bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational translation of drug effects from animal experiments to human ventricular myocytes
Authors: Tveito Aslak , Jæger Karoline Horgmo , Maleckar Mary M. , Giles Wayne R. , Wall Samuel 
Published: June 2020

AbstractUsing animal cells and tissues as precise measuring devices for developing new drugs presents a long-standing challenge for the pharmaceutical industry. Despite the very significant resources that continue to be dedicated to animal testing of new compounds, only qualitative results can be obtained. This often results in both false positives and false negatives. Here, we show how the effect of drugs applied to animal ventricular myocytes can be translated, quantitatively, to estimate a number of different effects of the same drug on human cardiomyocytes. We illustrate and validate our methodology by translating, from animal to human, the effect of dofetilide applied to dog cardiomyocytes, the effect of E-4031 applied to zebrafish cardiomyocytes, and, finally, the effect of sotalol applied to rabbit cardiomyocytes. In all cases, the accuracy of our quantitative estimates are demonstrated. Our computations reveal that, in principle, electrophysiological data from testing using animal ventricular myocytes, can give precise, quantitative estimates of the effect of new compounds on human cardiomyocytes.
Mucus layer modeling of human colonoids during infection with enteroaggragative E. coli
Authors: Liu Lixia , Saitz-Rojas Waleska , Smith Rachel , Gonyar Laura , In Julie G. , Kovbasnjuk Olga , Zachos Nicholas C. , Donowitz Mark , Nataro James P. , Ruiz-Perez Fernando 
Published: June 2020

AbstractEAEC is a common cause of diarrheal illness worldwide. Pathogenesis is believed to occur in the ileum and colon, where the bacteria adhere and form a robust aggregating biofilm. Among the multiple virulence factors produced by EAEC, the Pic serine protease has been implicated in bacterial colonization by virtue of its mucinolytic activity. Hence, a potential role of Pic in mucus barrier disruption during EAEC infection has been long postulated. In this study, we used human colonoids comprising goblet cells and a thick mucin barrier as an intestinal model to investigate Pic’s roles during infection with EAEC. We demonstrated the ability of purified Pic, but not a protease defective Pic mutant to degrade MUC2. Western blot and confocal microscopy analysis revealed degradation of the MUC2 layer in colonoids infected with EAEC, but not with its isogenic EAECpic mutant. Wild-type and MUC2-knockdown colonoids infected with EAEC strains exposed a differential biofilm distribution, greater penetration of the mucus layer and increased colonization of the colonic epithelium by Wild-type EAEC than its isogenic Pic mutant. Higher secretion of pro-inflammatory cytokines was seen in colonoids infected with EAEC than EAECpic. Although commensal E. coli expressing Pic degraded MUC2, it did not show improved mucus layer penetration or colonization of the colonic epithelium. Our study demonstrates a role of Pic in MUC2 barrier disruption in the human intestine and shows that colonoids are a reliable system to study the interaction of pathogens with the mucus layer.
Plasma metabolome and cognitive skills in Down syndrome
Authors: Antonaros Francesca , Ghini Veronica , Pulina Francesca , Ramacieri Giuseppe , Cicchini Elena , Mannini Elisa , Martelli Anna , Feliciello Agnese , Lanfranchi Silvia , Onnivello Sara , Vianello Renzo , Locatelli Chiara , Cocchi Guido , Pelleri Maria Chiara , Vitale Lorenza , Strippoli Pierluigi , Luchinat Claudio , Turano Paola , Piovesan Allison , Caracausi Maria 
Published: June 2020

