bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphological differences between putative Paleolithic dogs and wolves: A commentary to Janssens et al. (2021)
Authors: Galeta Patrik , Lázničková‐Galetová Martina , Sablin Mikhail , Germonpré Mietje 
Published: April 2022

AbstractJanssens et al. (2021, doi: 10.1002/ar.24624) recently commented on our article (Galeta et al., 2021, doi: 10.1002/ar.24500) regarding the morphological differences between putative Paleolithic dog and Pleistocene wolf crania. The authors argued that these differences reflect the normal population variation of wolves, that some of the cranial measurements used do not reflect morphological changes during domestication, and that our canid dataset was small because we inexplicably omitted several specimens we analyzed in our previous publications. In this commentary, we briefly address the issue of within and between morpho‐population variability. The results based on our canid sample suggest that the magnitude of morphological differences between distinct morpho‐populations (i.e., recent northern dogs and wolves) is at least twice as large as that observed within morpho‐populations (between two groups of recent northern wolves segregated by cluster analysis). The morphological differences between putative Paleolithic dogs and Pleistocene wolves are relatively large, which may indicate that they did not likely represent a single Late Pleistocene morpho‐population. Finally, we clarified the rationale behind the composition of our 2021 dataset to show that we did not adjust the list of the analyzed specimens. Although the sample size was small, the randomization analysis published in 2021 confirmed that the unbalanced composition of the reference sample did not affect the reliability of the morphological segregation of putative Paleolithic dogs and Pleistocene wolves.
Synthesis of Novel Glycolipid Mimetics of Heparan Sulfate and Their Application in Colorectal Cancer Treatment in a Mouse Model
Authors: Spijkers‐Shaw Sam , Campbell Katrin , Shields Nicholas J. , Miller John H. , Rendle Phillip M. , Jiao Wanting , Young Sarah L. , Zubkova Olga V. 
Published: April 2022

AbstractHeparan sulfate (HS) is a highly sulfated natural carbohydrate that plays crucial roles in cancer, inflammation, and angiogenesis. Heparanase (HPSE) is the sole HS degrading endoglycosidase that cleaves HS at structure‐dependent sites along the polysaccharide chain. Overexpression of HPSE by cancer cells correlates with increased tumor size and enhanced metastasis. Previously we have shown that a tetramer HS mimetic is a potent HPSE inhibitor displaying remarkable anticancer activity in vivo. Building on that work, we report the synthesis and testing of a novel library of single entity trimer glycolipid mimetics that effectively inhibit HPSE at low nanomolar concentrations. A lipophilic arm was introduced to assess whether an improvement of pharmacokinetics and plasma residence time would offset the reduction in charge and multivalency. Preclinical tests in a mouse syngeneic model showed effective tumor growth inhibition by the tetramer but not the trimer glycomimetic.
Optimization of adaptive designs with respect to a performance score
Authors: Herrmann Carolin , Kieser Meinhard , Rauch Geraldine , Pilz Maximilian 
Published: April 2022

AbstractAdaptive designs are an increasingly popular method for the adaptation of design aspects in clinical trials, such as the sample size. Scoring different adaptive designs helps to make an appropriate choice among the numerous existing adaptive design methods. Several scores have been proposed to evaluate adaptive designs. Moreover, it is possible to determine optimal two‐stage adaptive designs with respect to a customized objective score by solving a constrained optimization problem. In this paper, we use the conditional performance score by Herrmann et al. (2020) as the optimization criterion to derive optimal adaptive two‐stage designs. We investigate variations of the original performance score, for example, by assigning different weights to the score components and by incorporating prior assumptions on the effect size. We further investigate a setting where the optimization framework is extended by a global power constraint, and additional optimization of the critical value function next to the stage‐two sample size is performed. Those evaluations with respect to the sample size curves and the resulting design's performance can contribute to facilitate the score's usage in practice.
RAD18 confers radioresistance of esophagus squamous cell carcinoma through regulating p‐DNA‐PKcs
Authors: Li Xiaoqing , Zou Shitao , Zhou Liangsu , Gao Aidi , Xu Jing , He Chao , Zhou Jundong , Wu Shuhua , Chen Yihong 
Published: April 2022

