bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining Endotheliopathy in Murine Polytrauma Models
Authors: Wallen Taylor E. , Singer Kathleen E. , Elson Nora C. , Baucom Matthew R. , England Lisa G. , Schuster Rebecca M. , Pritts Timothy A. , Goodman Michael D. 
Published: June 2022

ABSTRACT

Introduction:
“Endotheliopathy of trauma” is recognized as endothelial dysfunction following traumatic injury leading to poor patient outcomes. Acute post-traumatic disruptions in endothelial cell function have been associated with profound physiologic, hemodynamic, and coagulation derangements. The goal of this study was to define the generation and extent of endotheliopathy in murine polytrauma models by evaluating the post-traumatic release of serum biomarkers of ongoing cellular injury.

Methods:
Mice were randomized to undergo moderately severe concussive TBI by weight drop, 60-min hemorrhagic shock to MAP 25 mmHg with subsequent resuscitation with Lactated Ringer's, submandibular bleed (SMB), and/or midline laparotomy with rectus muscle crush. Mice were sacrificed at 1, 4, or 24 h for serum biomarker evaluation.

Results:
Serum biomarkers revealed differential timing of elevation and injury-dependent release.
At 24 h, soluble thrombomodulin was significantly elevated in combined TBI + shock + lap crush compared to untouched, and shock alone. Syndecan-1 levels were significantly elevated after shock 1 to 24 h compared to untouched cohorts with a significant elevation in TBI + shock + lap crush 24 h after injury compared to shock alone. UCHL-1 was significantly elevated in shock mice at 1 to 24 h post-injury compared to untouched mice. UCHL-1 was also significantly elevated in the TBI + shock cohort 24 h after injury compared to shock alone. Hyaluronic acid release at 4 h was significantly elevated in shock alone compared to the untouched cohort with further elevations in TBI + shock + lap crush and TBI + shock compared to shock alone at 24 h. Hyaluronic acid was also increased in lap crush and laparotomy only cohort compared to untouched mice 24 h after injury.

Conclusions:
A murine model of polytrauma including TBI, hemorrhagic shock, and laparotomy abdominal crush is a reliable method for evaluation of endotheliopathy secondary to trauma as indicated by differential changes in serum biomarkers.
Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation
Authors: Lindell Robert B. , Zhang Donglan , Bush Jenny , Wallace Douglas C. , Rabinowitz Joshua D. , Lu Wenyun , Wherry E. John , Weiss Scott L. , Henrickson Sarah E. 
Published: June 2022

ABSTRACT

Background:
Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use.

Objective:
To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis.

Methods:
Serial peripheral blood mononuclear cell (PBMC) samples were obtained from 14 sepsis patients (34 total samples) and 7 control patients for this observational study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by tumor necrosis factor-α (TNF-α) production capacity and monocyte human leukocyte antigen DR (HLA-DR) expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type.

Results:
Sepsis patients were older (15.9 years vs. 10.4 years, P = 0.02) and had higher illness severity by PRISM-III (12.0 vs. 2.0, P < 0.001) compared to controls; demographics were otherwise similar, though control patients were predominately male. Compared to controls, sepsis patients at timepoint 1 demonstrated lower monocyte HLA-DR expression (75% vs. 92%, P = 0.02), loss of peripheral of non-naïve CD4+ T cells (62.4% vs. 77.6%, P = 0.04), and reduced PBMC mitochondrial spare residual capacity (SRC; 4.0 pmol/s/106 cells vs. 8.4 pmol/s/106 cells, P = 0.01). At sepsis onset, immunoparalysis (defined as TNF-α production capacity < 200 pg/mL) was present in 39% of sepsis patients and not identified among controls. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naïve CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen.

