bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact monitoring of CFRP composites with acoustic emission and laser Doppler vibrometry
Authors: Grigg S , Almudaihesh F , Roberts M , Pullin R 
Published: January 2021

Abstract
The use of Acoustic Emission (AE) to detect impacts is of interest within industries where vital components are prone to impact damage, in particular where Carbon Fibre Reinforced Polymers (CFRP) are used, as damage can often go un-noticed within them. For AE monitoring of impacts piezoelectric sensors are used to detect the ultrasonic wave produced by an impact. Classification is also possible of these waves enabling a distinction between damaging and non-damaging impacts. These sensors do however have resonance, so do not give an accurate picture of how the waves propagate, better knowledge would enable better selection of sensors. Laser Doppler Vibrometry is a non-contact and non-resonant method of analysing the surface displacement on a structure. In this study, a vibrometer was used to monitor CFRP plates during impact to assess its applicability for distinguishing between damaging and non-damaging impacts, compared with a surface mounted AE sensor. The vibrometer was able to detect both low frequency flexural modes due to the impact process and the higher frequency extensional modes, initiated by damage. When compared to the AE sensor the vibrometer was comparable in its results, and unlike the sensor, not susceptible to resonance or decoupling. For the tested material the vibrometer identified frequencies greater than 20 kHz to be associated with damaging impacts.
Association of Longitudinal Changes in NT-proBNP With Changes in Left Atrial Volume and Function: MESA
Authors: Varadarajan Vinithra , Ambale-Venkatesh Bharath , Hong Seo Young , Habibi Mohammadali , Ashikaga Hiroshi , Wu Colin O , Chen Lin Y , Heckbert Susan R , Bluemke David A , Lima Joao A C 
Published: January 2021

Abstract

BACKGROUND
The mechanism of left atrial (LA) remodeling is poorly understood. The aim of this longitudinal study was to investigate whether changes in NT-proBNP levels relate to alterations of LA structure and function over time in a multiethnic population.

METHODS
From the prospective cohort study, the Multi-Ethnic Study of Atherosclerosis, our analysis included 1,838 participants who underwent cardiac magnetic resonance imaging at the baseline and 10-year examinations, had NT-proBNP levels available at both time points, and did not develop heart failure, myocardial infarction, and/or atrial fibrillation. Multivariable linear regression was used to analyze the association between NT-proBNP level (log-transformed) at the 2 time points and change in LA volumes, LA emptying fractions (total, active, and passive), and LA longitudinal strain. Log NT-proBNP was categorized into Low-Low (N = 681), Low-High (N = 238), High-Low (N = 237), and High-High (N = 682) based on the median value at both time points.

RESULTS
With the Low-Low group as the reference group, the High-High group experienced a greater increase in LA maximum and minimum indexed volumes: 3.1 ml/m2 (95% confidence interval 1.98, 4.20) and 2.7 ml/m2 (1.89, 3.51), respectively. The High-High group also experienced a greater decrease in LA total, passive, active emptying fraction, and longitudinal strain: −3.3% (−4.46, −2.11), −0.9% (−1.80, −0.02), −4.2% (−5.55, −2.76), and −2.3% (−3.80, −0.72), respectively. The Low-High group had similar associations, but the effect sizes were not as high.

CONCLUSIONS
Adverse LA remodeling over 10 years of follow-up strongly correlates with prolonged elevated levels of intracardiac stress, as assessed by NT-proBNP levels.
Genome-resolved metagenomics using environmental and clinical samples
Authors: Kayani Masood ur Rehman , Huang Wanqiu , Feng Ru , Chen Lei 
Published: January 2021