AbstractBackgroundRadiotherapy has recently become more common for the treatment of esophageal squamous cell carcinoma (ESCC). Radioresistance, on the other hand, continues to be a major issue because it interferes with the effectiveness of ESCC radiation. It has been demonstrated that RAD18, an E3 ubiquitin‐protein ligase that regulates translesion DNA synthesis (TLS), is implicated in the regulation of genomic integrity and DNA damage response.MethodsIn the present study, immunohistochemical staining and western blotting were utilized to determine RAD18 expression in ESCC tissues and cells. ESCC cell proliferation was determined using a colony formation assay. Immunofluorescence staining, comet assay, and homologous recombination (HR)/non‐homologous end‐joining (NHEJ) assays were conducted to examine the effect of RAD18 on the DNA damage response in ESCC cells.ResultsWe found that high RAD18 expression was positively associated with a poorer prognosis in patients with ESCC who received radiotherapy. Downregulation of RAD18 expression significantly increased the sensitivity of ESCC cells to irradiation. Moreover, RAD18 knockdown prolonged the repair kinetics of γH2AX foci and resulted in longer comet tails. Furthermore, loss of RAD18 expression markedly decreased non‐homologous end‐joining (NHEJ) activity, but it did not affect homologous recombination (HR)‐mediated double‐strand break repair in ESCC cells. RAD18 upregulated p‐DNA‐dependent protein kinase complex (p‐DNA‐PKc) expression in vivo and in vitro.ConclusionsThese data indicated that RAD18 may regulate radioresistance by facilitating NHEJ via phosphorylation of DNA‐PKcs in ESCC cells, providing a novel radiotherapy target for ESCC.
Guillain‐Barré syndrome after mRNA‐1273 (Moderna) COVID‐19 vaccination: A case report
Authors: Anjum Zauraiz , Iyer Charoo , Naz Sidra , Jaiswal Vikash , Nepal Gaurav , Laguio‐vila Maryrose , Anandaram Sanjay , Thapaliya Sahil 
Published: April 2022

AbstractGuillain‐Barre syndrome (GBS) is an acquired inflammatory polyradiculoneuropathy that often follows infection with a virus or bacteria and in rare occasions, vaccination may precede GBS. We present a case of 80‐year‐old male patient who presented with chief complaints of progressive, ascending bilateral lower extremity paresthesia and weakness following first dose of Moderna vaccine. His symptoms got exacerbated after 2nd dose. Clinical examination and investigation findings including lumbar puncture, nerve conduction study, and electromyography were consistent with the diagnosis of GBS. The patient received treatment with intravenous immunoglobulin and there was significant improvement toward the end of 5th day. Though rare, this case report suggest that physician should remain vigilant for GBS following COVID‐19 vaccination.
Estimating design operating characteristics in Bayesian adaptive clinical trials
Authors: Golchi Shirin 
Published: April 2022

AbstractBayesian adaptive designs have gained popularity in all phases of clinical trials with numerous new developments in the past few decades. During the COVID‐19 pandemic, the need to establish evidence for the effectiveness of vaccines, therapeutic treatments, and policies that could resolve or control the crisis emphasized the advantages offered by efficient and flexible clinical trial designs. In many COVID‐19 clinical trials, because of the high level of uncertainty, Bayesian adaptive designs were considered advantageous. Designing Bayesian adaptive trials, however, requires extensive simulation studies that are generally considered challenging, particularly in time‐sensitive settings such as a pandemic. In this article, we propose a set of methods for efficient estimation and uncertainty quantification for design operating characteristics of Bayesian adaptive trials. Specifically, we model the sampling distribution of Bayesian probability statements that are commonly used as the basis of decision making. To showcase the implementation and performance of the proposed approach, we use a clinical trial design with an ordinal disease‐progression scale endpoint that was popular among COVID‐19 trials. However, the proposed methodology may be applied generally in the clinical trial context where design operating characteristics cannot be obtained analytically.
The Impact of CYP2C9*11 Allelic Variant on the Pharmacokinetics of Phenytoin and (S)‐Warfarin
Authors: Wanounou Maor , Shaul Chanan , Abu Ghosh Zahi , Alamia Shoshana , Caraco Yoseph 
Published: April 2022

Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)‐warfarin. Single 300‐mg phenytoin and 20‐mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)‐warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin in 24‐hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)‐warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no‐function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti‐inflammatory drugs, or siponimod.
Photoresponsive Porphyrin‐DNA Complexes Constructed through Intercalation‐like Binding
Authors: Takada Tadao , Shimogaki Nao , Naruo Moe , Nakamura Mitsunobu , Yamana Kazushige 
Published: April 2022

AbstractThe molecular arrangement of functional chromophores is essential to construct functional nanomaterials. Synthetic DNA has been used as a structural scaffold to control and construct molecular assembly. We now describe the formation of artificial DNA/porphyrin complexes where porphyrins working as photoactive molecules were placed at specific locations on the DNA through a non‐covalent interaction. Spectroscopic analysis by UV/vis, circular dichroism (CD), and melting temperature measurements showed that the binding of water‐soluble porphyrin derivatives with methylpyridinium groups (TMPyP and DMPyP) to DNA can be directed by hydrophobic cavities composed of a pair of abasic site analogs (dS). CD measurements showed that the two porphyrins can be accommodated at two specific sites when the DNA molecule had two cavities, as evidenced by the exciton‐coupled CD spectra of the porphyrins. Photoelectrochemical experiments showed that the DNA complexes accommodating DMPyP at specific locations can respond to light excitation to generate a photocurrent when immobilized on the electrode surface. Our results demonstrated that the control of the porphyrin binding using the dS/dS pair is a useful approach to construct artificial DNA with porphyrin molecules, leading to the design of photoresponsive materials and photoelectrochemical sensors.
Forward Genetic Screens of Human Glycosylation Pathways Using the GlycoGene CRISPR Library
Authors: Kelkar Anju , Groth Theodore , Neelamegham Sriram 
Published: April 2022

AbstractCRISPR‐Cas9‐based forward genetic screens represent a powerful discovery platform to uncover genes regulating specific biological processes. This article describes a method for utilizing a freely available GlycoGene CRISPR library to knock out any gene participating in human glycosylation in arbitrary cell types. The end product is a stable GlycoGene CRISPR knockout cell library, where each cell contains one or more sgRNA and lacks corresponding function. The cell library can be screened using various lectin/antibody reagents. It can also be applied in functional assays to establish glycan structure‐glycogene‐glycopathway relationships. This is a powerful systems glycobiology strategy for dissecting glycosylation pathways and processes. © 2022 Wiley Periodicals LLC.Basic Protocol 1: Scale‐up and NGS validation of the GlycoGene CRISPR plasmid libraryBasic Protocol 2: Preparation of a GlycoGene CRISPR lentivirus pool and an isogenic cell line stably expressing Cas9 nucleaseBasic Protocol 3: Preparation of a GlycoGene CRISPR cell library, self‐inactivation of Cas9, and library validation by NGSBasic Protocol 4: Enrichment of lectin‐binding or non‐binding cells and related multiplex NGS data acquisitionBasic Protocol 5: Bioinformatics pathway analysis
Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis
Authors: Meiman Elizabeth J. , Kick Grace Robinson , Jensen Cheryl A. , Coates Joan R. , Katz Martin L. 
Published: April 2022