Conclusion:
Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.
Whole Blood Selective Aortic Arch Perfusion for Exsanguination Cardiac Arrest: Assessing Myocardial Tolerance to the Duration of Cardiac Arrest
Authors: Madurska Marta J. , Abdou Hossam , Elansary Noha N. , Edwards Joseph , Patel Neerav , Stonko David P. , Richmond Michael J. , Scalea Thomas M. , Rasmussen Todd E. , Morrison Jonathan J. 
Published: June 2022

ABSTRACT

Introduction:
Selective aortic arch perfusion (SAAP) is an endovascular technique that consists of aortic occlusion with perfusion of the coronary and cerebral circulation. It been shown to facilitate return of spontaneous circulation (ROSC) after exanguination cardiac arrest (ECA), but it is not known how long arrest may last before the myocardium can no longer be durably recovered. The aim of this study is to assess the myocardial tolerance to exsanguination cardiac arrest before successful ROSC with SAAP.

Methods:
Male adult swine (n = 24) were anesthetized, instrumented, and hemorrhaged to arrest. Animals were randomized into three groups: 5, 10, and 15 min of cardiac arrest before resuscitation with SAAP. Following ROSC, animals were observed for 60 min in a critical care environment. Primary outcomes were ROSC, and survival at 1-h post-ROSC.

Results:
Shorter cardiac arrest time was associated with higher ROSC rate and better 1-h survival. ROSC was obtained for 100% (8/8) of the 5-min ECA group, 75% (6/8) of the 10-min group, 43% (3/7) of the 15-min group (P = 0.04). One-hour post-ROSC survival was 75%, 50%, and 14% in 5-, 10-, and 15-min groups, respectively (P = 0.02). One-hour survivors in the 5-min group required less norepinephrine (1.31 mg ± 0.83 mg) compared with 10-SAAP (0.76 mg ± 0.24 mg), P = 0.008.

Conclusion:
Whole blood SAAP can accomplish ROSC at high rates even after 10 min of unsupported cardiac arrest secondary to hemorrhage, with some viability beyond to 15 min. This is promising as a tool for ECA, but requires additional optimization and clinical trials.
Animal Use Protocol, IACUC: 0919015.
Protective Effect of Cardiomyocyte-Specific Prolyl-4-Hydroxylase 2 Inhibition on Ischemic Injury in a Mouse MI Model
Authors: Pradeep Seetur R , Lim Sue Ting , Thirunavukkarasu Mahesh , Joshi Mandip , Cernuda Bryan , Palesty J Alexander , Maulik Nilanjana 
Published: June 2022

BACKGROUND:
Our earlier studies showed that inhibiting prolyl-4-hydroxylase enzymes (PHD-1 and PHD-3) improves angiogenesis, heart function, and limb perfusion in mouse models via stabilizing hypoxia-inducible transcription factor-alpha (HIF-1α). The present study explored the effects of the prolyl-4-hydroxylase enzyme, PHD-2, on ischemic heart failure using cardiac-specific PHD-2 gene knockout (KO) mice (PHD2−/−).

STUDY DESIGN:
Adult wild-type (WT) and PHD2−/− mice, 8–12 weeks old, were subjected to myocardial infarction (MI) by irreversibly ligating the left anterior descending (LAD) coronary artery. All sham group mice underwent surgery without LAD ligation. Animals were divided into 4 groups: (1) wild-type sham (WTS); (2) wild-type myocardial infarction (WTMI); (3) PHD2KO sham (PHD2−/−S); (4) PHD2KO myocardial infarction (PHD2−/−MI). Left ventricular tissue samples collected at various time points after surgery were used for microRNA expression profiling, Western blotting, and immunohistochemical analysis.

RESULTS:
Volcano plot analysis revealed 19 differentially-expressed miRNAs in the PHD2−/−MI group compared with the WTMI group. Target analysis using Ingenuity Pathway Analysis showed several differentially regulated miRNAs targeting key signaling pathways such as Akt, VEGF, Ang-1, PTEN, apoptosis, and hypoxia pathways. Western blot analysis showed increased HIF-1α, VEGF, phospho-AKT, β-catenin expression and reduced Bax expression for the PHD2−/−MI group compared with the WTMI group. Echocardiographic analysis showed preserved heart functions, and picrosirius red staining revealed decreased fibrosis in PHD2−/−MI compared with the WTMI group.