AbstractTrisomy 21 (Down syndrome, DS) is the main human genetic cause of intellectual disability (ID). Lejeune hypothesized that DS could be considered a metabolic disease, and we found that subjects with DS have a specific plasma and urinary metabolomic profile. In this work we confirmed the alteration of mitochondrial metabolism in DS and also investigated if metabolite levels are related to cognitive aspects of DS. We analyzed the metabolomic profiles of plasma samples from 129 subjects with DS and 46 healthy control (CTRL) subjects by 1H Nuclear Magnetic Resonance (NMR). Multivariate analysis of the NMR metabolomic profiles showed a clear discrimination (up to 94% accuracy) between the two groups. The univariate analysis revealed a significant alteration in 7 metabolites out of 28 assigned unambiguously. Correlations among the metabolite levels in DS and CTRL groups were separately investigated and statistically significant relationships appeared. On the contrary, statistically significant correlations among the NMR-detectable part of DS plasma metabolome and the different intelligence quotient ranges obtained by Griffiths-III or WPPSI-III tests were not found. Even if metabolic imbalance provides a clear discrimination between DS and CTRL groups, it appears that the investigated metabolomic profiles cannot be associated with the degree of ID.
Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP+ in human SH-SY5Y neuroblastoma cells
Authors: Cai Yousheng , Shen Hui , Weng Huidan , Wang Yingqing , Cai Guoen , Chen Xiaochun , Ye Qinyong 
Published: June 2020

AbstractParkinson’s disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP+ treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP+ through LRPPRC signaling, thus maintain mitochondrial homeostasis.
Effect of donor age and 3D-cultivation on osteogenic differentiation capacity of adipose-derived mesenchymal stem cells
Authors: Payr Stephan , Schuseil Tim , Unger Marina , Seeliger Claudine , Tiefenboeck Thomas , Balmayor Elizabeth R. , van Griensven Martijn 
Published: June 2020

AbstractBackground and Purpose:Age and co-morbidities compromise healing tendencies of traumatic fractures in geriatric patients. Non-healing fractures may need regenerative medicine techniques involving autologous mesenchymal stem cells (MSCs). Donor age may affect the viability and differentiation capacity of MSCs. We investigated age-related differences in adipose-derived MSCs (AMSCs) concerning osteogenic potential in 2D and 3D cultivation.Materials and Methods:AMSCs were harvested from young (mean age: 37.5 ± 8.6 years) and old (mean age: 75.8 ± 9.2 years) patients. Cells were induced to osteogenic differentiation and cultivated in 2D and 3D for 14 days. Alkaline phosphatase (ALP) activity, mineralization and gene expression were investigated.Results:ALP activity revealed highest levels in 3D of old AMSCs after 14 days. ALP expression showed significant rises in old vs. young cells in 2D (p = 0.0024). Osteoprotegerin revealed the highest levels in old AMSCs in 2D. Highest osteocalcin levels presented in young cells compared to old cells in 2D (p = 0.0258) and young cells in 3D (p = 0.0014).Conclusion:3D arrangement of old AMSCs without growth factors is not ensuring superior osteogenesisin vitro. AMSCs, especially cells from older patients, reveal higher osteogenic potential in 2D than in 3D. 3D arrangement favors osteogenic potential of young cells.
Comparison between Surgical Outcomes of LASIK with and without Laser Asymmetric Keratectomy to Avoid Conventional Laser Refractive Surgery Adverse Effects
Authors: Min Ji Sang , Min Byung Moo 
Published: June 2020

AbstractThis study compared one-year postoperative outcomes of laser refractive surgery combined with laser asymmetric keratectomy (LAK) and laser in situ keratomileusis (LASIK)for myopia correction in middle-aged patients (aged 40–49 years) with a total corneal thickness deviation (summed across four directions) ≥ 80 microns. The control group (n = 26; 52 eyes) underwent LASIK; the comparison group (n = 26; 52 eyes) underwent combined laser refractive surgery and LAK. Age, spherical equivalence, uncorrected visual acuity (near and far), corneal irregularity on the Orbscan map, sum of corneal thickness deviations in four directions, corneal thickness distribution, distance between the maximum posterior elevation (best-fit sphere; BFS) and visual axis, and postoperative blurring scores were analysed retrospectively between the groups. Both groups had similar preoperative findings. Postoperatively, the sum of corneal thickness deviations in four directions (p = 0.000), distance between maximum posterior elevation (BFS) and visual axis (p = 0.003),blurring score (p = 0.001), and corneal irregularity in the 3.0 and 5.0 mm zones on the Orbscan map (p = 0.033 and p < 0.0001, respectively) were significantly lower in the comparison group (p = 0.000). LAK reduced total corneal thickness deviation, improved corneal symmetry, and reduced blurring scores significantly, one-year postoperatively. LAK could resolve shortcomings of LASIK, producing better surgical outcomes.
Glycogen as an advantageous polymer carrier in cancer theranostics: Straightforward in vivo evidence
Authors: Gálisová Andrea , Jirátová Markéta , Rabyk Mariia , Sticová Eva , Hájek Milan , Hrubý Martin , Jirák Daniel 
Published: June 2020

