bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational principles and practice for decoding immune contexture in the tumor microenvironment
Authors: Zhang Zicheng , Bao Siqi , Yan Congcong , Hou Ping , Zhou Meng , Sun Jie 
Published: April 2020

Abstract
Tumor-infiltrating immune cells (TIICs) have been recognized as crucial components of the tumor microenvironment (TME) and induced both beneficial and adverse consequences for tumorigenesis as well as outcome and therapy (particularly immunotherapy). Computer-aided investigation of immune cell components in the TME has become a promising avenue to better understand the interplay between the immune system and tumors. In this study, we presented an overview of data sources, computational methods and software tools, as well as their application in inferring the composition of tumor-infiltrating immune cells in the TME. In parallel, we explored the future perspectives and challenges that may be faced with more accurate quantitative infiltration of immune cells in the future. Together, our study provides a little guide for scientists in the field of clinical and experimental immunology to look for dedicated resources and more competent tools for accelerating the unraveling of tumor-immune interactions with the implication in precision immunotherapy.
Codon optimization: a mathematical programing approach
Authors: Şen Alper , Kargar Kamyar , Akgün Esma , Pınar Mustafa Ç 
Published: April 2020

Abstract

Motivation
Synthesizing proteins in heterologous hosts is an important tool in biotechnology. However, the genetic code is degenerate and the codon usage is biased in many organisms. Synonymous codon changes that are customized for each host organism may have a significant effect on the level of protein expression. This effect can be measured by using metrics, such as codon adaptation index, codon pair bias, relative codon bias and relative codon pair bias. Codon optimization is designing codons that improve one or more of these objectives. Currently available algorithms and software solutions either rely on heuristics without providing optimality guarantees or are very rigid in modeling different objective functions and restrictions.

Results
We develop an effective mixed integer linear programing (MILP) formulation, which considers multiple objectives. Our numerical study shows that this formulation can be effectively used to generate (Pareto) optimal codon designs even for very long amino acid sequences using a standard commercial solver. We also show that one can obtain designs in the efficient frontier in reasonable solution times and incorporate other complex objectives, such as mRNA secondary structures in codon design using MILP formulations.

Availability and implementation
http://alpersen.bilkent.edu.tr/codonoptimization/CodonOptimization.zip.
Christian Integrity Regained: Reformational Worldview Engagement for Everyday Medical Practice
Authors: Tilburt Jon , Pacyna Joel , Rusthoven James 
Published: April 2020

AbstractHow does one committed to the claims of Christ and a biblical story of redemption live Christianly and navigate the competing worldviews encountered in everyday medical practice? Adopting the practical conceptual framework promoted by Reformed Christian philosopher and theologian Albert Wolters, we argue for an all-encompassing biblical understanding of God’s cosmic redemption plan for the entire creation order in contrast to a more typical sacred/secular duality. We then apply the concepts of structure and direction, drawn from a pretheological understanding of human life drawn from the Scripture, to a semi-fictional case study in discerning Christian faithfulness in everyday mundane aspects of medicine. Our subsequent analysis seeks to render an interpretation of what it means to live life consistent with that worldview when confronted with challenges like those presented in the case.
Cost-effectiveness of Antenatal Rescreening Among Pregnant Women for Hepatitis C in the United States
Authors: Chaillon Antoine , Wynn Adriane , Kushner Tatyana , Reau Nancy , Martin Natasha K 
Published: April 2020

Abstract
To inform proposed changes in hepatitis C virus (HCV) screening guidelines in the United States, we assessed the cost-effectiveness of HCV antenatal rescreening for women without evidence of HCV during a prior pregnancy, using a previously published model. Universal HCV rescreening among pregnant women was cost-effective (incremental cost-effectiveness ratio, $6000 per quality-adjusted life-year) and should be recommended nationally.
Revenant: a database of resurrected proteins
Authors: Carletti Matias Sebastian , Monzon Alexander Miguel , Garcia-Rios Emilio , Benitez Guillermo , Hirsh Layla , Fornasari Maria Silvina , Parisi Gustavo 
Published: April 2020