CONCLUSIONS:
PHD2 inhibition showed preserved heart function, enhanced angiogenic factor expression, and decreased apoptotic markers after MI. Overall, cardiac PHD2 gene inhibition is a promising candidate for managing cardiovascular diseases.
A resilience sensing system for the biosphere
Authors: Lenton Timothy M. , Buxton Joshua E. , Armstrong McKay David I. , Abrams Jesse F. , Boulton Chris A. , Lees Kirsten , Powell Thomas W. R. , Boers Niklas , Cunliffe Andrew M. , Dakos Vasilis 
Published: June 2022

We are in a climate and ecological emergency, where climate change and direct anthropogenic interference with the biosphere are risking abrupt and/or irreversible changes that threaten our life-support systems. Efforts are underway to increase the resilience of some ecosystems that are under threat, yet collective awareness and action are modest at best. Here, we highlight the potential for a biosphere resilience sensing system to make it easier to see where things are going wrong, and to see whether deliberate efforts to make things better are working. We focus on global resilience sensing of the terrestrial biosphere at high spatial and temporal resolution through satellite remote sensing, utilizing the generic mathematical behaviour of complex systems—loss of resilience corresponds to slower recovery from perturbations, gain of resilience equates to faster recovery. We consider what subset of biosphere resilience remote sensing can monitor, critically reviewing existing studies. Then we present illustrative, global results for vegetation resilience and trends in resilience over the last 20 years, from both satellite data and model simulations. We close by discussing how resilience sensing nested across global, biome-ecoregion, and local ecosystem scales could aid management and governance at these different scales, and identify priorities for further work.
This article is part of the theme issue ‘Ecological complexity and the biosphere: the next 30 years’.
Scaling up our understanding of tipping points
Authors: Kéfi Sonia , Saade Camille , Berlow Eric L. , Cabral Juliano S. , Fronhofer Emanuel A. 
Published: June 2022

Anthropogenic activities are increasingly affecting ecosystems across the globe. Meanwhile, empirical and theoretical evidence suggest that natural systems can exhibit abrupt collapses in response to incremental increases in the stressors, sometimes with dramatic ecological and economic consequences. These catastrophic shifts are faster and larger than expected from the changes in the stressors and happen once a tipping point is crossed. The primary mechanisms that drive ecosystem responses to perturbations lie in their architecture of relationships, i.e. how species interact with each other and with the physical environment and the spatial structure of the environment. Nonetheless, existing theoretical work on catastrophic shifts has so far largely focused on relatively simple systems that have either few species and/or no spatial structure. This work has laid a critical foundation for understanding how abrupt responses to incremental stressors are possible, but it remains difficult to predict (let alone manage) where or when they are most likely to occur in more complex real-world settings. Here, we discuss how scaling up our investigations of catastrophic shifts from simple to more complex—species rich and spatially structured—systems could contribute to expanding our understanding of how nature works and improve our ability to anticipate the effects of global change on ecological systems.This article is part of the theme issue ‘Ecological complexity and the biosphere: the next 30 years’.
Preclinical model for the study of immune responses specific for a hepatic self-antigen
Authors: Cardon Anaïs , Judor Jean-Paul , Guinebretière Thomas , Danger Richard , Nicot Arnaud , Brouard Sophie , Conchon Sophie , Renand Amédée 
Published: June 2022