AbstractRecent advances in high-throughput sequencing technologies and computational methods have added a new dimension to metagenomic data analysis i.e. genome-resolved metagenomics. In general terms, it refers to the recovery of draft or high-quality microbial genomes and their taxonomic classification and functional annotation. In recent years, several studies have utilized the genome-resolved metagenome analysis approach and identified previously unknown microbial species from human and environmental metagenomes. In this review, we describe genome-resolved metagenome analysis as a series of four necessary steps: (i) preprocessing of the sequencing reads, (ii) de novo metagenome assembly, (iii) genome binning and (iv) taxonomic and functional analysis of the recovered genomes. For each of these four steps, we discuss the most commonly used tools and the currently available pipelines to guide the scientific community in the recovery and subsequent analyses of genomes from any metagenome sample. Furthermore, we also discuss the tools required for validation of assembly quality as well as for improving quality of the recovered genomes. We also highlight the currently available pipelines that can be used to automate the whole analysis without having advanced bioinformatics knowledge. Finally, we will highlight the most widely adapted and actively maintained tools and pipelines that can be helpful to the scientific community in decision making before they commence the analysis.
Large-scale model selection in misspecified generalized linear models
Authors: Demirkaya Emre , Feng Yang , Basu Pallavi , Lv Jinchi 
Published: January 2021

SummaryModel selection is crucial both to high-dimensional learning and to inference for contemporary big data applications in pinpointing the best set of covariates among a sequence of candidate interpretable models. Most existing work implicitly assumes that the models are correctly specified or have fixed dimensionality, yet both model misspecification and high dimensionality are prevalent in practice. In this paper, we exploit the framework of model selection principles under the misspecified generalized linear models presented in Lv & Liu (2014), and investigate the asymptotic expansion of the posterior model probability in the setting of high-dimensional misspecified models. With a natural choice of prior probabilities that encourages interpretability and incorporates the Kullback–Leibler divergence, we suggest using the high-dimensional generalized Bayesian information criterion with prior probability for large-scale model selection with misspecification. Our new information criterion characterizes the impacts of both model misspecification and high dimensionality on model selection. We further establish the consistency of covariance contrast matrix estimation and the model selection consistency of the new information criterion in ultrahigh dimensions under some mild regularity conditions. Our numerical studies demonstrate that the proposed method enjoys improved model selection consistency over its main competitors.
Mir21 modulates inflammation and sensorimotor deficits in cervical myelopathy: data from humans and animal models
Authors: Laliberte Alex M , Karadimas Spyridon K , Vidal Pia M , Satkunendrarajah Kajana , Fehlings Michael G 
Published: January 2021

Abstract
Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the sub-acute and chronic neuroinflammatory environment after spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male:33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, Von Frey filament and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by ∼50% relative to wild-type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased after exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory) and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication.
Daily Consumption of a Specially Formulated Essential Amino Acid-Based Dietary Supplement Improves Physical Performance in Older Adults With Low Physical Functioning
Authors: Azhar Gohar , Wei Jeanne Y , Schutzler Scott E , Coker Karen , Gibson Regina V , Kirby Mitchell F , Ferrando Arny A , Wolfe Robert R 
Published: January 2021

Abstract
We have investigated the hypothesis that nutritional supplementation of the diet in low-physical-functioning older individuals with a specially formulated composition based on essential amino acids (EAAs) would improve physical function as compared to supplementation with the same amount of whey protein. A third group of comparable volunteers were given nutrition education but no supplementation of the diet. After 6 weeks of whey protein supplementation (n = 32), there was no effect on the distance walked in 6 minutes, but the distance walked improved significantly from the pre-value after 12 weeks of whey supplementation. EAA consumption (n = 28) significantly improved walking distance at both 6 and 12 weeks. The distance walked at 12 weeks (419.0 ± 25.0 m) was 35.4 m greater than the pre-value of 384.0 ± 23.0 m (p &lt; .001). The increase in distance walked by the EAA group was also significantly greater than that in the whey group at both 6 and 12 weeks (p &lt; .01). In contrast, a decrease in distance walked was observed in the control group (n = 32) (not statistically significant, NS). EAA supplementation also improved grip strength and leg strength, and decreased body weight and fat mass. Plasma low-density lipoprotein concentration was significantly reduced in the EAA group, as well as the concentration of macrophage migration inhibitory factor. There were no adverse responses in any groups, and compliance was greater than 95% in all individuals consuming supplements. We conclude that dietary supplementation with an EAA-based composition may be a beneficial therapy in older individuals with low physical functional capacity.
Clinical Trials Registration Number: This study was registered with ClinicalTrials.gov: NCT 03424265—“Nutritional interventions in heart failure.”
DIETARY FIBER GUAR GUM EXACERBATES COLONIC INFLAMMATION IN MULTIPLE EXPERIMENTAL MODELS OF INFLAMMATORY BOWEL DISEASE
Authors: Nair Divek V T , Paudel Devendra , Cantorna Margherita , Singh Vishal 
Published: January 2021

