bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unravelling how in vitro capacitation alters ram sperm chromatin before and after cryopreservation
Authors: Peris‐Frau Patricia , Álvarez‐Rodríguez Manuel , Martín‐Maestro Alicia , Iniesta‐Cuerda María , Sánchez‐Ajofrín Irene , Medina‐Chávez Daniela Alejandra , Garde José Julián , Villar Margarita , Rodríguez‐Martínez Heriberto , Soler Ana Josefa 
Published: September 2020

AbstractBackgroundSperm chromatin structure provides valuable information for the prediction of male fertility and can be altered during different procedures. Previous studies have shown that sperm chromatin condensation decreased during in vitro capacitation. Moreover, cryopreservation can affect sperm DNA integrity and chromatin compaction.ObjectivesThis study aimed to investigate dynamic modifications produced in the chromatin structure of ram spermatozoa during in vitro capacitation before and after cryopreservation.Materials and methodsChromatin decondensation (AB+), DNA methylation, DNA fragmentation index (%DFI) and high DNA stainability (HDS) were evaluated in fresh and frozen‐thawed ram spermatozoa incubated under capacitating (CAP) conditions at 1, 5, 15, 30, 60, 120, 180 and 240 minutes and under non‐capacitating (NC) conditions at 0, 15 and 240 minutes.ResultsIncubation in NC conditions did not induce significant changes in chromatin condensation (P > .05; AB + and HDS). However, incubation of fresh and cryopreserved ram spermatozoa under CAP conditions significantly increased chromatin decondensation (P < .05), reaching the highest percentage of AB + and HDS from 180 to 240 minutes in fresh samples and from 5 to 30 minutes in cryopreserved samples. Both variables (HDS and AB+) were positively correlated with tyrosine phosphorylation, total motility, progressive motility, curvilinear velocity and amplitude of lateral head displacement, as well as between them under CAP conditions in fresh and cryopreserved spermatozoa. DNA methylation significantly increased in cryopreserved spermatozoa (P < .05), but only after extended incubation under CAP conditions (60‐240 minutes), while the %DFI, albeit higher in cryopreserved samples, remained constant under CAP and NC conditions in both types of sample (P > .05).Discussion and conclusionsOur results suggest that sperm chromatin condensation decreased progressively during in vitro capacitation of ram spermatozoa, while sperm DNA integrity remained intact. Such changes in chromatin condensation appeared faster after sperm cryopreservation.
Non‐medical use of benzodiazepines and GABA analogues in Europe
Authors: Hockenhull Joanna , Amioka Elise , Black Joshua C. , Forber Alyssa , Haynes Colleen M. , Wood David M. , Dart Richard C. , Dargan Paul I. 
Published: September 2020

AimsWe investigated the prevalence of non‐medical use (NMU) of benzodiazepines and GABA analogues in Europe.MethodsData were collected using the online Non‐Medical Use of Prescription Drugs (NMURx) survey from France, Germany, Italy, Spain and the UK.ResultsThe study included 55 223 eligible surveys which, after post‐stratification weights were applied, represented approximately 260 million European adults. Lifetime NMU of benzodiazepines was highest in Spain (6.5%, 95% CI: 6.0–7.0) and lowest in Germany (1.7%, 1.5–2.0). Lifetime NMU of GABA analogues was highest in Germany (5.4%, 5.0–5.7) and lowest in France (2.2%, 1.9–2.5) and the UK (2.2%, 1.9–2.6) While no notable difference was observed for France or the UK, there was a higher prevalence of last 12‐month NMU of benzodiazepines compared to GABA analogues in Italy (2.4 times higher) and Spain (3.0 times higher) and a higher prevalence of NMU of GABA analogues compared to benzodiazepines in Germany (2.6 times higher).ConclusionThis study shows that there is variation in NMU of benzodiazepines and GABA analogues among countries. Of particular interest is the high incidence of GABA analogue NMU in Germany and benzodiazepine NMU in Spain. Further research to identify factors and motivations responsible for the higher prevalence observed are essential to inform public health policies in those countries.
Towards intervention development to increase the uptake of COVID‐19 vaccination among those at high risk: Outlining evidence‐based and theoretically informed future intervention content
Authors: Williams Lynn , Gallant Allyson J. , Rasmussen Susan , Brown Nicholls Louise A. , Cogan Nicola , Deakin Karen , Young David , Flowers Paul 
Published: September 2020