AbstractThe liver displays a strong capacity to induce tolerance toward hepatic antigens. However, hepatic tolerance can be overcome with the development of local autoimmune diseases such as autoimmune hepatitis (AIH). This chronic inflammatory disorder leads to a progressive destruction of liver parenchyma if non-treated. Although the CD4+ T cell response seems a key player of this immune disorder, the dynamics and biology of emerging liver antigen-specific CD4+ T cells are poorly described. Here, we developed a new murine model which mimics hepatic autoreactivity allowing the study and monitoring of antigen-specific CD4+ T cells from their emergence to local immune response. We show that the induction of the expression of an antigen in the liver in non-inflammatory condition leads to antigen tolerance. In inflammatory condition, using viral vector transduction, we observe the development of a complete adaptive immune response concomitant with the antigen expression in the liver. The presence of antigen-specific CD4+ T cells in the liver is associated to transient hepatic damages. Interestingly, the neo-antigen expression by hepatocytes after peripheral immunisation induces the recruitment of antigen-specific CD4+ T cells and hepatic damages. These data demonstrate that the recruitment of antigen-specific CD4+ T cells in the liver is conditioned by an immune coordination between surface antigen expression by hepatocytes and peripheral immune response and mimics the first step of a local autoreactive process. In the long-term, we observe that the hepatic environment has the capacity to control the local, but not the systemic, antigen-specific CD4+ T cells. Additional immune events might be involved in the long-term chronic immune reactivity in the liver, following the first steps described in this study.Key pointsAntigen expression in the liver in non-inflammatory condition leads to antigen toleranceAntigen expression in the liver in immunization condition (concomitant or pre-existing) is sufficient to induce liver recruitment of antigen-specific CD4+ T cells and hepatic damagesThis model mimics the first step of an autoreactive process against a liver antigenIn the long-term, the hepatic environment induces a local tolerance toward the antigen expression and the clearance of liver-infiltrating, but not peripheral, antigen-specific CD4+ T cellsThis new murine model can be of interest for the analysis of the immunomodulatory pathways implicated in liver tolerization of autoreactive CD4+ T cells and identification of potential extrinsic factors implicated in an acute-to-chronic transition as observed during autoimmune hepatitis
Mass Enhanced Node Embeddings for Drug Repurposing
Authors: Chatzianastasis Michail , Nikolentzos Giannis , Vazirgiannis Michalis 
Published: June 2022

AbstractGraph representation learning has recently emerged as a promising approach to solve pharmacological tasks by modeling biological networks. Among the different tasks, drug repurposing, the task of identifying new uses for approved or investigational drugs, has attracted a lot of attention recently. In this work, we propose a node embedding algorithm for the problem of drug repurposing. The proposed algorithm learns node representations that capture the influence of nodes in the biological network by learning a mass term for each node along with its embedding. We apply the proposed algorithm to a multiscale interactome network and embed its nodes (i. e., proteins, drugs, diseases and biological functions) into a low-dimensional space. We evaluate the generated embeddings in the drug repurposing task. Our experiments show that the proposed approach outperforms the baselines and offers an improvement of 53.33% in average precision over typical walk-based embedding approaches.
Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype
Authors: Sung Jin Hee , Ou Yang , Barger Steven W. 
Published: June 2022

AbstractThe apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimer’s disease, wherein the ε4 allele confers a dramatically elevated risk compared to the more common ε3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murineApoegene has undergone targeted replacement with sequences encoding human ApoE3 or -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without Aβ accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42. In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry anAPOEε4 allele. The fact that ApoE4 generally failed to exacerbate the effects of Aβ on glucose further highlights the growing distinction between the glycemic effects of Aβ versus those of peripheral insulin resistance.
The ExtRA Capacity Test: Reliability and validity study of a new tool for assessing shoulder muscle performance
Authors: Ford Harry , Lewis Jeremy , Tyros Vasileios , Davare Marco , Low Daniel , Shaheen Aliah 
Published: June 2022

