bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comprehensive Overview of Structure‐Activity Relationships of Small‐Molecule Splicing Modulators Targeting SF3B1 as Anticancer Agents
Authors: Zhang Datong , Meng Fancui 
Published: October 2020

AbstractThe pre‐mRNA splicing factor SF3B1 shows recurrent mutations among hematologic malignancies and some solid tumors. In 2007, the identification of two cytotoxic natural products, which showed splicing inhibition by binding to SF3b, prompted the development of small‐molecule splicing modulators of SF3B1 as therapeutics for cancer. Recent studies suggested that spliceosome‐mutant cells are preferentially sensitive to pharmacologic splicing modulation; therefore, exploring the clinical utility of splicing modulator therapies in patients with spliceosome‐mutant hematologic malignancies who have failed current therapies is greatly needed, as these patients have few treatment options. H3B‐8800 had unique pharmacological activity and exhibited favorable data in phase I clinical trials to treat patients with advanced myeloid malignancies, indicating that further clinical trials are promising. The most established small‐molecule modulators of SF3B1 can be categorized into three classes: the bicycles, the monopyranes, and the 12‐membered macrolides. This review provides a comprehensive overview of the structure‐activity relationships of small‐molecule SF3B1 modulators, with a detailed analysis of interactions between modulators and protein binding pocket. The future strategy for splicing modulators development is also discussed.
Sex‐specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors
Authors: Rivera Patricia , Aranda Jesús , Alén Francisco , Vargas Antonio , Serrano Antonia , Pavón Francisco Javier , Orio Laura , Rubio Leticia , Moratalla Rosario , de Fonseca Fernando Rodríguez , Suárez Juan 
Published: October 2020

AbstractAdult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex‐specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in (a) cell proliferation (5′‐bromo‐2′‐deoxyuridine [BrdU]), (b) neural precursor (nestin), (c) neuronal phenotype (BrdU/β3‐tubulin), and (d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1−/−, D2−/−) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 hr later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1−/− mice and reduced in SCH23390‐treated mice. Activity responses to cocaine were reduced in D2−/− males, but absent in D2−/− females and increased in Raclopride‐treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine‐exposed D1−/− males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2−/− mice had lower proliferative and neural precursor responses. Cocaine in D2−/− females or coadministered with Raclopride in wild‐type females improved SVZ cell proliferation, an effect that positively correlated with plasma brain‐derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex‐specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.
Optimal structural pattern for maximal compliance using topology optimization based on phasefields: Application to improve skin graft meshing efficiency
Authors: Sutula Danas , Henyš Petr , Čapek Lukáš 
Published: October 2020

AbstractThis article focuses on the problem of maximal compliance design of a hyper‐elastic solid with the optimal design of human skin grafts as the application in mind. The solution method is a phasefield‐based topology optimization method that supposes multiple local phasefields and a minimum distance constraint in order to prevent the phasefields from merging. Consequently, structurally disintegrating solutions such as by the coalescence of voids can be prevented. The method is used to find an optimal graft meshing pattern for a sample that is subjected to a biaxial extension of up to 150%, which corresponds to an expansion ratio of 1 : 2.25. Three prospective unitcell solutions that exhibit meta‐material behavior are proposed for a periodic graft pattern. The results are a step toward improving the skin graft meshing efficiency. This work does not cover experimental validation.
Model‐Based Quantification of Impact of Genetic Polymorphisms and Co‐Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer
Authors: Puszkiel Alicja , Arellano Cécile , Vachoux Christelle , Evrard Alexandre , Le Morvan Valérie , Boyer Jean‐Christophe , Robert Jacques , Delmas Caroline , Dalenc Florence , Debled Marc , Venat‐Bouvet Laurence , Jacot William , Dohollou Nadine , Bernard‐Marty Chantal , Laharie‐Mineur Hortense , Filleron Thomas , Roché Henri , Chatelut Etienne , Thomas Fabienne , White‐Koning Melanie 
Published: October 2020