Abstract
The role of fermentable dietary fibers in patients with inflammatory bowel disease (IBD) is not understood. Herein, we elucidated the effect of dietary fiber guar gum, commonly added to a wide range of processed foods, on colonic inflammation. The use of three different IBD models allowed us to examine the effect of guar gum on various aspects of human IBD, such as immune hyperactivity [IL-10 receptor (IL-10R) neutralization], epithelial injury [dextran sulfate sodium (DSS)], and infection [Citrobacter rodentium (CR)]-mediated inflammation.
Wild-type (WT, C57BL/6) mice fed either control cellulose (insoluble fiber, aka non-fermentable fiber) or guar gum (soluble fiber, aka fermentable fiber, 7.5% w/w) were administered four weekly injections of IL-10R neutralizing antibody (α-IL-10R) to induce immune-hyperactivation mediated chronic colitis. Guar gum treated mice developed robust α-IL-10R mediated colitis. Guar gum fed mice had splenomegaly, colomegaly, elevated systemic proinflammatory markers [serum amyloid A (SAA), lipocalin 2 (Lcn2) and keratinocyte-derived chemokine (KC)] and elevated colonic Lcn2 and interleukin (IL)-1β, and histopathology scores compared to control, cellulose-fed, mice. Similar results were observed in Toll-like receptor 5 deficient mice, which are prone to develop microbiota-dependent colitis. Next, to examine the effect of guar gum on the epithelial injury model, mice were treated with DSS (1.4% w/v in drinking water) for seven days. The guar gum fed group developed severe colitis, including reduced body weight, diarrhea, rectal bleeding, shortening of colon length, and elevated levels of pro-inflammatory markers (Lcn2, KC, and SAA)compared to the control group. The last model to be tested was infection-induced colitis. Since inflammation is required to clear the infection, we hypothesized that guar gum fed mice might clear CR infection better than controls. To our surprise, guar gum fed WT mice shed higher numbers of CR in the feces than the cellulose group. The guar gum fed mice had lower body weights, colomegaly, an elevated level of colonic and serum Lcn2, and higher serum SAA than the control group. Collectively, guar gum failed to protect against CR-induced colonic pathology. Altogether, the work demonstrates that guar gum feeding may exacerbate colonic inflammation following immune-hyperactivation, chemical, and infectious injury. Cautioning IBD patients to monitor their consumption of guar gum fiber might be a way to reduce the severity of intestinal inflammation.
NANOPARTICLE-ENCAPSULATED BROMODOMAIN-CONTAINING PROTEIN 4 INHIBITORS FOR THERAPEUTICS OF INFLAMMATORY BOWEL DISEASE
Authors: Shah Mansi , Li Yi , Pingyuan Wang , Chen Haiying , Liu Zhiqing , Cong Yingzi , Pinchuk Irina , Rytting Erik , Zhou Jia , Tian Bing 
Published: January 2021