AbstractObjectivesThe primary objective was to evaluate the reliability of a new tool for assessing shoulder muscle performance: The ExtRA Capacity Test. The secondary objective was to assess whether this tool was a valid measure for assessing shoulder strength.MethodsThe ExtRA Capacity test involves two measures: maximal scapular plane lateral raises to 90° abduction with 2.5kg of external load and the maximal number of prone lying unsupported external rotations with the shoulder at 90° abduction. Both capacity tests are completed to a metronome set to 30 beats per minute 20 asymptomatic participants were sampled on 2 separate sessions, 1 week apart. The ExtRA Capacity Test was completed by the lead researcher and an independent physiotherapist. Shoulder strength was also measured using isokinetic dynamometry.ResultsThe test showed excellent inter-rater reliability (mean abduction ICC= 0.969, mean external rotation ICC= 0.822, with a 95% CI). Mean intra-rater variability was 3.96± 4.09 for the abduction measure and 1.70± 1.17 for the external rotation measure. Validity was calculated using Pearson correlation coefficient. The abduction measure showed good/ moderate correlation for the majority of strength measurements taken using isokinetic dynamometry however the external rotation capacity test did not correlate closely to isokinetic dynamometry strength measures.ConclusionThe abduction component of the ExtRA Capacity Test is a suitable measure for assessing shoulder strength in clinical practice. The external rotation measure is of suitable reliability however if used in clinical practice, it should not be used to assess shoulder strength, instead it may be suitable to assess movement control of the shoulder.SummaryVarious methods of measuring shoulder strength exist, ranging from cost free, relatively inaccurate methods to costly, complex methods which are of high reliability and validity but are challenging to use in a fast-pace, clinical environment. Objective outcome measures are used within a rehabilitation setting however at present there is no upper limb muscle performance test that is suitable to use on all people, regardless of strength or fitness level. Capacity testing of movements provides a functional, insight into strength specific to a real world/ sporting environment with lower limb capacity tests providing clear objective baselines that can be used for goal setting and providing return to play criteria following injury. This study proves the reliability and validity of the ExtRA Capacity Test which is a measure of shoulder muscle performance, suitable for people of all physical activity levels and upper limb strength.
The Optimal Combination of Scanning Speed and Fiber-to-Stone Distance for Effective and Efficient Dusting during Holmium: YAG Laser Lithotripsy
Authors: Chen Junqin , Li Daiwei , Yu Wenjun , Ma Zhiteng , Li Chenhang , Xiang Gaoming , Wu Yuan , Yao Junjie , Zhong Pei 
Published: June 2022

AbstractObjectivesTo investigate mechanistically the effects of fiber scanning speed (vfiber) and fiber tip-to-stone standoff distance (SD) on dusting efficiency during Holmium (Ho): YAG laser lithotripsy (LL)Materials and MethodsPre-soaked BegoStone samples (23 × 23 × 4 mm, W x L x H) were treated in water using a clinical Ho:YAG laser in dusting mode (0.2 J pulse energy delivered at 20 Hz frequency) at three different SDs (0.10, 0.25 and 0.50 mm) with vfiber in the range of 0 to 10 mm/s. Stone damage was quantified by optical coherence tomography, bubble dynamics were captured by high-speed imaging, and associated pressure transients were measured using a needle hydrophone. To compare photothermal ablation vs. cavitation in stone dusting, the experiments were further repeated in air (photothermal ablation only), and in water with the fiber tip advanced at a short (0.25 mm) offset distance (OSD) from a ureteroscope to mitigate the bubble collapse toward the stone surface, thus eliminating cavitation-induced damage.ResultsCompared to the craters produced by a stationary fiber, the damage troughs produced by a scanning fiber after 100 pulses were significantly larger in volume. The optimal vfiber for maximum dusting efficiency was found to be 3.5 mm/s for SD = 0.10 ∼ 0.25 mm, resulting in long (17.5 mm), shallow (0.14 – 0.15 mm) and narrow (0.3 – 0.4 mm) troughs. In contrast, the maximum stone damage was produced at an optimal vfiber of 0.5 mm/s for SD = 0.50 mm, which generates much shorter (2.5 mm), yet deeper (0.35 mm) and wider (1.4 mm) troughs. Greater stone damage was produced in water than in air, especially at vfiber = 0 – 3.5 mm/s. With the scope end placed near the fiber tip, stone damage could be significantly reduced in water by 29% - 58% for SD = 0.10 mm, by 51% - 82% for SD = 0.25 mm, and by 66% - 100 % for SD = 0.50 mm, compared to those produced without the scope. Together, these findings suggest that cavitation plays an indispensable role in stone dusting by scanning treatment. Moreover, under clinically relevant vfiber (1 ∼ 3 mm/s), dusting at SD = 0.5 mm (i.e., non-contact mode) may leverage higher frequency of the laser (e.g., 40 to 120 Hz) to harvest the full potential of cavitation damage while significantly reducing the procedure time, compared to its counterpart at SD = 0.1 mm (i.e., contact mode) that promotes photothermal ablation.ConclusionDusting efficiency during Ho:YAG LL may be substantially improved by utilizing the optimal combination of vfiber and SD for a given frequency.