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration‐time data for TAM and 6 metabolites come from a prospective, multicenter, 3‐year follow‐up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7‐compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra‐rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N‐desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose‐adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient’s CYP2D6 phenotype for TAM dose adaptation.
Clinical and laboratory features associated with myeloperoxidase expression in pediatric B‐lymphoblastic leukemia
Authors: McGinnis Eric , Yang David , Au Nicholas , Morrison Douglas , Chipperfield Kate M. , Setiadi Audi F. , Liu Lorraine , Tsang Angela , Vercauteren Suzanne M. 
Published: October 2020

AbstractBackgroundB‐lymphoblastic leukemia (B‐ALL) is the most common childhood malignancy, and its diagnosis requires immunophenotypically demonstrating blast B cell lineage differentiation. Expression of myeloperoxidase (MPO) in B‐ALL is well‐described and it has been recognized that a diagnosis of mixed phenotype acute leukemia should be made cautiously if MPO expression is the sole myeloid feature in these cases. We sought to determine whether MPO expression in pediatric B‐ALL was associated with differences in laboratory, immunophenotypic, or clinical features.MethodsWe reviewed clinical, diagnostic bone marrow flow cytometry, and laboratory data for all new B‐ALL diagnoses at our pediatric institution in 5 years. Cases were categorized as MPO positive (MPO+) or negative (MPO−) using a threshold of ≥20% blasts expressing MPO at intensity greater than the upper limit of normal lymphocytes on diagnostic bone marrow flow cytometry.ResultsA total of 148 cases were reviewed, 32 of which (22%) were MPO+. MPO+ B‐ALL was more frequently hyperdiploid and less frequently harbored ETV6‐RUNX1; no MPO+ cases had KMT2A rearrangements or BCR‐ABL1. Although not significantly so, MPO+ B‐ALL was less likely than MPO− B‐ALL to have positive end‐of‐induction minimal residual disease studies (9.4 and 24%, respectively), but relapse rates and stem cell transplantation rates were similar between groups. Aberrant expression of other more typically myeloid markers was similar between these groups.ConclusionIn our study cohort, MPO+ B‐ALL showed minimal residual disease persistence less often after induction chemotherapy but otherwise had similar clinical outcomes to MPO− B‐ALL, with similar rates of additional myeloid antigen aberrancy.
Cumyl‐CBMICA: A new synthetic cannabinoid receptor agonist containing a cyclobutyl methyl side chain
Authors: Halter Sebastian , Pulver Benedikt , Wilde Maurice , Haschimi Belal , Westphal Folker , Riedel Jan , Pütz Michael , Schönberger Torsten , Stoll Stefanie , Schäper Jan , Auwärter Volker 
Published: October 2020

AbstractSince the beginning of the phenomenon of new psychoactive substances (NPS), synthetic cannabinoid receptor agonists (SCRAs) have been the largest and most prevalent subclass of these drugs in Europe. Many countries implemented specific legislation scheduling classes of substances defined on the basis of their chemical structure to reduce supply. We describe the identification and analytical characterization within the EU project ADEBAR plus of 1‐(cyclobutylmethyl)‐N‐(2‐phenylpropan‐2‐yl)‐1H‐indole‐3‐carboxamide which resulted in the formal notification through the Early Warning System of the European Monitoring Centre for Drug and Drug Addiction (EMCDDA). This is the first identification of this new SCRA worldwide and the analytical data was distributed (inter‐)nationally right after identification in 2019. First, the substance was isolated from the herbal material using preparative high‐performance liquid chromatography (HPLC). Structure elucidation and analytical characterization were performed using gas chromatography–mass spectrometry (GC–MS), gas chromatography‐solid state infrared spectroscopy (GC‐sIR), liquid chromatography‐electrospray ionization‐quadrupole time of flight‐mass spectrometry (LC‐ESI‐qToF‐MS), Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The new compound contains a cyclobutyl methyl group as a side chain and has not been described in any patent to our knowledge. Based on the semisystematic nomenclature of SCRAs, we propose Cumyl‐CBMICA as a short name for the compound.
Detection of the selective androgen receptor modulator GSK2881078 and metabolites in urine and hair after single oral administration
Authors: Rading Alina , Anielski Patricia , Thieme Detlef , Keiler Annekathrin Martina 
Published: October 2020

