bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cetuximab produced from a goat mammary gland expression system is equally efficacious as innovator cetuximab in model systems of cancer
Authors: Wang Qian , Gavin William , Masiello Nick , Tran Khanh B. , Laible Götz , Shepherd Peter R 
Published: June 2020

AbstractHumanised monoclonal antibodies have proven a very effective mode of therapy for a wide range of conditions. With many of the monoclonal antibody drugs now coming off patent there is an increasing interest in developing biosimilar, or even biobetter, forms of these drugs. With the commercial competition associated with such generic products there is increasing demand for improved production and purification system for biosimilars. Cetuximab, also known as ‘Erbitux’, is widely used in cancer therapy, especially in advanced colorecal cancer, metastatic non-small cell lung cancer and head and neck cancer and it will come off patent in the near future. We have previously reported on a genetically engineered goat system to produce cetuximab (gCetuximab) in milk. Herein we now report on the further charactization of the gCetuximab produced utilizing additional and more sophisticated biological assays. There is similar bioactivity of the gCetuximab compared with the commercial product produced in mammalian cell culture. In particular both cetuximab antibodies selectively target EGFR and induce its internalization to down regulate EGFR signaling. Both forms have very similar half life in animals and in a HT29 colorectal cancer xenograft model have similar efficacy. We also show that the toxin MMAE can be conjugated to gCetuximab, that this targets it to cells and that this results in direct cell killing in HT29 cells. This demonstrates that the gCetuximab will also be a viable vehicle for antibody drug conjugate based therapies. Taken together, this shows that the goat milk monoclonal antibody production system is an effective way of producing a biosimilar form of cetuximab.
Three-photon imaging of synthetic dyes in deep layers of the neocortex
Authors: Liu Chao J. , Roy Arani , Simons Anthony A. , Farinella Deano M. , Kara Prakash 
Published: June 2020

AbstractMultiphoton microscopy has emerged as the primary imaging tool for studying the structural and functional dynamics of neural circuits in brain tissue, which is highly scattering to light. Recently, three-photon microscopy has enabled high-resolution fluorescence imaging of neurons in deeper brain areas that lie beyond the reach of conventional two-photon microscopy, which is typically limited to ~450 μm. Three-photon imaging of neuronal calcium signals, through the genetically-encoded calcium indicator GCaMP6, has been used to successfully record neuronal activity in deeper neocortical layers and parts of the hippocampus. Bulk-loading cells in deeper cortical layers with synthetic calcium indicators could provide an alternative strategy for labelling that obviates dependence on viral tropism and promoter penetration. Here we report a strategy for visualized injection of a calcium dye, Oregon Green BAPTA-1 AM (OGB-1 AM), at 500–600 μm below the surface of the mouse visual cortex in vivo. We demonstrate successful OGB-1 AM loading of cells in cortical layers 5–6 and subsequent three-photon imaging of orientation- and direction-selective visual responses from these cells.
Multiple spatial behaviours govern social network positions in a wild ungulate
Authors: Albery Gregory F , Morris Alison , Morris Sean , Pemberton Josephine M , Clutton-Brock Tim H. , Nussey Daniel H , Firth Josh A 
Published: June 2020

AbstractThe structure of wild animal social systems depends on a complex combination of intrinsic and extrinsic drivers. Population structuring and spatial behaviour are key determinants of individuals’ observed social behaviour, but quantifying these spatial components alongside multiple other drivers remains difficult due to data scarcity and analytical complexity. We used a 43-year dataset detailing a wild red deer population to investigate how individuals’ spatial behaviours drive social network positioning, while simultaneously assessing other potential contributing factors. Using Integrated Nested Laplace Approximation (INLA) multi-matrix animal models, we demonstrate that social network positions are shaped by two-dimensional landscape locations, pairwise space sharing, individual range size, and spatial and temporal variation in population density, alongside smaller but detectable impacts of a selection of individual-level phenotypic traits. These results indicate strong, multifaceted spatiotemporal structuring in this society, emphasising the importance of considering multiple spatial components when investigating the causes and consequences of sociality.Authorship StatementGFA conceived the study, analysed the data, and wrote the manuscript, advised by JAF. AM and SM collected the data. JAF, JMP, THCB, and DN commented on the manuscript.Data Accessibility StatementThe code used here is available athttps://github.com/gfalbery/Spocial_Deer. On acceptance, the data will be uploaded to the same repo, which will be archived on Zenodo.
A robust two-sample Mendelian Randomization method integrating GWAS with multi-tissue eQTL summary statistics
Authors: Gleason Kevin J. , Yang Fan , Chen Lin S. 
Published: June 2020