AbstractAs a natural polysaccharide polymer, glycogen possesses suitable properties for use as a nanoparticle carrier in cancer theranostics. Not only it is inherently biocompatible, it can also be easily chemically modified with various moieties. Synthetic glycogen conjugates can passively accumulate in tumours due to enhanced permeability of tumour vessels and limited lymphatic drainage (the EPR effect). For this study, we developed and examined a glycogen-based carrier containing a gadolinium chelate and near-infrared fluorescent dye. Our aim was to monitor biodistribution and accumulation in tumour-bearing rats using magnetic resonance and fluorescence imaging. Our data clearly show that these conjugates possess suitable imaging and tumour-targeting properties, and are safe under both in vitro and in vivo conditions. Additional modification of glycogen polymers with poly(2-alkyl-2-oxazolines) led to a reduction in the elimination rate and lower uptake in internal organs (lower whole-body background: 45% and 27% lower MRI signals of oxazoline-based conjugates in the liver and kidneys, respectively compared to the unmodified version). Our results highlight the potential of multimodal glycogen-based nanopolymers as a carrier for drug delivery systems in tumour diagnosis and treatment.
Ultrasensitive amplicon barcoding for next-generation sequencing facilitating sequence error and amplification-bias correction
Authors: Ahmed Ibrahim , Tucci Felicia A. , Aflalo Aure , Smith Kenneth G. C. , Bashford-Rogers Rachael J. M. 
Published: June 2020

AbstractThe ability to accurately characterize DNA variant proportions using PCR amplification is key to many genetic studies, including studying tumor heterogeneity, 16S microbiome, viral and immune receptor sequencing. We develop a novel generalizable ultrasensitive amplicon barcoding approach that significantly reduces the inflation/deflation of DNA variant proportions due to PCR amplification biases and sequencing errors. This method was applied to immune receptor sequencing, where it significantly improves the quality and estimation of diversity of the resulting library.
Gabapentin-induced drug-seeking-like behavior: a potential role for the dopaminergic system
Authors: Althobaiti Yusuf S. , Alghorabi Amal , Alshehri Fahad S. , Baothman Bandar , Almalki Atiah H. , Alsaab Hashem O. , Alsanie Walaa , Gaber Ahmed , Almalki Hussam , Alghamdi Abdulrahman S. , Basfer Ahmad , Althobaiti Sultan , Hardy Ana Maria Gregio , Shah Zahoor A. 
Published: June 2020

AbstractDrugs of abuse represent a growing public health crisis. Accumulating evidence indicates that gabapentin (GBP), a prescription drug, is prone to misuse, abuse, withdrawal, and dependence. Commonly, drugs of abuse modulate the dopaminergic system to induce addiction. In this study, we used the conditioned place preference (CPP) model to investigate the involvement of the dopamine 1 (D1) receptor on the reward and reinforcement behavior of GBP. Under a CPP paradigm, male BALB/c mice were intraperitoneally injected either saline or 100, 200, or 300 mg/kg of GBP and confined to the injection-paired chamber for 30 min. In the pre-conditioning phase, mice were conditioned for 3 days, and baseline data were collected. In the conditioning phase, mice were given once-daily alternating injections of either GBP or saline for 8 days and subsequently assessed in a post-conditioning test. Injections of 300 mg/kg of GBP significantly increased the time spent in the drug-paired chamber compared to the saline-paired chamber. However, lower doses of GBP (100 and 200 mg/kg) showed no effect. Pre-treatment with SKF-83566, a D1 receptor antagonist, attenuated GBP-induced CPP. Thus, for the first time, we show that GBP can induce CPP through a dopaminergic-dependent mechanism.
PEGylated lipid nanocarrier for enhancing photodynamic therapy of skin carcinoma using curcumin: in-vitro/in-vivo studies and histopathological examination
Authors: Abdel Fadeel Doaa A. , Kamel Rabab , Fadel Maha 
Published: June 2020