AbstractHair and urine concentrations of the nonsteroidal selective androgen receptor modulator GSK2881078 were examined following single oral administration to investigate its hair incorporation and estimate the general suitability of hair testing for selected androgen receptor modulators. Hair segments were collected following a single dose of 1.5 mg GSK2881078 by repeated shaving of scalp hair at Week 0 (blank), Week 1 (representing the pre‐application period), Week 3 (ideally focusing the time of incorporation), and Weeks 5 and 9 (post‐administration period). The intact compound and various (at least 4) hydroxy‐metabolites exhibited similar elimination profiles. The peak urinary concentration (approximately 920 pg/ml) was observed after 8 h and is reduced to the detection limit (2 pg/ml) on Day 42 following administration of 760 μg GSK2881078. Correspondingly, hair concentrations of GSK2881078 (intact compound only) following a single oral dose of 1.5 mg GSK2881078 reached a peak concentration of 1.7 pg/mg in the segments collected 3 weeks post administration, representing the time of ingestion. The concentration rapidly declined to trace amounts of 0.7 (Week 5) and 0.2 pg/mg (Week 9), respectively. In conclusion, measurement of the intact compound GSK2881078 is feasible for both urine and hair analysis. However, concentrations in hair after single oral administration are in the low pg/mg range and can only be detected, if the segments cover the administration period.
Wild strawberry shows genetic variation in tolerance but not resistance to a generalist herbivore
Authors: Wang Minggang , Muola Anne , Anderson Peter , Stenberg Johan A. 
Published: October 2020

AbstractPlants’ defenses against herbivores usually include both resistance and tolerance mechanisms. Their deployment has predominantly been studied in either single‐plant genotypes or multiple genotypes exposed to single herbivores. In natural situations, however, most plants are attacked by multiple herbivores. Therefore, aims of this study were to assess and compare the effects of single and multiple herbivores on plant resistance and tolerance traits, and the consequences for overall plant performance. For this, we exposed multiple genotypes of wild woodland strawberry (Fragaria vesca) to jasmonic acid (JA), to mimic chewing herbivory and induce the plants’ defense responses, and then introduced the generalist herbivore Spodoptera littoralis to feed on them. We found that woodland strawberry consistently showed resistance to S. littoralis herbivory, with no significant genetic variation between the genotypes. By contrast, the studied genotypes showed high variation in tolerance, suggesting evolutionary potential in this trait. Prior JA application did not alter these patterns, although it induced an even higher level of resistance in all tested genotypes. The study provides novel information that may be useful for breeders seeking to exploit tolerance and resistance mechanisms to improve strawberry crops’ viability and yields, particularly when multiple herbivores pose significant threats.
Thermal sensitivity of feeding and burrowing activity of an invasive crayfish in UK waters
Authors: Rodríguez Valido César A. , Johnson Matthew F. , Dugdale Stephen J. , Cutts Vanessa , Fell Henry G. , Higgins Emma A. , Tarr Simon , Templey Clare M. , Algar Adam C. 
Published: October 2020

AbstractClimate change and invasive species are among the biggest threats to global biodiversity and ecosystem function. Although the individual impacts of climate change and invasive species are commonly assessed, we know far less about how a changing climate may impact invading species. Increases in water temperature due to climate change are likely to alter the thermal regime of UK rivers, and this in turn may influence the performance of invasive species such as signal crayfish (Pacifastacus leniusculus), which are known to have deleterious impacts on native ecosystems. We evaluate the relationship between water temperature and two key performance traits in signal crayfish—feeding and burrowing rate—using thermal experiments on wild‐caught individuals in a laboratory environment. Although water temperature was found to have no significant influence on burrowing rate, it did have a strong effect on feeding rate. Using the thermal performance curve for feeding rate, we evaluate how the thermal suitability of three UK rivers for signal crayfish may change as a result of future warming. We find that warming rivers may increase the amount of time that signal crayfish can achieve high feeding rate levels. These results suggest that elevated river water temperatures as a result of climate change may promote higher signal crayfish performance in the future, further exacerbating the ecological impact of this invasive species.
Sex and oestrogen receptor β have modest effects on gene expression in the mouse brain posterior cortex
Authors: Fels Jasmine A. , Casalena Gabriella A. , Manfredi Giovanni 
Published: October 2020