AbstractRevenant is a database of resurrected proteins coming from extinct organisms. Currently, it contains a manually curated collection of 84 resurrected proteins derived from bibliographic data. Each protein is extensively annotated, including structural, biochemical and biophysical information. Revenant contains a browse capability designed as a timeline from where the different proteins can be accessed. The oldest Revenant entries are between 4200 and 3500 million years ago, while the younger entries are between 8.8 and 6.3 million years ago. These proteins have been resurrected using computational tools called ancestral sequence reconstruction techniques combined with wet-laboratory synthesis and expression. Resurrected proteins are commonly used, with a noticeable increase during the past years, to explore and test different evolutionary hypotheses such as protein stability, to explore the origin of new functions, to get biochemical insights into past metabolisms and to explore specificity and promiscuous behaviour of ancient proteins.
Patient preferences for preventive health checks in Danish general practice: a discrete choice experiment among patients at high risk of noncommunicable diseases
Authors: Larsen Lars Bruun , Thilsing Trine , Pedersen Line Bjørnskov 
Published: April 2020

AbstractBackgroundPreventive health checks targeted at the at-risk population can be a way of preventing noncommunicable diseases. However, evidence on patient preferences for preventive health checks is limited, especially among patients with a high risk of noncommunicable diseases.ObjectiveTo examine patient preferences for preventive health checks in Danish general practice, targeting persons at high risk of a noncommunicable disease.MethodsThe method used in this study was a discrete choice experiment (DCE) with five attributes: assess, advice, agree, assist and arrange. The attributes were inspired by the 5A model for behaviour change counselling but was altered for the purpose of this study to grasp the entirety of the general practice-based intervention. Moreover, the attribute levels were defined to resemble daily clinical practice. The experimental design of the DCE was an efficient Bayesian main effects design and the results were analysed using a random utility theory framework.ResultsA total of 148 patients completed the DCE. Patients at high risk of a noncommunicable disease have positive preferences for: giving brief explanations about own lifestyle, practicing shared decision-making with the general practitioner (GP), follow-up counselling with the GP after the preventive health check and scheduling a new appointment right after the preventive health check.ConclusionsThe results provide Danish GPs with evidence on their patients’ preferences towards preventive health checks which will enable the GPs to tailor these consultations. Moreover, the results suggest that pre-appointment measures, such as a health profile, may mediate a preference for more action-oriented attributes.Trial registrationRegistered at Clinical Trial Gov (Unique Protocol ID: TOFpilot2016, https://clinicaltrials.gov/ct2/show/NCT02797392?term=TOFpilot2016&rank=1). Prospectively registered on the 29th of April 2016.
Elucidating the unusual reaction kinetics of D-glucuronyl C5-epimerase
Authors: Vaidyanathan Deepika , Paskaleva Elena , Vargason Troy , Ke Xia , McCallum Scott A , Linhardt Robert J , Dordick Jonathan S 
Published: April 2020

Abstract
The chemoenzymatic synthesis of heparin, through a multienzyme process, represents a critical challenge in providing a safe and effective substitute for this animal-sourced anticoagulant drug. D-glucuronyl C5-epimerase (C5-epi) is an enzyme acting on a heparin precursor, N-sulfoheparosan, catalyzing the reversible epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA). The absence of reliable assays for C5-epi has limited elucidation of the enzymatic reaction and kinetic mechanisms. Real time and offline assays are described that rely on 1D 1H NMR to study the activity of C5-epi. Apparent steady-state kinetic parameters for both the forward and the pseudo-reverse reactions of C5-epi are determined for the first time using polysaccharide substrates directly relevant to the chemoenzymatic synthesis and biosynthesis of heparin. The forward reaction shows unusual sigmoidal kinetic behavior, and the pseudo-reverse reaction displays nonsaturating kinetic behavior. The atypical sigmoidal behavior of the forward reaction was probed using a range of buffer additives. Surprisingly, the addition of 25 mM each of CaCl2 and MgCl2 resulted in a forward reaction exhibiting more conventional Michaelis–Menten kinetics. The addition of 2-O-sulfotransferase, the next enzyme involved in heparin synthesis, in the absence of 3′-phosphoadenosine 5′-phosphosulfate, also resulted in C5-epi exhibiting a more conventional Michaelis–Menten kinetic behavior in the forward reaction accompanied by a significant increase in apparent Vmax. This study provides critical information for understanding the reaction kinetics of C5-epi, which may result in improved methods for the chemoenzymatic synthesis of bioengineered heparin.
AMS Neve and Others (C-172/18): Looking for a Greater ‘Degree of Consistency’ Between the Special Jurisdiction Rule for EU Trade Marks and National Trade Marks
Authors: Lundstedt Lydia 
Published: April 2020