AbstractGolden Retriever dogs with a frameshift variant in CLN5 (c.934_935delAG) suffer from a progressive neurodegenerative disorder analogous to the CLN5 form of neuronal ceroid lipofuscinosis (NCL). Five littermate puppies homozygous for the deletion allele were identified prior to the onset of disease signs. Studies were performed to characterize the onset and progression of the disease in these dogs. Neurological signs that included restlessness, unwillingness to cooperate with the handlers, and proprioceptive deficits first became apparent at approximately 12 months of age. The neurological signs progressed over time and by 21 to 23 months of age included general proprioceptive ataxia, menace response deficits, aggressive behaviors, cerebellar ataxia, intention tremors, decreased visual tracking, seizures, cognitive decline, and impaired prehension. Due to the severity of these signs, the dogs were euthanized between 21 and 23 months of age. Magnetic resonance imaging revealed pronounced progressive global brain atrophy with a more than sevenfold increase in the volume of the ventricular system between 9.5 and 22.5 months of age. Accompanying this atrophy were pronounced accumulations of autofluorescent inclusions throughout the brain and spinal cord. Ultrastructurally, the contents of these inclusions were found to consist primarily of membrane‐like aggregates. Inclusions with similar fluorescence properties were present in cardiac muscle. Similar to other forms of NCL, the affected dogs had low plasma carnitine concentrations, suggesting impaired carnitine biosynthesis. These data on disease progression will be useful in future studies using the canine model for therapeutic intervention studies.
Response Surface Optimization of Enzyme Pretreatment Improves Yield of Ethanol‐Extracted Lipids from Nannochloropsis oceanica
Authors: Zhao Kangyu , Zhang Liwei , Zhang Meilan , Tian Hua , He Dongping , Zheng Jingcheng 
Published: April 2022

AbstractNannochloropsis oceanica are marine microalgae that are rich in eicosapentaenoic acid (EPA); in the future, they may become one of the most effective sources of EPA. The cell walls of N. oceanica contain a three‐layered dense structure called algaenan, which hinders the extraction of intracellular lipids. Here, the main variables for the enzyme pretreatment of N. oceanica are optimized using response surface methodology. Under the optimal variables for enzyme pretreatment, the lipid yield and EPA content are increased to 26.9% and 20.7 g/100 g, respectively. Furthermore, lipidomics analysis is carried out utilizing ultra‐high performance liquid‐quadrupole‐time‐of‐flight mass spectrometry to identify the obtained lipids. After enzyme treatment, the betaine lipids (BL) content significantly increases, probably due to laccase and cellulase promoting the release of BL from membrane structure. In comparison, the hydrolysis of neutral lipids, glycolipids, and phospholipids during the enzyme treatment reduces their respective contents. The results of this study suggest that using compound enzymes to pretreat N. oceanica can effectively increase lipids extraction yields by ethanol and improve the EPA contents in lipids.Practical applications: This study indicates that enzyme pretreatment can promote the extraction of lipids, especially lipids with EPA, from N. oceanica or other marine microalgae.
Retrospective, cohort review of pharmacists' impact on disparities in care in the management of type 2 diabetes with glucagon‐like peptide‐1 agonists and sodium glucose co‐transporter 2 inhibitors
Authors: Howell Chandler , Schmelz Andrew , Albertson Shelby , Hamm Jay , Meredith Ashley H. , Pence Lauren , Triboletti Jessica , Gonzalvo Jasmine 
Published: April 2022