ObjectivesDevelopment of a vaccine against COVID‐19 will be key to controlling the pandemic. We need to understand the barriers and facilitators to receiving a future COVID‐19 vaccine so that we can provide recommendations for the design of interventions aimed at maximizing public acceptance.DesignCross‐sectional UK survey with older adults and patients with chronic respiratory disease.MethodsDuring the UK’s early April 2020 ‘lockdown’ period, 527 participants (311 older adults, mean age = 70.4 years; 216 chronic respiratory participants, mean age = 43.8 years) completed an online questionnaire assessing willingness to receive a COVID‐19 vaccine, perceptions of COVID‐19, and intention to receive influenza and pneumococcal vaccinations. A free text response (n = 502) examined barriers and facilitators to uptake. The Behaviour Change Wheel informed the analysis of these responses, which were coded to the Theoretical Domains Framework (TDF). Behaviour change techniques (BCTs) were identified.ResultsEighty‐six per cent of respondents want to receive a COVID‐19 vaccine. This was positively correlated with the perception that COVID‐19 will persist over time, and negatively associated with perceiving the media to have over‐exaggerated the risk. The majority of barriers and facilitators were mapped onto the ‘beliefs about consequences’ TDF domain, with themes relating to personal health, health consequences to others, concerns of vaccine safety, and severity of COVID‐19.ConclusionsWillingness to receive a COVID‐19 vaccination is currently high among high‐risk individuals. Mass media interventions aimed at maximizing vaccine uptake should utilize the BCTs of information about health, emotional, social and environmental consequences, and salience of consequences.
Hungarian Roma and musical talent: Minority group members’ experiences of an apparently positive stereotype
Authors: Dobai Anna , Hopkins Nick 
Published: September 2020

Minorities do not always welcome apparently positive stereotypes of their group. At first sight, this may appear churlish. However, we show that minority group members’ theorizing on the production and operation of apparently positive stereotypes helps explain such a negative reaction. Reporting interview data (N = 30) gathered with Hungarian Roma, we differentiated several bases for a negative response to the popular stereotype of Roma as possessing a distinctive musical talent. Although participants recognized the stereotype had instrumental value in easing everyday intergroup encounters, they also reported that the stereotype reflected the majority group’s power to define Roma identity; constrained recognition of qualities that they themselves valued; limited their abilities to act on terms that were their own; and could facilitate the reproduction of more negative Roma stereotypes. Taken together, these findings imply our participants saw this apparently positive stereotype as speaking volumes about the majority’s power to define Roma identity without reference to how they themselves defined their identity. We conclude with a discussion of the analytic value of the concept of ‘misrecognition’ in explaining negative responses to a positive stereotype. We also discuss the potential for such an apparently positive stereotype to facilitate improvements in intergroup relations.
Pseudoirreversible slow‐binding inhibition of trypanothione reductase by a protein–protein interaction disruptor
Authors: de Lucio Héctor , Toro Miguel A. , Camarasa María‐José , Velázquez Sonsoles , Gago Federico , Jiménez‐Ruiz Antonio 
Published: September 2020

Background and PurposePeptide P4 was described as a dimerization disruptor of trypanothione reductase (TryR), a homodimeric enzyme essential for survival of trypanosomatids. Determination of the true inhibitory constant (Ki) for P4 was not achieved because reaction rates continuously decreased with time, even when substrate concentration was kept constant. The aim of this study was to find a suitable kinetic model that could allow characterization of the complex pattern of TryR inhibition caused by P4.Experimental ApproachAfter showing the slow‐binding and pseudoirreversible activity of P4 against Leishmania infantum trypanothione reductase (Li‐TryR), analysis of the curvatures of the reaction progress curves at different inhibitor concentrations allowed us to define the apparent inhibitory constants (Kiapp) at five different substrate concentrations. Analysis of the changes in Kiapp values allowed precise definition of the type of inhibition.Key ResultsLi‐TryR inhibition by P4 requires two sequential steps that involve rapid generation of a reversible enzyme–inhibitor complex followed by a pseudoirreversible slow inactivation of the enzyme. Recovery of enzyme activity after inhibitor dissociation is barely detectable. P4 is a non‐competitive pseudoirreversible inhibitor of Li‐ TryR that displays an overall inhibition constant (Ki*) smaller than 0.02 μM.Conclusion and ImplicationsLi‐TryRdimer disruption by peptide P4 is a pseudoirreversible time‐dependent process which is non‐competitive with respect to the oxidized trypanothione (TS2) substrate. Therefore, unlike reversible Li‐TryR competitive inhibitors, enzyme inhibition by P4 is not affected by the TS2 accumulation observed during oxidant processes such as the oxidative burst in host macrophages.
Cancer stem cells and their niche in the progression of squamous cell carcinoma
Authors: Oshimori Naoki 
Published: September 2020