Abstract
The Court of Justice of the European Union’s (CJEU) judgment in AMS Neve and others (C-172/18) clarifies how to interpret the concept ‘the Member State in which the act of infringement has been committed or threatened’ in the rule on special jurisdiction in the European Union Trade Mark Regulation. The CJEU held that Art. 125(5) should be interpreted to mean that the right holder may bring an action before an EU trade mark court of the Member State within which the consumers or traders to whom advertising and offers for sale are directed are located, even if the defendant took decisions and steps in another Member State to bring about that electronic display.
With this judgment the CJEU introduces a targeting approach, which is something it has declined to do for the corresponding rule in Art. 7(2) Brussels Recast that applies to infringements of national trade marks. While the targeting approach is encouraging, the CJEU will need to clarify it to fulfil the objective of legal certainty. In addition, the CJEU appears to have interpreted Art. 125(5) EUTMR to exclude the Member State of activation. This is in contrast to Art. 7(2) Brussels Recast, which gives a right holder a choice between the Member State of activation and the Member State where the trade mark is registered. The article concludes that there is no justification for these differences in the special rules on jurisdiction applicable to EU trade marks and national trades.
Fisheries for the future: greenhouse gas emission consequences of different fishery reference points
Authors: Hornborg Sara , Smith Anthony D M 
Published: April 2020

Abstract
Global fisheries have for long been scrutinized in terms of ecosystem effects but only more recently for their greenhouse gas emissions. These emissions are dominated by fuel use on fishing vessels and the levels are often neglected side effects of resource overexploitation. Using a simple production model, Pella-Tomlinson, we illustrate how fuel efficiency (fuel use per unit of catch) varies with the level of exploitation and biomass depletion. For this model, fuel use per unit catch rises hyperbolically with fishing effort—it is relatively flat at low levels of effort but rises steeply as effort increases and biomass and catch decline. In light of these findings, the general fuel efficiency relationship with common fishery reference points on stock status is discussed, as well as other means of reducing fuel use and thus greenhouse gas emissions. We conclude that much may be gained by considering fuel efficiency in setting reference points for target stock biomass in fisheries and encourage further investigations.
Roles of FadRACB system in formaldehyde detoxification, oxidative stress alleviation and antibiotic susceptibility in Stenotrophomonas maltophilia
Authors: Li Li-Hua , Wu Cheng-Mu , Lin Yi-Tsung , Pan Sz-Yun , Yang Tsuey-Ching 
Published: April 2020

AbstractBackgroundFormaldehyde toxicity is invariably stressful for microbes. Stenotrophomonas maltophilia, a human opportunistic pathogen, is widely distributed in different environments and has evolved an array of systems to alleviate various stresses.ObjectivesTo characterize the role of the formaldehyde detoxification system FadRACB of S. maltophilia in formaldehyde detoxification, oxidative stress alleviation and antibiotic susceptibility.MethodsPresence of the fadRACB operon was verified by RT–PCR. Single or combined deletion mutants of the fadRACB operon were constructed for functional assays. Formaldehyde, menadione and quinolone susceptibilities were assessed by observing cell viability in formaldehyde-, menadione- and quinolone-containing media, respectively. Susceptibility to hydrogen peroxide was evaluated by disc diffusion assay. The agar dilution method was used to assess bacterial antibiotic susceptibilities. Expression of fadRACB was assessed by quantitative RT–PCR.ResultsThe fadR, fadA, fadC and fadB genes were arranged in an operon. Mutants of fadA and/or fadB were more susceptible to formaldehyde and oxidative stress than the WT KJ strain of S. maltophilia. No significant difference was observed in the ability of a fadC single mutant to ameliorate formaldehyde and oxidative stress; however, simultaneous inactivation of fadA, fadB and fadC further enhanced susceptibility to formaldehyde and oxidative stress. In addition, compared with WT KJ, the triple mutant KJΔFadACB was more susceptible to quinolones and more resistant to aminoglycosides. FadR functions as a repressor for the fadRACB operon. The FadRACB operon has moderate expression in aerobically grown WT KJ and is further derepressed by formaldehyde challenge or oxidative stress, but not by antibiotics.ConclusionsThe FadACB system contributes to mitigation of formaldehyde toxicity and oxidative stress and cross-protects S. maltophilia from quinolones.
Bernese periacetabular osteotomy: functional outcomes in patients with untreated intra-articular lesions
Authors: Lara Joaquín , Garín Alan , Herrera Cristhián , Abara Selim , Besomi Javier , Villegas Diego , Neumann Hassan , Tobar Carlos 
Published: April 2020