AbstractBackgroundThe American Diabetes Association recommend glucagon‐like peptide‐1 (GLP‐1) agonists and sodium glucose co‐transporter 2 (SGLT‐2) inhibitors be considered as first‐line therapy for type 2 diabetes. A secondary analysis of the Look AHEAD study determined these agents are disproportionately prescribed at higher rates to White patients compared with Black patients.ObjectivesThe objective of this study is to evaluate if a disparity exists between the prescribing of SGLT‐2 inhibitors and GLP‐1 agonists between White patients and Black patients at an academic, safety‐net health system.MethodsA single‐center retrospective chart review was conducted on patients seen at a pharmacist‐managed or provider‐managed clinic. The primary outcome is the difference in prescribing of SGLT‐2 inhibitors and GLP‐1 agonists between Black and White patients in the pharmacist and provider‐managed group. Secondary outcomes include differences in prescribing in Hispanic patients and patients with a serious mental illness.ResultsThe primary outcome of prescribing rates for GLP‐1 agonists and SGLT‐2 inhibitors did not differ significantly in the pharmacist comanaged group. The primary outcome in the provider managed group did differ significantly. The largest prescribing rate was in the “other” race category. Only two variables were found in the combined datasets to play a role in the prescribing of a GLP‐1 agonist or SGLT‐2 inhibitor. Having only a provider and not a pharmacist involved in care was predictive of not being prescribed either agent (odds ratio = 0.096, P = <.001). Insurance status was the other statistically significant predictor of being prescribed a GLP‐1 agonist or SGLT‐2 inhibitor (odds ratio = 1.592, P = .006).ConclusionA clinically significant difference in prescribing based on race did not exist in the pharmacist comanaged group or the provider only managed group. Pharmacist involvement and insurance status appear to have a positive impact on an SGLT‐2 inhibitor or GLP‐1 agonist being prescribed.
Osteomalacia as a Complication of Intravenous Iron Infusion: A Systematic Review of Case Reports
Authors: Vilaca Tatiane , Velmurugan Nalini , Smith Christopher , Abrahamsen Bo , Eastell Richard 
Published: April 2022

ABSTRACT
Randomized control trials (RCTs) have shown that certain intravenous iron preparations can induce high levels of fibroblast growth factor 23 (FGF-23) and persistent hypophosphatemia. Repeated iron infusions may lead to prolonged hypophosphatemia and osteomalacia events not captured by RCTs. Several previous case reports have described skeletal adverse effects after repeated iron infusions. To characterize these effects, we conducted a systematic review of case reports. MEDLINE, Embase, Web of Science, and Cochrane databases were searched in March 2021. We selected case reports of patients ≥16 years old. Study quality was assessed using the tool from Murad and colleagues. We report the results in a narrative summary. We identified 28 case reports, reporting 30 cases. Ages ranged from 28 to 80 years (median 50 years). Most patients (n = 18) received ferric carboxymaltose (FCM), whereas 8 received saccharated ferric oxide (SFO) and 3 received iron polymaltose (IPM). All but 2 cases had more than five infusions (range 2 to 198, median 17). The lowest phosphate levels ranged from 0.16 to 0.77 mmol/L (median 0.36 mmol/L). Intact FGF-23 (iFGF-23) was high when measured. Serum 25OH vitamin D was low in 10 of 21 cases measured and 1,25(OH)2 vitamin D in 12 of 18. Alkaline phosphatase was high in 18 of 22 cases. Bone or muscle pain was reported in 28 of the 30 cases. Twenty patients had pseudofractures, 9 had fractures, and 6 patients had both. All 15 available bone scans showed focal isotope uptake. Case reports tend to report severe cases, so potential reporting bias should be considered. Osteomalacia is a potential complication of repeated iron infusion, especially in patients with gastrointestinal disorders receiving prolonged therapy. Pain and fractures or pseudofractures are common clinical findings, associated with low phosphate, high iFGF-23, high alkaline phosphatase, and abnormal isotope bone scan. Discontinuing or switching the iron formulation was an effective intervention in most cases. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Time‐dependent density functional theory study of the optical properties of tetrahedral aluminum nanoparticles
Authors: Bae Gyun‐Tack , Aikens Christine M. 
Published: April 2022

AbstractThe plasmonic properties of tetrahedral aluminum nanoparticles have been investigated using time‐dependent functional theory (TDDFT) calculations. The excitation energies are calculated for tetrahedral aluminum nanoparticles (Aln, n = 10–120) with different charge states. The BP86/DZ model is used to perform geometric optimization calculations for these clusters. The SAOP/DZ and LB94/DZ levels of theory have been used for the excitation energy calculations of these tetrahedral aluminum clusters. The absorption peaks are red‐shifted upon increasing the size of the aluminum nanoparticles.