in patients presenting with massive pulmonary embolism, RV myocardial infarction, and postcardiotomy shock associated with cardiac surgery. Functional assessment of the right side of the heart can be hindered by its complex geometry. Multiple hemodynamic and biochemical markers are associated with worsening RHF and can serve to guide clinical assessment and therapeutic decision making. Pharmacological and mechanical interventions targeting isolated acute and chronic RHF have not been well investigated. Specific therapies promoting stabilization and recovery of RV function are lacking.

Conclusions:
RHF is a complex syndrome including diverse causes, pathways, and pathological processes. In this scientific statement, we review the causes and epidemiology of RV dysfunction and the pathophysiology of acute and chronic RHF and provide guidance for the management of the associated conditions leading to and caused by RHF.
Machine Learning Methods Improve Prognostication, Identify Clinically Distinct Phenotypes, and Detect Heterogeneity in Response to Therapy in a Large Cohort of Heart Failure Patients
Authors: Ahmad Tariq , Lund Lars H. , Rao Pooja , Ghosh Rohit , Warier Prashant , Vaccaro Benjamin , Dahlström Ulf , O'Connor Christopher M. , Felker G. Michael , Desai Nihar R. 
Published: April 2018

Background

Whereas heart failure (
HF
) is a complex clinical syndrome, conventional approaches to its management have treated it as a singular disease, leading to inadequate patient care and inefficient clinical trials. We hypothesized that applying advanced analytics to a large cohort of
HF
patients would improve prognostication of outcomes, identify distinct patient phenotypes, and detect heterogeneity in treatment response.

Methods and Results

The Swedish Heart Failure Registry is a nationwide registry collecting detailed demographic, clinical, laboratory, and medication data and linked to databases with outcome information. We applied random forest modeling to identify predictors of 1‐year survival. Cluster analysis was performed and validated using serial bootstrapping. Association between clusters and survival was assessed with Cox proportional hazards modeling and interaction testing was performed to assess for heterogeneity in response to
HF
pharmacotherapy across propensity‐matched clusters. Our study included 44 886
HF
patients enrolled in the Swedish Heart Failure Registry between 2000 and 2012. Random forest modeling demonstrated excellent calibration and discrimination for survival (C‐statistic=0.83) whereas left ventricular ejection fraction did not (C‐statistic=0.52): there were no meaningful differences per strata of left ventricular ejection fraction (1‐year survival: 80%, 81%, 83%, and 84%). Cluster analysis using the 8 highest predictive variables identified 4 clinically relevant subgroups of
HF
with marked differences in 1‐year survival. There were significant interactions between propensity‐matched clusters (across age, sex, and left ventricular ejection fraction and the following medications: diuretics, angiotensin‐converting enzyme inhibitors, β‐blockers, and nitrates,
P
<0.001, all).

Conclusions

Machine learning algorithms accurately predicted outcomes in a large data set of
HF
patients. Cluster analysis identified 4 distinct phenotypes that differed significantly in outcomes and in response to therapeutics. Use of these novel analytic approaches has the potential to enhance effectiveness of current therapies and transform future
HF
clinical trials.
American Heart Association's Life Simple 7 and Risk of Atrial Fibrillation in a Population Without Known Cardiovascular Disease: The ARIC (Atherosclerosis Risk in Communities) Study
Authors: Garg Parveen K. , O'Neal Wesley T. , Chen Lin Y. , Loehr Laura R. , Sotoodehnia Nona , Soliman Elsayed Z. , Alonso Alvaro 
Published: April 2018

Background

The American Heart Association has defined metrics of ideal cardiovascular health known as Life's Simple 7 (
LS
7) to prevent cardiovascular disease. We examined the association between
LS
7 and incident atrial fibrillation (
AF
) in a biracial cohort of middle‐ and older‐aged adults without known cardiovascular disease.

Methods and Results

This analysis included 13 182 ARIC (Atherosclerosis Risk in Communities) study participants (mean baseline age=54±5.7 years; 56% women; 25% black) free of
AF
and cardiovascular disease. An overall
LS
7 score was calculated as the sum of the
LS
7 component scores and classified as inadequate (0‐4), average (5‐9), or optimal (10‐14) cardiovascular health. The primary outcome was incident
AF
, identified primarily by ECG and hospital discharge coding of
AF
through December 31, 2014. A total of 2266 (17%) incident
AF
cases were detected over a median follow‐up of 25.1 years. Compared with the inadequate category (n=1057), participants in the average (n=8629) and optimal (n=3496) categories each had a lower risk of developing
AF
in a multivariable Cox proportional hazards model (hazard ratio 0.59, 95% confidence interval 0.51, 0.67 for average; and hazard ratio 0.38, 95% confidence interval 0.32, 0.44 for optimal). In a similar model, a 1‐point‐higher
LS
7 score was associated with a 12% lower risk of incident
AF
(hazard ratio 0.88, 95% confidence interval 0.86, 0.89).

Conclusions

A higher
LS
7 score is strongly associated with a lower risk of
AF
in individuals without baseline cardiovascular disease. Determining whether interventions that improve the population's cardiovascular health also reduce
AF
incidence is needed.
Reformation and Secularity
Authors: Goroncy Jason 
Published: April 2018

Abstract
Among a growing body of recent scholarship that has shown interest in the geneses, definitions, and assessments of secularism is Brad Gregory’s book The Unintended Reformation. This essay begins with a brief assessment of Gregory’s thesis. By way of response, it then offers four reflections on what are live challenges for those Christian communities committed to a refusal to withdraw from sharing and creating common life with others, and for whom the various reformations of the sixteenth century remain critical for the formation of their identities. The reflections concern (1) the character and conditions of belief; (2) the existence of the church in late Christendom; (3) the church’s worldliness; and (4) the character of faithful public life. Each of these themes has pressing implications for the ongoing life of the reformed project.
Tales of Darkness and Light
Authors: Tham Soso 
Published: April 2018

Soso Tham (1873–1940), the acknowledged poet laureate of the Khasis of northeastern India, was one of the first writers to give written poetic form to the rich oral tradition of his people.
Poet of landscape, myth and memory, Soso Tham paid rich and poignant tribute to his tribe in his masterpiece The Old Days of the Khasis. Janet Hujon’s vibrant new translation presents the English reader with Tham’s long poem, which keeps a rich cultural tradition of the Khasi people alive through its retelling of old narratives and acts as a cultural signpost for their literary identity.
This book is essential reading for anyone with an interest in Indian literature and culture and in the interplay between oral traditions and written literary forms.
This edition includes:
• Original text • English translation
• Critical apparatus • Embedded audio recordings of the original text