AbstractIn the post-genome-wide association era, two-sample Mendelian Randomization (MR) methods have been applied to detect genetically-regulated risk factors for complex diseases. Two-sample MR considers single nucleotide polymorphisms (SNPs) associated with a putative exposure as instrumental variables (IVs) to assess the effect of the exposure on an outcome by leveraging two sets of summary statistics: IV-to-exposure and IV-to-outcome statistics from existing GWASs. Traditional MR methods impose strong assumptions on the validity of IVs, and recent literature has relaxed the assumptions allowing some IVs to be invalid but generally requiring a large number of nearly independent IVs. When treating expression-quantitative-trait-loci (eQTLs) as IVs to detect gene expression levels affecting diseases, existing methods are limited in applicability since the numbers of independent eQTLs for most genes in the genome are limited. To address those challenges, we propose a robust two-sample MR framework that requires fewer IVs and allows moderate IV correlations and some IVs to be invalid. This is achieved by leveraging existing multi-tissue eQTL summary statistics (multiple sets of IV-to-exposure statistics) and GWAS statistics in a mixed model framework. We conducted simulation studies to evaluate the performance of the proposed method and apply it to detect putative causal genes for schizophrenia.
Computational assessment of transport distances in living skeletal muscle fibers studied in situ
Authors: Hansson Kenth-Arne , Solbrå Andreas Våvang , Gundersen Kristian , Bruusgaard Jo Christiansen 
Published: June 2020

AbstractTransport distances in skeletal muscle fibers are mitigated by these cells having multiple nuclei. We have studied mouse living slow (soleus) and fast (extensor digitorum longus) muscle fibers in situ and determined cellular dimensions and the positions of all the nuclei within fiber segments. We modelled the effect of placing nuclei optimally and randomly using the nuclei as the origin of a transportation network. It appeared that an equidistant positioning of nuclei minimizes transport distances along the surface for both muscles. In the soleus muscle however, which were richer in nuclei, positioning of nuclei to reduce transport distances to the cytoplasm were of less importance, and these fibers exhibit a pattern not statistically different from a random positioning of nuclei. Together, these results highlight the importance of spatially distribute nuclei to minimize transport distances to the surface when nuclear density is low, while it appears that the distribution are of less importance at higher nuclear densities.
Design of a Novel Multiplex Real Time RT-PCR Assay for SARS-CoV-2 Detection
Authors: Zhen Wei , Berry Gregory J. 
Published: June 2020

AbstractCoronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 386,000 deaths globally as of June 4, 2020. In this study, we developed a novel multiplex real time reverse transcription (RT)-PCR test for detection of SARS-CoV-2, with primers designed to amplify a 108 bp target on the spike surface glycoprotein (S gene) of SARS-CoV-2 and a hydrolysis Taqman probe designed to specifically detect SARS-CoV-2. Following our design, we evaluated the Limit of detection (LOD) and clinical performance of this laboratory-developed test (LDT). A LOD study with inactivated whole virus exhibited equal performance to that seen in the modified CDC assay with a final LOD of 1,301 ± 13 genome equivalents/ml for our assay vs 1,249 ± 14 genome equivalents/ml for the modified CDC assay. In addition, a clinical evaluation with 270 nasopharyngeal (NP) swab specimens exhibited 98.5% positive percent agreement and 99.3% negative percent agreement with the modified CDC assay. The multiplex design of this assay allows the testing of 91 patients per plate, versus a maximum of 29 patients per plate on the modified CDC assay, providing the benefit of testing significantly more patients per run and saving reagents during a time when both of these parameters have been critical. Our results demonstrate that our multiplex assay performs as well as the modified CDC assay, but is more efficient and cost effective and is therefore adequate for use as a diagnostic assay and for epidemiological surveillance and clinical management of SARS-CoV-2.
The unconventional cytoplasmic sensing mechanism for ethanol chemotaxis inBacillus subtilis
Authors: Tohidifar Payman , Bodhankar Girija A. , Pei Sichong , Cassidy C. Keith , Walukiewicz Hanna E. , Ordal George W. , Stansfeld Phillip J. , Rao Christopher V. 
Published: June 2020