Abstract
Ulcerative Colitis (UC) and Crohn’s disease (CD), the two major types of inflammatory bowel disease (IBD), are chronic diseases with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is among the major factors contributing to neoplastic transformation and the development of colitis-associated colorectal cancer. There exists a lack of efficient medications for IBD, primarily due to either limited efficacy or side effects. Targeting bromodomain-containing protein 4 (BRD4) represents a novel therapeutic strategy for IBD. Recently, we have successfully identified proprietary, highly potent, and specific BRD4 inhibitors which significantly suppressed the initiation of mucosal inflammation and chronicity in proof-of-concept studies in several animal models of IBD.
One of the most pressing challenges in current IBD research is to develop technologies to enable mucosal targeted drug delivery systems that enhance efficacy and decrease side effects. Intriguingly, we found that local delivery of our first-generation BRD4 inhibitors encapsulated in nanoparticles can achieve significantly higher in vivo efficacy at much lower doses than that attained by systemic administration. Local delivery of nanoparticle-encapsulated BRD4 inhibitors by designing nanoparticles that bind to inflamed epithelium would offer superior pharmacotherapy for IBD with higher efficacy, specific delivery, long-lasting release, and a better therapeutic and safety window. We have successfully encapsulated our BRD4 inhibitors in biodegradable nanoparticles with excellent encapsulation efficiency and favorable particle size. Our new generation of BRD4 inhibitors ZL0513, ZL0742, and ZL0591 were encapsulated by a modified solvent displacement method using a polymeric matrix of PEGylated poly (lactic-co-glycolic acid) (PLGA). To evaluate their potential cytotoxic effects, we incubated human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with PEGylated-PLGA-ZL0513, ZL0591, and ZL0742 overnight. No apparent increase in cell death was detected in HCECs or PBMCs even at 40 μM. Furthermore, oral administration of our nano-encapsulated BRD4 inhibitors at the dosage of 2 mg/kg effectively block colonic inflammation in both IBD animal models of dextran sulfate sodium (DSS)-induced colitis and oxazolone (OXA)-induced colitis.
Collectively, our compelling in vivo efficacy data support that our nano-encapsulated BRD4 inhibitors effectively block colonic inflammation in animal models of IBD. Local delivery of nanoparticle-encapsulated BRD4 inhibitors may offer superior pharmacotherapy for IBD patients.
Funding support: Crohn’s & Colitis Foundation Entrepreneurial Investing (EI) Initiative award and Litwin IBD Pioneers Program award from the Crohn’s & Colitis Foundation of America.
THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE
Authors: Chami Belal , Ahmad Gulfam , Schroder Angie , Gabriel Patrick San , Witting Paul 
Published: January 2021

Abstract
Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury.
We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut.
Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.
TOXICOLOGICAL FINDINGS OF A RECOMBINANT CHOLERA TOXIN B SUBUNIT VARIANT WITH THERAPEUTIC POTENTIAL IN ULCERATIVE COLITIS
Authors: Reeves Micaela , Tuse Daniel , Hamorsky Krystal , Royal Joshua , Matoba Nobuyuki 
Published: January 2021

Abstract

Background
The cholera toxin B subunit (CTB) is the nontoxic and homopentameric component of the holotoxin. Upon binding to GM1 ganglioside on the surface of epithelial cells, CTB mediates entry and retrograde transport through the endomembrane system and disengages the catalytic A subunit in the endoplasmic reticulum (ER). EPICERTIN (EPT) is a recombinant variant of CTB with a non-native C-terminal extension harboring an ER-retention motif, KDEL. We have found that increased ER-retention time resulting from this modification allowed EPT to induce an unfolded protein response and TGF-β signaling in colon epithelial cells, triggering wound healing activity in preclinical colitis models. The unique epithelial repair activity of EPT hints at its therapeutic potential in ulcerative colitis.

Objective
We aim to develop data supporting a first-in-human clinical trial with an EPT enema indicated for ulcerative colitis. Here, we evaluated the efficacy and toxicity of intrarectal (IR) administration of EPT in preclinical rodent models.

Results
IR administration of EPT at 0.1 and 1 µM to female C57/BL6 mice (0.6 and 6.1 μg/animal) with acute dextran sodium sulfate (DSS)-induced colitis resulted in decreased disease activity index scores and increased body weight recovery, supporting a target therapeutic dose of ≤1 µM for clinical administration. A dose-escalation study was performed following a single IR exposure at 1, 2 and 5 µM (61.4, 122.8 and 307 μg/animal) in male and female Sprague Dawley rats. No drug-related adverse effects were evident in clinical observations, including clinical pathology and gross necropsy, even at the highest dose tested. A pharmacokinetics study was performed in male and female mice dosed with a 1 or 10 µM (6.1 and 61.4 μg/animal) IV bolus of EPT. Plasma samples were collected periodically for up to 24 h postdose. EPT concentrations were highest at first collection and decreased steadily until unquantifiable by 4 h. The elimination phase half-life was 0.26 to 0.3 h. When healthy and DSS-induced colitic mice (n = 72) were dosed with 1 or 10 µM EPT IR, marginal amounts of EPT were found in only 4 plasma samples scattered across groups and time points, suggesting that systemic exposure after IR administration is negligible.

Conclusion
These data support further development of EPT as a potential therapeutic for ulcerative colitis.