AbstractMost cancers harbor a small population of highly tumorigenic cells known as cancer stem cells (CSCs). Because of their stem cell‐like properties and resistance to conventional therapies, CSCs are considered to be a rational target for curable cancer treatment. However, despite recent advances in CSC research, CSC‐targeted therapies are not as successful as was initially hoped. The proliferative, invasive, and drug‐resistant properties of CSCs are regulated by the tumor microenvironment associated with them, the so‐called CSC niche. Thus, targeting tumor‐promoting cellular crosstalk between CSCs and their niches is an attractive avenue for developing durable therapies. Using mouse models of squamous cell carcinoma (SCC), we have demonstrated that tumor cells responding to transforming growth factor β (TGF‐β) function as drug‐resistant CSCs. The gene expression signature of TGF‐β–responding tumor cells has accelerated the identification of novel pathways that drive invasive tumor progression. Moreover, by focusing on the cytokine milieu and macrophages in the proximity of TGF‐β–responding tumor cells, we recently uncovered the molecular basis of a CSC–niche interaction that emerges during early tumor development. This review article summarizes the specialized tumor microenvironment associated with CSCs and discusses mechanisms by which malignant properties of CSCs are maintained and promoted.
Icaritin‐induced immunomodulatory efficacy in advanced hepatitis B virus‐related hepatocellular carcinoma: Immunodynamic biomarkers and overall survival
Authors: Qin Shu‐Kui , Li Qing , Ming Xu Jian , Liang Jun , Cheng Ying , Fan Ying , Jiang Jun , Ye Hao , Tao Huimin , Li Lian , Zheng Limin , Wei Zhaohui , Li Shu , Meng Kun , Ye Bin , Sun Yan 
Published: September 2020

AbstractAdvanced hepatitis B virus (HBV)‐related hepatocellular carcinoma HCC with poor prognosis is often associated with chronic inflammation, immune tolerance, and marked heterogeneity. The interleukin‐6 (IL‐6)/JAK/STAT3 signal pathways play multiple regulatory roles in modulating inflammation and immunity in cancers. Polarization of myeloid‐derived suppressor cells (MDSCs) is involved in HBV‐related immunosuppression and CD8+ T‐cell activation through ERK/IL‐6/STAT3. Icaritin is a small molecule that has displayed anticancer activities through IL‐6/JAK/STAT3 pathways in tumor cells and immune cells including CD8+ T cells, MDSCs, neutrophils, and macrophages. This study aimed to confirm icaritin immunomodulation in advanced HBV‐related HCC patients with poor prognosis. Immunomodulation of MDSCs was evaluated in BALB/c mice in vivo. Immunomodulation of serum cytokines and a panel of immune checkpoint proteins were assessed in HBV‐related, histologically confirmed HCC patients. Poor prognostic characteristics included HBV infection, bulky tumors, Child‐Pugh B classification, and metastasis. Clinical end‐points included safety, tumor response, and overall survival (OS). Icaritin treatment‐induced dynamics of serum cytokines IL‐6, IL‐8, IL‐10, and tumor necrosis factor‐α, and soluble immune checkpoint proteins TIM3, LAG3, CD28, CD80, and CTLA‐4 were assessed. No grade III/IV treatment‐related adverse events were observed. Time‐to‐progression was significantly associated with the prognostic factors. Improved survival was observed in the advanced HCC patients with dynamic changes of cytokines, immune checkpoint proteins, and immune cells. Median OS (329‐565 days) was significantly correlated with baseline hepatitis B surface antigen positivity, cytokines, tumor neoantigens, and Stenotrophomonas maltophilia infection. Composite biomarker scores of high‐level α‐fetoprotein and T helper type I (Th1)/Th2 cytokines associated with favorable survival warrant further clinical development of icaritin as an alternative immune‐modulatory regimen to treat advanced HCC patients with poor prognosis.
Ribosome assembly factor URB1 contributes to colorectal cancer proliferation through transcriptional activation of ATF4
Authors: Wang Tao , Li Lai‐Yuan , Chen Yi‐Feng , Fu Si‐Wu , Wu Zhi‐Wei , Du Bin‐Bin , Yang Xiong‐Fei , Zhang Wei‐Sheng , Hao Xiang‐Yong , Guo Tian‐Kang 
Published: September 2020