AbstractMotile bacteria sense chemical gradients using chemoreceptors, which consist of distinct sensing and signaling domains. The general model is that the sensing domain binds the chemical and the signaling domain induces the tactic response. Here, we investigated the unconventional sensing mechanism for ethanol taxis inBacillus subtilis. Ethanol and other short-chain alcohols are attractants forB. subtilis. Two chemoreceptors, McpB and HemAT, sense these alcohols. In the case of McpB, the signaling domain directly binds ethanol. We were further able to identify a single amino-acid residue Ala431on the cytoplasmic signaling domain of McpB, that when mutated to a serine, reduces taxis to ethanol. Molecular dynamics simulations suggest ethanol binds McpB near residue Ala431and mutation of this residue to serine increases coiled-coil packing within the signaling domain, thereby reducing the ability of ethanol to bind between the helices of the signaling domain. In the case of HemAT, the myoglobin-like sensing domain binds ethanol, likely between the helices encapsulating the heme group. Aside from being sensed by an unconventional mechanism, ethanol also differs from many other chemoattractants because it is not metabolized byB. subtilisand is toxic. We propose thatB. subtilisuses ethanol and other short-chain alcohols to locate prey, namely alcohol-producing microorganisms.ImportanceEthanol is a chemoattractant forBacillus subtiliseven though it is not metabolized and inhibits growth.B. subtilislikely uses ethanol to find ethanol-fermenting microorganisms for prey. Two chemoreceptors sense ethanol: HemAT and McpB. HemAT’s myoglobin-like sensing domain directly binds ethanol, but the heme group is not involved. McpB is a transmembrane receptor consisting of an extracellular sensing domain and a cytoplasmic signaling domain. While most attractants bind the extracellular sensing domain, we found that ethanol directly binds between inter-monomer helices of the cytoplasmic signaling domain of McpB, using a mechanism akin to those identified in many mammalian ethanol-binding proteins. Our results indicate that the sensory repertoire of chemoreceptors extends beyond the sensing domain and can directly involve the signaling domain.
Recombinant Expression of Metal-Binding Proteins (Bacterioferritin, MBP, Metallothionein, and OprF) and Pesticide-Binding Proteins (LC-Cutinase and OpdA) in Escherichia coli for Detection of Agricultural Contaminants
Authors: Hwang Kimberly , Kuo Allison , Choi Eugene , Chen Jessica , Hsu Jonathan , Clapper Jude 
Published: June 2020

AbstractWe consume fruits and vegetables every day without knowing whether or not agricultural residues (i.e. pesticides & heavy metals) are present on them. Current methods of agricultural residue detection are not easily accessible to the public and are inconvenient for everyday use. Thus, we want to develop a convenient visualization of agricultural residues by designing metal-binding and pesticide-binding proteins along with colored proteins that can directly interact with these residues. We worked with metal-binding proteins including Bacterioferritin, MBP, Metallothionein, and OprF. We also utilized pesticide-binding proteins LC Cutinase and OpdA. In this paper, we envision a system in which our residue-binding proteins are fused with chromoproteins to allow for the visible detection of agricultural residues on produce. Our final product can be used by consumers, distributors and farmers alike.
Prevalence and risk/protective indicators of peri-implant diseases: a university-representative cross-sectional study
Authors: Romandini Mario , Lima Cristina , Pedrinaci Ignacio , Araoz Ana , Soldini Maria Costanza , Sanz Mariano 
Published: June 2020