AbstractThe use of (PEG)-grafted materials has a positive impact on drug delivery. In this study we designed PEGylated lipid nanocarriers (PLN) loaded with curcumin (Cur) to target skin cancer by photodynamic therapy. Cur is a polyphenolic compound having vast biological effects masked due to its low aqueous solubility. PLN were prepared using Tefose 1500 with different surfactants. PLN3, containing Tween 80, had the smallest particle size (167.60 ± 15.12 nm), Z = − 26.91 mV and, attained the highest drug release (Q24 = 75.02 ± 4.61% and Q48 = 98.25 ± 6.89%). TEM showed spherical, well-separated nanoparticles. The dark and photo-cytotoxicity study on a human skin cancer cell line (A431) revealed that, at all tested concentrations, the viability of cells treated with PLN3 was significantly lower than those treated by Cur suspension and, it decreased upon irradiation by blue light (410 nm). The amount of Cur extracted from the skin of mice treated by PLN3 was twice that of mice treated by aqueous drug suspension, this was confirmed by the increase in fluorescence intensity measured by confocal laser microscopy. Histopathological studies showed that PLN3 could extend Cur effect to deeper skin layers, especially after irradiation. This study highlights the possible efficacy of curcumin-loaded PEGylated lipidic nanoparticles to combat skin cancer by photodynamic therapy.
Prevalence and incidence of visual impairment in patients with proliferative diabetic retinopathy in India
Authors: Khan Rehana , Chandra Shruti , Rajalakshmi Ramachandran , Rani Padmaja Kumari , Anantharaman Giridhar , Sen Alok , Desai Abhishek , Roy Rupak , Natarajan Sundaram , Chen Lanin , Chawla Gajendra , Behera Umesh Chandra , Gopal Lingam , Gurudas Sarega , Sivaprasad Sobha , Raman Rajiv 
Published: June 2020

AbstractTo provide the real-world outcomes of people with proliferative diabetic retinopathy (PDR) in India and highlight opportunities for improvement of their disease status and to evaluate their visual acuity (VA) status. A multicenter retrospective study in which ten centers in India with established vitreoretinal services for over 10 years were invited to provide long-term data on PDR. This study population were of Indian nationality. Patients with a diagnosis of type 1 or 2 diabetes with a clinical diagnosis of active PDR in any or both eyes, who had long term follow-up for up to 10 years were included. Baseline data collected included age, sex, duration of diabetes, source of referral and best-corrected visual acuity, diabetic retinopathy status in both eyes. Available follow-up data on VA were collected at 6 months post baseline, 5 years and 10 years within a ± 3 months window. Evaluating the presenting VA of people with PDR, short-term outcomes at 6 months and the incidence of visual impairment (VI) at 5 and 10 years are the main outcome of the study. Data was available for 516, 424 and 455 patients at baseline, 5 years and 10 years respectively. Gender and duration of diabetes did not have statistically significant effect on VI outcomes. Eyes receiving treatment early in the disease course (i.e. baseline VA ≥ 6/12) had significantly better VA outcomes at 10 years versus eyes treated at a later stage (i.e. baseline VA < 6/12) (p = <0.0001). On comparing eyes with stable treated PDR and persistent PDR at end of 10 year follow up, a significantly higher percentage of eyes in the stable treated group maintained VA of ≥ 6/12 (55.1% vs. 24.2%) (p = < 0.0001), indicating persistent disease activity due to inadequate treatment results in worse VA outcomes. We found no trend in VI or blindness with increasing levels of age at both 5- and 10-year time points (p > 0.05). The age standardized incidence for VI was 11.10% (95% CI 8.1, 14.2) and for blindness was found to be 7.7% (95% CI 5.2, 10.3). Our results suggest that despite robust recent clinical trial results showing that pan retinal photocoagulation is an excellent treatment for PDR, people with diabetes in India need to be made aware of annual screening and treatment of their eyes to avoid vision impairment and blindness.
The impact of climate change and glacier mass loss on the hydrology in the Mont-Blanc massif
Authors: Laurent Léa , Buoncristiani Jean-François , Pohl Benjamin , Zekollari Harry , Farinotti Daniel , Huss Matthias , Mugnier Jean-Louis , Pergaud Julien 
Published: June 2020