AbstractRibosome assembly factor URB1 is essential for ribosome biogenesis. However, its latent role in cancer remains unclear. Analysis of The Cancer Genome Atlas database and clinical tissue microarray staining showed that URB1 expression was upregulated in colorectal cancer (CRC) and prominently related to clinicopathological characteristics. Silencing of URB1 hampered human CRC cell proliferation and growth in vitro and in vivo. Microarray screening, ingenuity pathway analysis, and JASPAR assessment indicated that activating transcription factor 4 (ATF4) and X‐box binding protein 1 (XBP1) are potential downstream targets of URB1 and could transcriptionally interact through direct binding. Silencing of URB1 significantly decreased ATF4 and cyclin A2 (CCNA2) expression in vivo and in vitro. Restoration of ATF4 effectively reversed the malignant proliferation phenotype of URB1‐silenced CRC cells. Dual‐luciferase reporter and ChIP assays indicated that XBP1 transcriptionally activated ATF4 by binding with its promoter region. X‐box binding protein 1 colocalized with ATF4 in the nuclei of RKO cells, and ATF4 mRNA expression was positively regulated by XBP1. This study shows that URB1 contributes to oncogenesis and CRC growth through XBP1‐mediated transcriptional activation of ATF4. Therefore, URB1 could be a potential therapeutic target for CRC.
Gallotannins are non‐specific inhibitors of α‐amylase: Aggregates are the active species taking part in inhibition
Authors: Szabó Kármen , Hámori Csaba , Gyémánt Gyöngyi 
Published: September 2020

AbstractThe versatile biological activity of gallotannins has been investigated for a long time, including their use asα‐amylase inhibitors for the treatment of diabetes and its complications. The effectiveness of gallotannins on a wide range of enzymes refers to promiscuity. We proved that gallotannins are non‐specific promiscuousα‐amylase inhibitors, which exert their effect through their aggregates. A gallotannin of Aleppo oak origin fulfilled all the criteria for aggregators; significant changes could be observed in the IC50values in the presence of Triton™X‐100 detergent (from 2.3 to 110 μg/ml) and after enzyme–inhibitor preincubation (from 2.3 to 0.65 μg/ml). Increasing the enzyme concentration also led to the moderation of the inhibition by gallotannin. In addition, we observed that gallotannin molecules are those, which are involved in aggregation, and discrete protein molecules are adsorbed to the aggregates. This was revealed by the increasing particle size of gallotannin, which became three orders of magnitude higher after 150 min, whereas the size ofα‐amylase remained unchanged. Consequently, gallotannins should be used as anti‐diabetic drugs only if the necessity of higher dose due to their promiscuity is taken into account. Aggregation propensity should not be ignored in case of in vivo applications.
Design, synthesis and anti‐inflammatory study of novel N‐heterocyclic substituted Aloe‐emodin derivatives
Authors: Qiu Xiang , Pei Heying , Ni Hengfan , Su Zhengying , Li Yong , Yang Zhuang , Dou Caixia , Chen Lijuan , Wan Li 
Published: September 2020

AbstractA novel series of Aloe‐emodin derivatives containing N‐heterocyclic moieties was designed and synthesized. The structure‐activity relationship studies (SARs) indicated that the replacement of hydroxyethyl and benzhydryl piperazine groups could improve efficacy. Compounds 12r and 14a–14c exhibited a higher inhibitory effect on LPS‐induced nitric oxide (NO) production in RAW264.7 macrophages than Aloe‐emodin did. Among them, 12r showed the most potent inhibition with an IC50 value of 5.66 ± 0.47 μM. Further toxicity and pharmacokinetic studies were carried out and 12r was found to be the most active structure with low toxicity risk and good metabolic properties. It could also decrease the levels of IL‐1β, TNF‐α, PGE2 and inhibit the activation of nuclear factor‐κB signalling pathway. Importantly, 12r showed oral bioavailability of up to 55.16% and attenuated the inflammatory symptoms in an ulcerative colitis mouse model in vivo. These results indicate that 12r is suitable for development as an anti‐inflammatory agent.
Behavioral Inhibition in Early Childhood and Adjustment in Late Adolescence in China
Authors: Chen Xinyin , Fu Rui , Li Dan , Chen Huichang , Wang Zhengyan , Wang Li 
Published: September 2020