AbstractAimTo evaluate the prevalence of peri-implant diseases and to identify risk/protective indicators of peri-implantitis.Materials and Methods240 randomly selected patients from a university clinic database were invited to participate. Those who accepted, once data from their medical and dental history was collected, were examined clinically and radiographically to assess the prevalence of peri-implant health and diseases. A multilevel multivariate logistic regression analysis was carried out to identify those factors associated either positively (risk) or negatively (protective) with peri-implantitis defined as BoP/SoP and bone levels ≧2 mm.Results99 patients with a total of 458 dental implants were analyzed. The prevalence of preperiimplantitis and of peri-implantitis were respectively 56.6% and 31.3% at patient-level, while 27.9% and 31.7% at implant-level. The following factors were identified as risk indicators for periimplantitis: smoking (OR = 3.59; 95%CI:1.52–8.45), moderate/severe periodontitis (OR = 2.77; 95%CI:1.20–6.36), < 16 remaining teeth (OR = 2.23; 95%CI:1.05–4.73), plaque (OR = 3.49; 95%CI:1.13–10.75), implant malposition (too vestibular: OR = 2.85; 95%CI:1.17–6.93), implant brand (Nobel vs. Straumann: OR = 4.41;95% CI:1.76–11.09), restoration type (bridge: OR = 2.47; 95%CI:1.19–5.12), and trauma as reason of tooth loss (OR = 6.51;95% CI:1.45–29.26). Conversely, the following factors were identified as protective indicators: interproximal flossing/brushing (OR = 0.27; 95%CI:0.11–0.68), proton pump inhibitors (OR = 0.08; 95%CI:0.01–0.90) and anticoagulants (OR = 0.08; 95%CI:0.01–0.56).ConclusionsPeri-implant diseases are highly prevalent among patients with dental implants in this university-based population. Several factors were identified as risk- and protective-indicators of peri-implantitis.
Cervical Spine Assessment Techniques and Neck Strength Profiles of Elite Rugby Union Players Using an Innovative Measurement Approach
Authors: McBride Lesley , Oxford Samuel W 
Published: June 2020

ABSTRACTObjectivesNeck injuries and concussion commonly occur in the sport of Rugby Union. This study analyses the current practices of medical staff in assessment of the neck and proposes a new position-specific method using a commercially available setup for the assessment of neck strength.MethodsA survey was employed and distributed to 40 Premiership and Championship Rugby Union clubs. Thirty-eight University students (18 males and 20 females) were tested on two occasions at least 72hrs apart to determine reliability and 131 elite Rugby Union players (forwards n = 82, backs n = 49) were tested on a single occasion. Isometric neck strength was measured using a commercially available rig and digital load cell, for flexion (Flex), extension (Ext), left side flexion (LSF) and right-side flexion (RSF). Peak of three trials for each position was used for statistical analysis.ResultsSurvey findings indicated no standard practice used in the assessment of the neck across the professional teams. Intra-rater reliability interclass correlation values > 0.924 when using peak neck strength across all directions, thus indicating excellent reliability. Forwards recorded significantly greater absolute values for cervical spine strength across all directions (p < 0.01) however, relative values showed no significant difference between players (p > 0.05)ConclusionThe results show that the commercially available rig and digital load cell are a reliable tool for the assessment of isometric strength of the cervical spine and provide reference values for healthy males as well as elite Rugby Union forwards and backs.
ACE2 levels are altered in comorbidities linked to severe outcome in COVID-19
Authors: Emilsson Valur , Gudmundsson Elias F , Aspelund Thor , Jonsson Brynjolfur G , Gudjonsson Alexander , Launer Lenore J. , Lamb John R , Gudmundsdottir Valborg , Jennings Lori L , Gudnason Vilmundur 
Published: June 2020