AbstractDevelopmental dysplasia of the hip (DDH) has been recognized to be a condition leading to osteoarthritis. Periacetabular osteotomy (PAO) has showed good results on hip preservation treatment for these cases. Nevertheless, intra-articular damage may be responsible for persistent post-operative symptoms, so treat the articular damage before or during the PAO has emerged as an alternative to address it. The objective is to identify the prevalence of intra-articular damage, functional outcomes of patients undergoing PAO with untreated intra-articular lesions and the survivorship free total hip arthroplasty (THA) at long-term follow-up. A retrospective review of 103 hips in 92 patients, mean age 26 years old (19–31), 96% females. Mean follow-up 7 years (range: 3–16). Intra-articular damage was evaluated with high-resolution magnetic resonance imaging (MRI) previous to perform the PAO, the chondral damage was evaluated using International Cartilage Repair Society classification. Harris Hip Score (HHS) was obtained in all patients. One hundred per cent of the cases had labral tears on MRI, hypertrophic labrum in 80.8% and paralabral cysts in 20.8%. Acetabular chondral damage was Grade 2 in 88.5% of the hips. HHS was good and excellent in 94%. Survivorship free of THA at 15 years was 87%. Chondrolabral damage is a common finding in patients with DDH. Despite that, excellent results are obtained with PAO without labral repair. We think the focus should be in the biomechanical and anatomical correction of the hip in patients with DDH.
Seasonal Changes of Host Use by Culiseta melanura (Diptera: Culicidae) in Central Florida
Authors: West Richard G , Mathias Derrick K , Day Jonathan F , Acevedo Carolina , Unnasch Thomas R , Burkett-Cadena Nathan D 
Published: April 2020

Abstract
The mosquito Culiseta melanura (Coquillett) is the primary enzootic vector of eastern equine encephalitis virus (EEEV), a zoonotic Alphavirus endemic to eastern North America. In its northern range, Cs. melanura is considered a strict avian biter, transmitting EEEV among susceptible birds in a cycle of enzootic amplification. In its southern range, however, Cs. melanura is more general in host use, feeding heavily upon birds but also reptiles and mammals. The goal of this study was to better understand how host use of Cs. melanura changes throughout the year in Florida, where year-round EEEV transmission is observed. Mosquitoes were sampled in 2018 from nine sites across three central Florida counties. In total, 213 Cs. melanura bloodmeals were identified by PCR consisting of 39 species of birds, reptiles, and mammals. Avian bloodmeals were prominent throughout the year (range = 30–85%), and songbirds were a large portion of identified bloodmeals (37.1%). Reptiles surpassed birds only in spring (April–June), and brown anole (Anolis sagrei Duméril and Bibron, 1837 [Reptilia: Dactyloidae]) was the most commonly detected single host species (22.1% overall). Mammalian bloodmeals were mainly observed in summer, with humans being the most fed on mammal (12.7% overall). This study reveals that in southern foci of EEEV transmission, Cs. melanura host use varies throughout the year with reptiles providing the majority of blood meals in spring (51.3%), and birds are fed on more than other host groups during all other seasons (50.6–70.1%). In addition, feeding on mammals increases during summer months, which may implicate Cs. melanura in epizootic transmission in Florida.
An unusual presentation of acute onset Charcot arthropathy
Authors: Al-Najjar Ammar , Al Shakarchi Julien , Pereira Melwyn , Downing Richard 
Published: April 2020