This study examined relations between behavioral inhibition in toddlerhood and social, school, and psychological adjustment in late adolescence in China. Data on behavioral inhibition were collected from a sample of 2‐year‐olds (initial N = 247). Follow‐up data were collected at 7 years for peer relationships and 19 years for adjustment across domains. The results showed that early inhibition positively predicted later social competence and school adjustment. Peer relationships in middle childhood served as a protective factor in the development of depression of inhibited children. The results indicate the distinct functional meaning of behavioral inhibition in the Chinese context from a developmental perspective.
Family Risk and Externalizing Problems in Chilean Children: Mediation by Harsh Parenting and Emotional Support
Authors: Ugarte Elisa , Narea Marigen , Aldoney Daniela , Weissman David G. , Hastings Paul D. 
Published: September 2020

Latent class analysis and multigroup mediation were used with 8,860 families in Chile to identify risk groups varying in socioeconomic status, family structure, and maternal depression, to determine whether profiles differed in children’s development of externalizing problems (EP) from 35 to 61 months, and maternal parenting that predicted EP. Four groups were identified: one no‐risk profile and three risk profiles, impoverished and undereducated, depressed and impoverished, and father‐absent and impoverished. All classes differed in EP. Maternal emotional support and harsh parenting were differentially associated with the development of EP across the three risk groups, relative to the low‐risk group. Thus, specific constellations of adversities differentially predicted children’s EP and socialization processes mediating links between risk and EP. Implications are discussed.
Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency
Authors: Alghamdi Malak , Bashiri Fahad A. , Abdelhakim Marwa , Adly Nouran , Jamjoom Dima Z. , Sumaily Khalid M. , Alghanem Bandar , Arold Stefan T. 
Published: September 2020

AbstractPyridoxamine‐5′‐phosphate oxidase (PNPO) deficiency is an autosomal recessive pyridoxal 5′‐phosphate (PLP)‐vitamin‐responsive epileptic encephalopathy. The emerging feature of PNPO deficiency is the occurrence of refractory seizures in the first year of life. Pre‐maturity and fetal distress, combined with neonatal seizures, are other associated key characteristics. The phenotype results from a dependency of PLP which regulates several enzymes in the body. We present the phenotypic and genotypic spectrum of (PNPO) deficiency based on a literature review (2002‐2020) of reports (n = 33) of patients with confirmed PNPO deficiency (n = 87). All patients who received PLP (n = 36) showed a clinical response, with a complete dramatic PLP response with seizure cessation observed in 61% of patients. In spite of effective seizure control with PLP, approximately 56% of patients affected with PLP‐dependent epilepsy suffer developmental delay/intellectual disability. There is no diagnostic biomarker, and molecular testing required for diagnosis. However, we noted that cerebrospinal fluid (CSF) PLP was low in 81%, CSF glycine was high in 80% and urinary vanillactic acid was high in 91% of the cases. We observed only a weak correlation between the severity of PNPO protein disruption and disease outcomes, indicating the importance of other factors, including seizure onset and time of therapy initiation. We found that pre‐maturity, the delay in initiation of PLP therapy and early onset of seizures correlate with a poor neurocognitive outcome. Given the amenability of PNPO to PLP therapy for seizure control, early diagnosis is essential.
Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency
Authors: Roifman Maian , Niles Kirsten M. , MacNeil Lauren , Blaser Susan , Noor Abdul , Godoy Ruth , van Mieghem Tim , Ryan Greg , Seaward Gareth , Sondheimer Neal , Mercimek‐Andrews Saadet , Schulze Andreas , Hewson Stacy , Ovadia Adi , Chitayat David , Morgen Eric K. , Hojilla Carlo , Kolomietz Elena , Watkins Nicholas , Häberle Johannes , Shannon Patrick 
Published: September 2020

AbstractGlutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate‐ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi‐organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post‐mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.