AbstractAimsSeverity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). We examined if serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were altered in these high-risk groups.MethodsAssociations of serum ACE2 levels to hypertension, T2D, obesity, CHD, smokers and males in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years).ResultsSmokers, males, and individuals with T2D or obesity have altered serum levels of ACE2 that may influence productive infection of SARS-CoV-2 in these high-risk groups.ConclusionACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as outcome in COVID-19. a circulating biomarker for severity of severity of outcome in COVID-19.Key PointsQuestionSeverity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). Thus, we asked if the coronavirus SARS-CoV-2 receptor ACE2 was altered in the sera from these high-risk groups?FindingsIn a single center population-based study of 5457 Icelanders, the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), we find that ACE2 levels are significantly elevated in serum from smokers, obese and diabetic individuals, while reduced in males.MeaningThese results demonstrate that individuals with comorbidities associated with infection of SARS-CoV-2 in these individuals. severe outcome in COVID-19 have altered serum levels of ACE2 that may influence productive
Local Aromatase Activity Alterations in Breast Cancer Tissues: A Potential Way of Decision Support for Clinicians
Authors: Tuzuner Mete Bora , Ozturk Tulin , Ilvan Sennur , Turna Hande , Yurdun Turkan , Yilmaz-Aydogan Hulya , Ozturk Oguz 
Published: June 2020

AbstractBackground and aimsIt is becoming evident that local estrogen exposure is important in postmenopausal breast cancer patients. The microenvironment is established by breast stromal cells based on communication with tumor cells that is essential to cancer development, invasion, and metastasis. Here we investigated aromatase activity levels in both tumor and matched stromal tissues by showing their impact on the manufacturing of local estrogen and tumor progression in cases of invasive ductal carcinoma (IDC).MethodsTumor (T) and tumor-associated stroma (TAS) neighboring tissues were acquired from each postmenopausal patient, diagnosed with IDC, and categorized as luminal A (n = 20). The control group was formed from tumorfree breast tissue samples (N, n = 12). A microsomal-based technique was created to compare breast tissue aromatase activities using liquid chromatography – mass spectrometry.FindingsWe observed that the TAS tissues have the highest aromatase activities (p < 0.05). High progesterone receptor (PR) intensity levels were found to be decreasing the activity level in these tissues significantly (p< 0.05). Tumor tissue specific aromatase activity levels of postmenopausal patients’ were tend to be lower compared to healthy premenopausal subjects’ (3 fold, p< 0.001). In addition low activity in tumor tissues were associated with low grade and late stage cancers.ConclusionsEarly detection and personalized therapy is essential for postmenopausal breast cancer patients. Together, our inhouse tandem mass spectrometry technique has the potential for further development and standardization for the measurement of aromatase activity and may assist clinicians decide on therapy policies for postmenopausal IDC patients which could be an invaluable asset for precise and specific evaluation.
What variables can better predict the number of infections and deaths worldwide by SARS-CoV-2? Variation through time
Authors: García de Alcañíz J. G. , Romero-López J. , Martínez-Esteban R. P. , López-Rodas V. , Costas E. 
Published: June 2020

ABSTRACTUsing data from 50 very different countries (which represent nearly 70% of world’s population) and by means of a regression analysis, we studied the predictive power of different variables (mobility, air pollution, health & research, economic and social & geographic indicators) over the number of infected and dead by SARS-CoV-2. We also studied if the predictive power of these variables changed during a 4 months period (March, April, May and June). We approached data in two different ways, cumulative data and non-cumulative data.The number of deaths by Covid-19 can always be predicted with great accuracy from the number of infected, regardless of the characteristics of the country.Inbound tourism emerged as the variable that best predicts the number of infected (and, consequently, the number of deaths) happening in the different countries. Electricity consumption and air pollution of a country (CO2emissions, nitrous oxide and methane) are also capable of predicting, with great precision, the number of infections and deaths from Covid-19. Characteristics such as the area and population of a country can also predict, although to a lesser extent, the number of infected and dead. All predictive variables remained significant through time.In contrast, a series of variables, which in principle would seem to have a greater influence on the evolution of Covid-19 (hospital bed density, Physicians per 1000 people, Researches in R & D, urban population…), turned out to have very little - or none- predictive power.Our results explain why countries that opted for travel restrictions and social withdrawal policies at a very early stage of the pandemic outbreak, obtained better results. Preventive policies proved to be the key, rather than having large hospital and medical resources.