AbstractIntroductionSex differences in brain cortical function affect cognition, behaviour and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Oestrogen and oestrogen receptors (ERs), specifically ERβ, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ERβ on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ERβ affects transcription.MethodsIn this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild‐type and ERβ knockout mice (n = 4/sex/genotype). We used unbiased clustering to analyse whole‐transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression.ResultsWe found only 27 significantly differentially expressed genes (DEGs) in wild‐type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ERβKO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function ‘cation channel activity’. Moreover, within each sex we found only a few DEGs in ERβKO vs WT mice (8 and 5 in males and females, respectively).ConclusionsOverall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region‐specific functional effects of ERβ may be largely post‐transcriptional.
Switzerland's COVID‐19 policy response: Consociational crisis management and neo‐corporatist reopening
Authors: Sager Fritz , Mavrot Céline 
Published: October 2020

AbstractSwitzerland responded to the first COVID‐19 wave fairly successfully by employing both public health and economic measures. During the state of emergency, the federal government made a firm decision to flatten the infection curve and to protect especially at‐risk populations. During the lockdown period, the focus of the political debate shifted from health to the economy as the Federal Council (i.e., the national executive) started to prepare for the country's reopening. While government still had full power due to the emergency situation defined under national epidemic law, the shift in the debate also meant a shift in the way that the government made decisions. Switzerland is a power‐sharing consociational democracy with strong neo‐corporatist features. While the executive untypically relied heavily on health experts within and outside the administration during the lockdown, the reopening strategy shows clear features of Swiss neo‐corporatism, including the resurgence and influence of the traditional big economic vested interests over the government's approach to decision making.
Clinical characteristics of epilepsy in resource‐limited communities in Punjab, Northwest India
Authors: Singh Gagandeep , Singhal Sachi , Sharma Suman , Paul Birinder S. , Bansal Namita , Chaudhary Anurag , Sharma Sarit , Bansal Rajnder K. , Goraya Jatinder S. , Setia Raj K. , Sander Josemir W. 
Published: October 2020

AbstractObjectivesTo describe clinical characteristics of a community‐based epilepsy cohort from resource‐limited communities in Punjab, Northwest India.MethodsThe cohort was gathered following a two‐stage screening survey. We cross‐sectionally examined and followed up the cohort for one year. A panel of neurologists assigned seizure types, syndromes, and putative etiologies and categorized drug responsiveness.ResultsThe cohort of 240 included 161 (67.1%) men, 109 (45.4%) illiterates and 149 (62.1%) unemployed. Current age was >18 years in 155 (64.6%) but age at epilepsy onset was <18 years in 173 (72.1%). Epilepsies due to structural and metabolic causes were diagnosed in 99 (41.3%), but syndromic assignments were not possible in 97 (40.4%). After one year, drug‐resistant epilepsy was established in 74 (30.8%). Perinatal events (n = 35; 14.6%) followed by CNS infections (n = 32; 13.3%) and traumatic brain injury (n = 12; 5.0%) were common risk factors. Most of those with CNS infections (n = 19; 63.3%), perinatal antecedents (n = 23; 76.7%), and other acquired risk factors (n = 27; 90.0%) presented with epilepsy due to structural and metabolic causes. Perinatal events were the putative etiology for nearly 40.7% of generalized epilepsies due to structural and metabolic causes and 28.2% of all epilepsies with onset <10 years.SignificanceExisting classifications schemes should be better suited to field conditions in resource‐limited communities in low‐ and middle‐income countries. The finding of drug‐resistant epilepsy in nearly at least a third in a community‐based sample underscores an unmet need for enhancing services for this segment within healthcare systems. Perinatal events, CNS infections, and head injury account for a third of all epilepsies and hence preventative interventions focusing on these epilepsy risk factors should be stepped up.
Volatility‐of‐volatility risk in the crude oil market
Authors: Roh Tai‐Yong , Tourani‐Rad Alireza , Xu Yahua , Zhao Yang 
Published: October 2020

AbstractThis paper examines the role of oil volatility‐of‐volatility (VOV) risk under a stochastic VOV framework. We show that oil VOV is a significant pricing factor in the cross‐sectional delta‐hedged gains constructed from oil options, and oil VOV also has predictive power for near‐term delta‐hedged option gains. Moreover, we show that the information contained in oil VOV is highly specific compared to its equity counterpart and other volatility‐related measures, from the perspective of its predictability of future economic conditions. Our findings are robust to alternative VOV risk measures and forecasting horizons.