Abstract
Charcot arthropathy is a progressive condition primarily affecting the lower limbs in patients with diabetes mellitus. It is a rare complication of diabetic neuropathy and if left untreated can lead to severe limb destruction necessitating major amputation. Here, we report the case of a 41-year-old female who presented with rapidly progressive Charcot foot over a 10-day period, necessitating open reduction and internal fixation of Lisfranc-type fracture dislocations. Her presentation with a rapidly progressing red, swollen foot with a blister on the plantar aspect prompted initial treatment on the basis of a diabetic foot infection. The report will therefore serve as a useful reminder to maintain a high index of suspicion for Charcot foot, which may present in an atypical manner.
The size of our causal Universe
Authors: Gaztañaga Enrique 
Published: April 2020

ABSTRACT
A Universe with finite age also has a finite causal scale. Larger scales cannot affect our local measurements or modelling, but far away locations could have different cosmological parameters. The size of our causal Universe depends on the details of inflation and is usually assumed to be larger than our observable Universe today. To account for causality, we propose a new boundary condition, that can be fulfill by fixing the cosmological constant (a free geometric parameter of gravity). This forces a cancellation of vacuum energy with the cosmological constant. As a consequence, the measured cosmic acceleration cannot be explained by a simple cosmological constant or constant vacuum energy. We need some additional odd properties such as the existence of evolving dark energy (DE) with energy-density fine tuned to be twice that of dark matter today. We show here that we can instead explain the current cosmic acceleration without DE (or modified gravity) as a the result of a primordial inflation with a causal scale smaller than the observable Universe today. Such scale corresponds to half the sky at z = 1 and 60 deg at z= 1100, which is consistent with the anomalous lack of correlations observed in the CMB.
In vitro modeling of glioblastoma initiation using PDGF-AA and p53-null neural progenitors
Authors: Bohm Alexandra K , DePetro Jessica , Binding Carmen E , Gerber Amanda , Chahley Nicholas , Berger N Dan , Ware Mathaeus , Thomas Kaitlin , Senapathi U , Bukhari Shazreh , Chen Cindy , Chahley Erin , Grisdale Cameron , Lawn Sam , Yu Yaping , Wong Raymond , Shen Yaoqing , Omairi Hiba , Mirzaei Reza , Alshatti Nourah , Pedersen Haley , Yong Wee , Weiss Samuel , Chan Jennifer , Cimino P J , Kelly John , Jones Steve , Holland Eric , Blough Michael , Cairncross Gregory 
Published: April 2020

Abstract

Background
Imagining ways to prevent or treat glioblastoma (GBM) has been hindered by a lack of understanding of its pathogenesis. Although overexpression of platelet derived growth factor with two A-chains (PDGF-AA) may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture. Here we report a model that overcomes this barrier to authenticity.

Methods
Using a method developed to establish neural stem cell cultures, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, one of the putative cells of origin of GBM. We microdissected SVZ tissue from p53-null and wild-type adult mice, cultured cells in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumorigenicity.

Results
Counterintuitive to its canonical role as a growth factor, we observed abrupt and massive cell death in PDGF-AA: wild-type cells did not survive, whereas a small fraction of null cells evaded apoptosis. Surviving null cells displayed attenuated proliferation accompanied by whole chromosome gains and losses. After approximately 100 days in PDGF-AA, cells suddenly proliferated rapidly, acquired growth factor independence, and became tumorigenic in immune-competent mice. Transformed cells had an oligodendrocyte precursor-like lineage marker profile, were resistant to platelet derived growth factor receptor alpha inhibition, and harbored highly abnormal karyotypes similar to human GBM.

Conclusion
This model associates genome instability in neural progenitor cells with chronic exposure to PDGF-AA and is the first to approximate the genomic landscape of human GBM and the first in which the earliest phases of the disease can be studied directly.