AbstractThe Mont-Blanc massif, being iconic with its large glaciers and peaks of over 4,000 m, will experience a sharp increase in summer temperatures during the twenty-first century. By 2100, the impact of climate change on the cryosphere and hydrosphere in the Alps is expected to lead to a decrease in annual river discharge. In this work, we modelled the twenty-first century evolution of runoff in the Arve river, downstream of Mont-Blanc’s French side. For the first time for this region, we have forced a hydrological model with output from an ice-dynamical glacier model and 16 downscaled climate projections, under RCP4.5 and RCP8.5 scenarios. By 2100, under RCP8.5 (high-emission scenario), the winter discharge of the Arve river remains low but is expected to increase by 80% when compared to the beginning of the century. By contrast, the summer season, currently the most important discharge period, will be marked by a runoff decrease of approximately 40%. These changes are almost similar according to a scenario with a lower warming (RCP4.5) and are mostly driven by glacier retreat. These shifts will have significant downstream impacts on water quantity and quality, affecting hydroelectric generation, agriculture, forestry, tourism and aquatic ecosystems.
Arthropod entombment in weathering-formed opal: new horizons for recording life in rocks
Authors: Chauviré Boris , Houadria Mickal , Donini Aline , Berger Brian T. , Rondeau Benjamin , Kritsky Gene , Lhuissier Pierre 
Published: June 2020

AbstractAnimal fossils preserved in various geological materials, such as limestone, claystone, or amber, provide detailed information on extinct species that is indispensable for retracing the evolution of terrestrial life. Here, we present the first record of an animal fossil preserved in opal formed by weathering with such high-resolution details that even individual cuticle hairs are observed. The fossil consists of the exoskeleton of a nymphal insect belonging to the order Hemiptera and either the family Tettigarctidae or the Cicadidae. This identification is based on anatomical details such as the tibial and femoral morphology of the forelegs. The exoskeleton of the insect was primarily zeolitized during the alteration of the host rocks and later sealed in opal deposited by silica-rich fluids derived from the continental weathering of the volcanic host rocks. Organic matter is preserved in the form of amorphous carbon. This finding makes opal formed by rocks weathering a new, complementary source of animal fossils, offering new prospects for the search for ancient life in the early history of Earth and possibly other terrestrial planets such as Mars, where weathering-formed opal occurs.
A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors
Authors: Hsu Kai-Cheng , HuangFu Wei-Chun , Lin Tony Eight , Chao Min-Wu , Sung Tzu-Ying , Chen Yi-Ying , Pan Shiow-Lin , Lee Jih-Chin , Tzou Shey-Cherng , Sun Chung-Ming , Yang Jinn-Moon 
Published: June 2020

AbstractThe immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC50 value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.
Three visual working memory representations simultaneously control attention
Authors: King Michael J. , Macnamara Brooke N. 
Published: June 2020

AbstractHow many items can we store in visual working memory while simultaneously conducting a visual search? Previous research has proposed that during concurrent visual search, only one visual working memory representation can be activated to directly influence attention. This previous research suggests that other visual working memory representations are “accessory items”, which have little direct influence on attention. However, recent findings provided evidence that not one, but two visual working memory representations can capture attention and interfere with concurrent visual search. We successfully replicate these findings, and further test whether the capacity of visual working memory during visual search extends to not two, but three representations that influence attention directly. We find evidence that three visual working memory representations can simultaneously control attention.